Dang Bao

An Tran

Rosa Santagata

Mathieu Manceau

Anne Cournol

Louis Lecordier

Bérengère Argence

Oliver Lopez

Sean K Tokunaga

Fabrice Wiotte

Haniffe Mouhamad

High-Precision Mid-Infrared Spectroscopy with a Widely Tuneable SI-Traceable Frequency-Comb-Stabilised QCL

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I. INTRODUCTION

HERE is an increasing demand for precise molecular spectroscopy, in particular in the mid-infrared fingerprint window, whether it be for modelling our atmosphere, interpreting astrophysical spectra or testing fundamental physics. We present a high-resolution mid-infrared spectrometer traceable to primary frequency standards providing a unique combination of resolution, tuneability, detection sensitivity and frequency control.

II. EXPERIMENTAL SETUP Fig. 1 shows the experimental setup, a mid-infrared spectrometer based on a widely tuneable, ultra-stable, and SItraceable quantum cascade laser (QCL) working at 10.3 µm.

This set up comprises a tuneable and ultra-stable optical local oscillator (OLO) based on a 1.54 µm laser diode of frequency 1. This reference signal, generated at the French national metrological institute (LNE-SYRTE), is a 1.54 µm laser locked to an ultra-stable cavity and its absolute frequency is calibrated there against some of the world's best atomic clocks. It is then transferred to Laboratoire de Physique des Lasers through a 43-km long fibre link with active compensation of the propagation-induced phase noise. The OLO frequency is then given by

1 OLO ref EOM f ν ν = - -Δ , (1)
with 1 Δ the frequency of the beat-note signal between

OLO EOM f ν + and ref ν .
An optical frequency comb (OFC) with two outputs centred at 1.55 and 1.85 µm is then used to transfer the spectral properties of the near-infrared reference signal to the QCL. We detect a beat-note signal between a comb tooth at frequency

p f ν Δ = -× . ( 2
)
The comb repetition rate is stabilized by locking 2 Δ to a fixed radio-frequency signal (typically 150 MHz) using phase-lock loop PLL2.

Finally, the QCL frequency is phase-locked to a high-order harmonic of the comb repetition rate. To this end, we perform sum-frequency generation between the comb output beam at 1.85 µm (comb mode frequency

rep ceo q f f × + with ~680 000
q
) and the QCL beam, which results a shifted comb centred at 1.55 µm with comb mode frequencies

rep ceo QCL q f f ν × + +
. In order to stabilize the QCL frequency, a beat-note signal at frequency ( )

3 rep QCL p q f ν Δ = - - between
the shifted comb and the original comb is detected on photodiode PD3. The QCL frequency is finally stabilized by locking this beat-note signal to a fixed radio frequency signal (typically 11 MHz) using phase-lock loop PLL3. The QCL frequency is given by the following equation, ( )

3 1 2 3 QCL rep ref EOM n n f f p ν ν = × -Δ = - -Δ -Δ -Δ , (3)
where ~120 000. n p q = -The experimental setup therefore allows the stability and SI-Dang Bao An Tran 1 , Rosa Santagata traceability of the optical frequency reference, and the tuneability of the OLO to be transferred to the QCL. This results in a ~0.1 Hz QCL linewidth, a stability below 10 -15 from 0.1 to 10 s and an uncertainty on the absolute frequency below 4×10 - 14 [START_REF] Argence | Quantum cascade laser frequency stabilization at the sub-Hz level[END_REF][START_REF] Santagata | High-precision methanol spectroscopy with a widely tunable SItraceable frequency-comb-based mid-IR QCL[END_REF]. The spectral range covered by our spectrometer is ~100 GHz limited by the spectral window of the QCL used. Scanning the OLO carrier frequency over 9 GHz allows the QCL frequency to be tuned over more than 1 GHz.

III. RESULTS

As illustrated in Fig. 1, we have used the apparatus to carry out ultra-high resolution spectroscopy of polyatomic molecules in a compact multipass absorption cell and few-meter-long Fabry-Perot cavities. We use frequency modulation to improve detection sensitivity.

In order to demonstrate the apparatus' potential for state-ofthe-art high-precision spectroscopic measurements, we have conducted saturated absorption spectroscopy of OsO4 using a Fabry-Perot cavity [START_REF] Argence | Quantum cascade laser frequency stabilization at the sub-Hz level[END_REF]. Fig. 2 shows a sub-Doppler spectrum of two rovibrational transitions of OsO4 averaged over ten up and down scans. It is recoded using frequency modulation and thirdharmonic detection. The QCL frequency is swept by scanning the frequency of the synthesizer used to phase-lock the QCL to the OFC. Typical experimental parameters are a pressure of 0.04 Pa, an intra-cavity power of 50 µW, and a beam diameter of 6 mm. The spectrum exhibits a peak-to-peak linewidth of ~25 kHz and a signal to noise ratio of 200. The data is fitted to a combination of a third and a fifth derivative of a Lorentzian to account for the line shape deformation caused by the choice of frequency modulation parameters. The line-centre frequencies of these transitions and others were determined at a level of accuracy ranging from 20 to 40 Hz (see [START_REF] Argence | Quantum cascade laser frequency stabilization at the sub-Hz level[END_REF] for more details).

As illustrated in Fig. 3, we have also carried out saturated absorption spectroscopy of several rovibrational transitions of methanol using a multipass absorption cell. Typical experimental conditions are a pressure of 1 Pa, an average intracell power of ~1 mW, a laser beam waist of ~1 mm and firstharmonic detection. The QCL frequency is swept by scanning the EOM frequency and in turn the OLO carrier frequency. Fig. 3(b) displays a sub-Doppler spectrum of the P(E,co,0,2,33) rovibrational line of methanol averaged over only one up and down scan. It exhibits a peak-to-peak linewidth of ~400 kHz and a signal-to-noise ratio of 310. The solid yellow line is a fit to the data (see [START_REF] Santagata | High-precision methanol spectroscopy with a widely tunable SItraceable frequency-comb-based mid-IR QCL[END_REF] for details of the line shape used). The linecentre frequency of the transition was determined with a statistical uncertainty of ~1 kHz and sub-10 kHz global uncertainty. Fig. 3(b) demonstrates the unprecedented continuous tuning capability resulting from using our widely tuneable and ultra-stable OLO. It shows a sub-Doppler spectrum of methanol around 971.565 cm -1 spanning 400 MHz and exhibiting five rovibrational transitions of methanol [START_REF] Santagata | High-precision methanol spectroscopy with a widely tunable SItraceable frequency-comb-based mid-IR QCL[END_REF].

To conclude, we have developed an apparatus showing an unprecedented combination of wide tuneability, high sensitivity, and spectral resolution and used it to carry out saturated absorption spectroscopy. We have demonstrated record uncertainties ranging from ~10 Hz to 10 kHz on rovibrational absolute frequencies of various species of interest for space and atmospheric physics, and for testing fundamental physics, including osmium tetroxide, methanol, ammonia, trioxane… This confirms our apparatus' potential for our ongoing precise spectroscopic measurements with molecules [START_REF] Cournol | A new experiment to test parity symmetry in cold chiral molecules using vibrational spectroscopy[END_REF].

OLOν.

  Two sidebands are generated in the OLO signal using an electro-optic modulator (EOM) driven by a home-made phasejump-free microwave synthesizer exhibiting a 9 GHz continuous tuning range. The upper sideband of frequency OLO EOM f ν + (with EOM f the microwave frequency driving the EOM) is phase-locked to a 1.54 µm remote optical frequency reference signal of frequency ref ν , using the phase-lock loop PLL1 shown in Fig.

Fig. 2 .

 2 Fig. 2. Saturated absorption spectrum of OsO4 recorded using a Fabry-Perot cavity. Two lines are recorded over a span of 5 MHz in steps of 5 kHz, using frequency modulation and third harmonic detection. Inset: spectrum of the reference line recorded over 200 kHz in steps of 1 kHz. Taken from [1].

Fig. 3 .

 3 Fig. 3. (a) Saturated absorption spectrum of the P(E,co,0,2,33) rovibrational transition of methanol, with fit and residuals. (b) Saturated absorption spectrum of methanol spanning 400 MHz. Taken from [2].

  1 , Mathieu Manceau 1 , Anne Cournol 1 , Louis Lecordier 1 , Bérengère Argence 1 , Oliver Lopez 1 , Sean K. Tokunaga 1 , Fabrice Wiotte 1 , Haniffe Mouhamad 1 , Andrei Goncharov 1 , Michel Abgrall 2 , Yann Le Coq 2 , Hector Alvarez-Martinez 2 , Rodolphe Le Targat 2 , Won Kiu Lee 2 , Dan Xu 2 , Paul-Eric Pottie 2 , Anne Amy-Klein 1 , and Benoît Darquié 1 1 Laboratoire de Physique des Lasers, Université Paris 13, Sorbonne Paris Cité, CNRS, Villetaneuse, France 2 LNE-SYRTE, Observatoire de Paris, Université PSL, CNRS, Sorbonne Université, Paris, France High-Precision Mid-Infrared Spectroscopy with a Widely Tuneable SI-Traceable Frequency-Comb-Stabilised QCL

T Fig. 1. Experimental setup. OFC: optical frequency comb; QCL: quantum cascade laser; PLL: phase-lock loop; EOM: electro-optic modulator; SFG: sum frequency generation, PD: photodiode, DDS: direct digital synthesizer, DAQ: acquisition card.


domain: chim sdv

text:
Shaker A Mousa

Raj Bawa

Gerald F Audette

MS Miora Rakotoarisoa

PhD, HDR Angelina Angelova

Chapter 33

Keywords: curcumin, amphiphilic nanoparticles, self-assembled nanoparticles, solid lipid nanoparticles, liposomes, liquid crystalline carriers, nanomedicine, drug delivery, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, Huntington disease, amyotrophic lateral sclerosis, oxidative stress, neuroprotection, antioxidant, blood-brain barrier, SHSY-5Y cells. 33.1

HAL is a

Introduction

Neurodegenerative diseases (Alzheimer's disease (AD), Parkinson's disease (PD), Huntington disease (HD), and amyotrophic lateral sclerosis (ALS)) are disabling chronic disorders characterized by the progressive loss of neurons in different areas of the central nervous system. Neuronal cell death leads to cognitive, behavioral, sensory, and motor dysfunctions [START_REF] Brookmeyer | Forecasting the prevalence of preclinical and clinical Alzheimer's disease in the United States[END_REF][START_REF] Jack | Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease[END_REF][START_REF] Haass | Soluble protein oligomers in neurodegeneration: Lessons from the Alzheimer's amyloid beta-peptide[END_REF][START_REF] Wakasaya | Factors responsible for neurofibrillary tangles and neuronal cell losses in tauopathy[END_REF][START_REF] Stoothoff | Tau phosphorylation: Physiological and pathological consequences[END_REF][START_REF] Wang | Synthesis and evaluation of multi-targetdirected ligands for the treatment of Alzheimer's disease based on the fusion of donepezil and melatonin[END_REF][START_REF] Cole | NSAID and antioxidant prevention of Alzheimer's disease: Lessons from in vitro and animal models[END_REF][START_REF] Alexander | Biology of Parkinson's disease: Pathogenesis and pathophysiology of a multisystem neurodegenerative disorder[END_REF][START_REF] Dauer | Parkinson's disease: Mechanisms and models[END_REF][START_REF] Landles | Huntingtin and the molecular pathogenesis of Huntington's disease: Fourth in molecular medicine review series[END_REF][START_REF] Zuccato | Brain-derived neurotrophic factor in patients with Huntington's disease[END_REF][START_REF] Zhou | Amyotrophic lateral sclerosis in Beijing: Epidemiologic features and prognosis from 2010 to 2015[END_REF][START_REF] Glajch | Microneurotrophins improve survival in motor neuron-astrocyte co-cultures but co cot improve disease phenotypes in a mutant SOD1 mouse model of amyotrophic lateral sclerosis[END_REF]. Currently, age-related neuronal diseases have higher incidences because of increasing life expectancies. Neurodegenerative disorders are caused by multiple factors, such as the accumulation of misfolded proteins, the depletion of endogenous antioxidant enzyme activity, mitochondrial dysfunction, and the deficiency of neurotrophin brain-derived neurotrophic factor (BDNF), neuro-inflammation, as well as various genetic mutations [START_REF] Varinderpal | Mutations that affect mitochondrial functions and their association with neurodegenerative diseases[END_REF][START_REF] Barnham | Neurodegenerative diseases and oxidative stress[END_REF][START_REF] Jiang | Oxidative stress: A major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson's disease and Alzheimer's disease[END_REF][START_REF] Gilgun-Sherki | Oxidative stress induced-neurodegenerative diseases: The need for antioxidants that penetrate the blood brain barrier[END_REF][START_REF] Uttara | Oxidative stress and neurodegenerative diseases: A review of upstream and downstream antioxidant therapeutic options[END_REF][START_REF] Dumont | Neuroprotective strategies involving ROS in Alzheimer disease[END_REF][START_REF] Zhong | Quantitative proteomics study of the neuroprotective effects of B12 on hydrogen peroxide-induced apoptosis in SH-SY5Y cells[END_REF][START_REF] Onyango | Mitochondria in the pathophysiology of Alzheimer's and Parkinson's diseases[END_REF][START_REF] Ankarcronaa | Thinking Alzheimer's disease therapy: Are mitochondria the key?[END_REF][START_REF] Federico | Mitochondria, oxidative stress and neurodegeneration[END_REF][START_REF] Stahon | Age-related changes in axonal and mitochondrial ultrastructure and function in white matter[END_REF][START_REF] Cho | Mitochondrial dynamics in cell death and neurodegeneration[END_REF][START_REF] Lu | Metformin prevents dopaminergic neuron death in MPTP/Pinduced mouse model of Parkinson's disease via autophagy and mitochondrial ROS clearance[END_REF][START_REF] Zádori | Mitochondrial disturbances, excitotoxicity, neuroinflammation and kynurenines: Novel therapeutic strategies for neurodegenerative disorders[END_REF][START_REF] Rahimifard | Targeting the TLR4 signaling pathway by polyphenols: A novel therapeutic strategy for neuroinflammation[END_REF][START_REF] Géral | From molecular to nanotechnology strategies for delivery of neurotrophins: Emphasis on brain-derived neurotrophic factor (BDNF)[END_REF][START_REF] Angelova | Neurotrophin delivery using nanotechnology[END_REF].

In recent years, several studies have shown that curcumin is a safe natural compound which may prevent the deleterious effects of risk factors causing brain damage as well as slowing down the progressive neuronal loss via different pathways . However, clinical studies performed with AD patients with various degrees of progression have reported poor results on the AD symptoms following curcumin treatment [START_REF] Baum | Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease[END_REF][START_REF] Ringman | Oral curcumin for Alzheimer's disease: Tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study[END_REF][START_REF] Hishikawa | Effects of turmeric on Alzheimer's disease with behavioral and psychological symptoms of dementia[END_REF][START_REF] Mazzanti | Curcumin and resveratrol in the management of cognitive disorders: What is the clinical evidence?[END_REF]. This did not allow firm conclusions about the therapeutic or neuroprotective potential of curcumin to be drawn. The obstacles for curcumin utilization as a drug originate from its limited water solubility, poor physicochemical stability, high-grade metabolism, and low plasma concentrations [START_REF] Serafini | Curcumin in Alzheimer's disease: Can we think to new strategies and perspectives for this molecule?[END_REF][START_REF] Hishikawa | Effects of turmeric on Alzheimer's disease with behavioral and psychological symptoms of dementia[END_REF][START_REF] Mazzanti | Curcumin and resveratrol in the management of cognitive disorders: What is the clinical evidence?[END_REF][START_REF] Ireson | Metabolism of the cancer chemopreventive agent curcumin in human and rat intestine[END_REF]. The development of nanoparticulate delivery systems for curcumin has attracted scientific interest in order to improve its bioavailability and stability as a drug compound [START_REF] Marczylo | Rapid analysis of curcumin and curcumin metabolites in rat biomatrices using a novel ultraperformance liquid chromatography (UPLC) method[END_REF][START_REF] Marczylo | Comparison of systemic availability of curcumin with that of curcumin formulated with phosphatidylcholine[END_REF][START_REF] Ghalandarlaki | Nanotechnology-applied curcumin for different diseases therapy[END_REF][START_REF] Cox | Investigation of the effects of solid lipid curcumin on cognition and mood in a healthy older population[END_REF][START_REF] Modi | Advances in the treatment of neurodegenerative disorders employing nanotechnology[END_REF][START_REF] Sahni | Neurotherapeutic applications of nanoparticles in Alzheimer's disease[END_REF][START_REF] Craparo | Nanoparticulate systems for drug delivery and targeting to the central nervous system[END_REF][START_REF] Fonseca-Santos | Nanotechnology-based drug delivery systems for the treatment of Alzheimer's disease[END_REF][START_REF] Kanwar | Nanoparticles in the treatment and diagnosis of neurological disorders: Untamed dragon with fire power to heal[END_REF][START_REF] Gao | Progress and perspectives on targeting nanoparticles for brain drug delivery[END_REF]. Curcumin administration to neurodegenerative disease models by nanoparticles has been realized using liposomes, solid lipid nanoparticles, and polymeric particles. Delivery by other carriers such as amphiphilic proteins, e.g., casein, is also possible, but has not been examined as a means of transporting curcumin across the BBB towards neuro-regeneration.

In this review, we briefly summarize the in vitro and the in vivo evaluations of curcumin, which are linked to multiple risk factors and the multi-target mechanisms of neurodegenerative diseases, and discuss the reported clinical investigations of varying efficacy in humans. Then, we highlight the variety of amphiphilic curcumin-loaded nanocarriers including liposomes, liquid crystalline nanoparticles (cubosomes, hexosomes, and spongosomes), solid lipid nanoparticles, micelles, and polymeric nanoparticles as potential nanomedicine formulations in regeneration therapies of the major neurological disorders.

Risk Factors for Neurodegenerative Disorders

Alzheimer's disease (AD) is the most common cause of dementia. It currently affects about 10% of the world's population over 60-65 years of age, and about 50% over 85 years of age. More than 30 million people may expect to be affected by AD during the next 20 years due to the increasing lifespan of the world population [START_REF] Brookmeyer | Forecasting the prevalence of preclinical and clinical Alzheimer's disease in the United States[END_REF][START_REF] Jack | Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease[END_REF]. Major pathological features of AD include the accumulation of extracellular amyloid plaques and fibrils, intracellular neurofibrillary tangles, and disruption of the cholinergic transmission, including reduced acetylcholine levels in the basal forebrain (Table 33.1). The most common symptom is the short-term memory loss, i.e., difficulty in remembering recent events [START_REF] Jack | Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease[END_REF][START_REF] Haass | Soluble protein oligomers in neurodegeneration: Lessons from the Alzheimer's amyloid beta-peptide[END_REF][START_REF] Wakasaya | Factors responsible for neurofibrillary tangles and neuronal cell losses in tauopathy[END_REF][START_REF] Stoothoff | Tau phosphorylation: Physiological and pathological consequences[END_REF]. Other symptoms include disorientation, mood, language, and behavioral issues, and loss of motivation, depending on the progression of the disease. The treatments of AD have employed acetylcholinesterase inhibitors (tacrine, rivastigmine, galantamine, and donepezil) to overcome the decrease of the ACh levels as a result of the death of cholinergic neurons. The NMDA receptor antagonist (memantine) acts by inhibiting the overstimulation by glutamate, which can cause cell death. Atypical antipsychotics have modest efficacy in reducing the aggression and psychosis of AD patients. These medications provide little benefit, and provoke various adverse effects [START_REF] Wang | Synthesis and evaluation of multi-targetdirected ligands for the treatment of Alzheimer's disease based on the fusion of donepezil and melatonin[END_REF][START_REF] Cole | NSAID and antioxidant prevention of Alzheimer's disease: Lessons from in vitro and animal models[END_REF].

The second most common disorder, Parkinson's disease (PD), affects more than 1% of the population over 60 years of age and 5% over 85. PD is characterized by progressive impairments in locomotive ability such as tremor, rigidity, and bradykinesia. These symptoms are attributed to the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies in the brain [START_REF] Alexander | Biology of Parkinson's disease: Pathogenesis and pathophysiology of a multisystem neurodegenerative disorder[END_REF][START_REF] Dauer | Parkinson's disease: Mechanisms and models[END_REF]. Treatments are symptomatic and aim at boosting the depleted levels of dopamine (Table 33.1). The most used drug is levodopa. Dopamine agonists are used when the treatment by levodopa becomes less efficient. The inhibitors of MAO-B and COMT (safinamide, selegiline, rasagiline, and tolcapone) are used to inhibit the activity of the enzymes which degrade dopamine. These medications become less effective as the neurons are continuously lost during disease progression. At the same time, they produce complications marked by the involuntary movements of the patients [START_REF] Alexander | Biology of Parkinson's disease: Pathogenesis and pathophysiology of a multisystem neurodegenerative disorder[END_REF][START_REF] Dauer | Parkinson's disease: Mechanisms and models[END_REF].

Huntington disease (HD) is a rare disease which affects about 1/10,000 people (usually between 30 to 50 years of age) in the United States and 1/18,000 people in Europe. It is a poly-glutamine (PolyQ) autosomal genetic disorder characterized by impairments of cognitive, psychiatric, and motor functions [START_REF] Landles | Huntingtin and the molecular pathogenesis of Huntington's disease: Fourth in molecular medicine review series[END_REF]. The hallmark of the HD pathology is the abnormal accumulation of misfolded mutated huntingtin protein (mHTT) as intracellular aggregates. They cause selective neuronal loss, primarily in the cortex and in the medium spiny neurons of striatum. Symptoms develop from a general lack of coordination to apparent uncoordinated, jerky body movements [START_REF] Zuccato | Brain-derived neurotrophic factor in patients with Huntington's disease[END_REF]. The physical abilities of the patients gradually worsen until coordinated movement becomes difficult. There is no effective cure available to HD (Table 33.1). The only approved medication, tetrabenazine, and other tested drugs (neuroleptics and antipsychotics) help to reduce chorea and psychiatric symptoms.

Amyotrophic lateral sclerosis (ALS) is a severe debilitating disease caused by motors neurons degeneration in the brain and the spinal cord. It is generally characterized by progressive paralysis starting at the limbs and ultimately leading to death caused by respiratory failure within 3 to 5 years after the onset of the symptoms. There is no cure for ALS (Table 33.1). The approved medication, riluzole, may extend life by just a few months [START_REF] Zhou | Amyotrophic lateral sclerosis in Beijing: Epidemiologic features and prognosis from 2010 to 2015[END_REF][START_REF] Glajch | Microneurotrophins improve survival in motor neuron-astrocyte co-cultures but co cot improve disease phenotypes in a mutant SOD1 mouse model of amyotrophic lateral sclerosis[END_REF].

The pathological characteristics, genetic factors, clinical symptoms, and actual medications of these diseases are summarized in Table 33.1. It should be emphasized that the existing therapeutic approaches do not exert disease-modifying effects on the neurodegeneration. The associated economic and societal challenges lead to a growing public health burden. Although the etiology and the pathological mechanism of the neurodegenerative diseases are not completely understood, it has been established that the progressive loss of neurons results from the combination of multiple factors (Fig. 33.1). First, genetic factors are involved in the appearance of misfolded amyloid-Aβ protein and other misfolded mutant forms like hyperphosphorylated Tau (p-Tau) and Huntingtin proteins [3-5, 10, 14]. All these mutated proteins aggregate and form deposits. The resulting aggregates can be toxic and can affect the intracellular organelles such as mitochondria [START_REF] Varinderpal | Mutations that affect mitochondrial functions and their association with neurodegenerative diseases[END_REF][START_REF] Onyango | Mitochondria in the pathophysiology of Alzheimer's and Parkinson's diseases[END_REF][START_REF] Cho | Mitochondrial dynamics in cell death and neurodegeneration[END_REF][START_REF] Zádori | Mitochondrial disturbances, excitotoxicity, neuroinflammation and kynurenines: Novel therapeutic strategies for neurodegenerative disorders[END_REF]. The disruption of the mitochondrial membrane causes neuronal cell death [START_REF] Cho | Mitochondrial dynamics in cell death and neurodegeneration[END_REF][START_REF] Zádori | Mitochondrial disturbances, excitotoxicity, neuroinflammation and kynurenines: Novel therapeutic strategies for neurodegenerative disorders[END_REF]. Second, neurotrophic factors deficiency has been reported in the severe neurodegenerative disorders 33]. Neurotrophins regulate the neuronal survival, differentiation, growth, and regeneration, as well as the synaptic plasticity. Studies have shown that the levels of brain derived neurotrophic factor (BDNF) and its tropomyosin kinase B (TrkB) receptor are decreased in the hippocampus and the cerebral cortex at the beginning of the Alzheimer's disease [START_REF] Zuccato | Brain-derived neurotrophic factor in patients with Huntington's disease[END_REF]. In addition, the administration of BDNF mimetics into transgenic mouse models of AD has enhanced learning and memory capacities [START_REF] Devi | 7,8-Dihydroxyflavone, a small-molecule TrkB agonist, reverses memory deficits and BACE1 elevation in a mouse model of Alzheimer's disease[END_REF].

Third, oxidative stress is the most common feature of neurodegenerative diseases [START_REF] Barnham | Neurodegenerative diseases and oxidative stress[END_REF][START_REF] Jiang | Oxidative stress: A major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson's disease and Alzheimer's disease[END_REF][START_REF] Gilgun-Sherki | Oxidative stress induced-neurodegenerative diseases: The need for antioxidants that penetrate the blood brain barrier[END_REF][START_REF] Uttara | Oxidative stress and neurodegenerative diseases: A review of upstream and downstream antioxidant therapeutic options[END_REF][START_REF] Dumont | Neuroprotective strategies involving ROS in Alzheimer disease[END_REF][START_REF] Zhong | Quantitative proteomics study of the neuroprotective effects of B12 on hydrogen peroxide-induced apoptosis in SH-SY5Y cells[END_REF]. Reactive Oxygen Species (ROS) such as superoxide anions, hydroxyl radicals, and hydrogen peroxide (H2O2) are produced by the mitochondrial transport chain, the endoplasmic reticulum, the Krebs cycle, and the plasma membrane involving the superoxide-generating NADPH oxidase (NOX) macromolecular complex [START_REF] Gilgun-Sherki | Oxidative stress induced-neurodegenerative diseases: The need for antioxidants that penetrate the blood brain barrier[END_REF]. Oxidative stress occurs under environmental factors and when the generation of ROS exceeds the natural antioxidant defenses of the cell (promoted by superoxide dismutase, catalase, glutathione peroxidase, carotenoids, and vitamins E or C) [START_REF] Barnham | Neurodegenerative diseases and oxidative stress[END_REF][START_REF] Jiang | Oxidative stress: A major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson's disease and Alzheimer's disease[END_REF][START_REF] Gilgun-Sherki | Oxidative stress induced-neurodegenerative diseases: The need for antioxidants that penetrate the blood brain barrier[END_REF][START_REF] Uttara | Oxidative stress and neurodegenerative diseases: A review of upstream and downstream antioxidant therapeutic options[END_REF][START_REF] Dumont | Neuroprotective strategies involving ROS in Alzheimer disease[END_REF][START_REF] Zhong | Quantitative proteomics study of the neuroprotective effects of B12 on hydrogen peroxide-induced apoptosis in SH-SY5Y cells[END_REF]. ROS accumulation attacks proteins, nucleic acids, and membrane lipids, and thus, causes impairments of the neuronal cell functions and integrity [START_REF] Uttara | Oxidative stress and neurodegenerative diseases: A review of upstream and downstream antioxidant therapeutic options[END_REF][START_REF] Dumont | Neuroprotective strategies involving ROS in Alzheimer disease[END_REF][START_REF] Zhong | Quantitative proteomics study of the neuroprotective effects of B12 on hydrogen peroxide-induced apoptosis in SH-SY5Y cells[END_REF]. Mitochondrial lesions are also mediated by ROS. This leads to the alteration of the neuronal cell bioenergetics, the disruption of the calcium (Ca 2+ ) homeostasis, or the activation of the mitochondrial permeability transition pore (mPTP). Thus, a vicious cycle is formed (Fig. 33.1), which amplifies the cellular dysfunction and triggers neurodegeneration [START_REF] Gilgun-Sherki | Oxidative stress induced-neurodegenerative diseases: The need for antioxidants that penetrate the blood brain barrier[END_REF][START_REF] Uttara | Oxidative stress and neurodegenerative diseases: A review of upstream and downstream antioxidant therapeutic options[END_REF][START_REF] Dumont | Neuroprotective strategies involving ROS in Alzheimer disease[END_REF][START_REF] Zhong | Quantitative proteomics study of the neuroprotective effects of B12 on hydrogen peroxide-induced apoptosis in SH-SY5Y cells[END_REF][START_REF] Onyango | Mitochondria in the pathophysiology of Alzheimer's and Parkinson's diseases[END_REF][START_REF] Ankarcronaa | Thinking Alzheimer's disease therapy: Are mitochondria the key?[END_REF][START_REF] Federico | Mitochondria, oxidative stress and neurodegeneration[END_REF][START_REF] Stahon | Age-related changes in axonal and mitochondrial ultrastructure and function in white matter[END_REF][START_REF] Cho | Mitochondrial dynamics in cell death and neurodegeneration[END_REF][START_REF] Lu | Metformin prevents dopaminergic neuron death in MPTP/Pinduced mouse model of Parkinson's disease via autophagy and mitochondrial ROS clearance[END_REF].

Fourth, neuro-inflammation is a crucial factor that favors neurodegenerative disease development. Several inflammatory markers (such as chemokines, cytokines, or proteins in the acute phase) are upregulated and cause inflammation. In fact, elevated levels of the inflammatory markers have been found during the progression of the neurodegenerative diseases [START_REF] Zádori | Mitochondrial disturbances, excitotoxicity, neuroinflammation and kynurenines: Novel therapeutic strategies for neurodegenerative disorders[END_REF][START_REF] Rahimifard | Targeting the TLR4 signaling pathway by polyphenols: A novel therapeutic strategy for neuroinflammation[END_REF].

Curcumin Potential for Neuroprotection against Neurodegenerative Diseases

Curcumin is a hydrophobic polyphenolic substance (Fig. 33.2) produced in the root of the plant Curcuma Longa L. This antioxidant compound is extensively marketed worldwide as a nutraceutical in various preparations, because it has a very safe nutraceutical profile with low side effects. Curcumin has been reported to be well tolerated at doses up to 8 g per day over short periods in humans [START_REF] Soleimani | Turmeric (Curcuma longa) and its major constituent (curcumin) as nontoxic and safe substances[END_REF]. Research on the pharmacological activities of curcumin has attracted strong attention in relation to its multiple actions of therapeutic interest, e.g., the anti-inflammatory, antioxidant, antiviral, antibacterial, antifungal, and antitumor activities [START_REF] Serafini | Curcumin in Alzheimer's disease: Can we think to new strategies and perspectives for this molecule?[END_REF]. These activities appear to be dose-dependent [START_REF] Mahdavi | Review of the anti-oxidation, anti-inflammatory and anti-tumor properties of curcumin[END_REF].

In vitro and in vivo Studies of Curcumin Properties in

Neurodegenerative Disease Models

The neuroprotective potential of curcumin (Fig. 33.2) and its antioxidant, anti-inflammatory, and amyloid Aβ binding properties have been highlighted in in vitro and in vivo investigations of different neurodegenerative disease models [START_REF] Mahdavi | Review of the anti-oxidation, anti-inflammatory and anti-tumor properties of curcumin[END_REF][START_REF] Gupta | Therapeutic roles of curcumin: Lessons learned from clinical trials[END_REF][START_REF] Brondino | Curcumin as a therapeutic agent in dementia: A mini systematic review of human studies[END_REF][START_REF] Serafini | Curcumin in Alzheimer's disease: Can we think to new strategies and perspectives for this molecule?[END_REF][START_REF] Maiti | Use of curcumin, a natural polyphenol for targeting molecular pathways in treating agerelated neurodegenerative diseases[END_REF][START_REF] Haan | Different curcumin forms selectively bind fibrillar amyloid beta in post mortem Alzheimer's disease brains: Implications for in-vivo diagnostics[END_REF][START_REF] Samarghandian | Anti-oxidative effects of curcumin on immobilization-induced oxidative stress in rat brain, liver and kidney[END_REF][START_REF] Ahmad | Understanding curcumin-induced modulation of protein aggregation[END_REF][START_REF] Sarkar | Curcumin revitalizes Amyloid beta (25-35)-induced and organophosphate pesticides pestered neurotoxicity in SH-SY5Y and IMR-32 cells via activation of APE1 and Nrf2[END_REF][START_REF] Zhang | Curcumin exerts effects on the pathophysiology of Alzheimer's disease by regulating PI(3,5)P2 and transient receptor potential mucolipin-1 expression[END_REF]. Curcumin has been found to increase the levels of glutathione (GSH) and malondialdehyde (MDA), as well as the antioxidant enzyme [superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (CAT)] activities in the rat brain, thus preventing the stress-induced oxidative damage of brain [START_REF] Maiti | Use of curcumin, a natural polyphenol for targeting molecular pathways in treating agerelated neurodegenerative diseases[END_REF][START_REF] Samarghandian | Anti-oxidative effects of curcumin on immobilization-induced oxidative stress in rat brain, liver and kidney[END_REF]. The anti-inflammatory properties of curcumin have been characterized by the inhibition of the inflammatory chemokines, by increased levels of the anti-inflammatory cytokines, and by enhanced expression levels of induced nitric oxide synthase (iNOS) and the transcription factor NF-Kb [START_REF] Samarghandian | Anti-oxidative effects of curcumin on immobilization-induced oxidative stress in rat brain, liver and kidney[END_REF]. Curcumin has been shown to prevent the fibrillation of α-synuclein at the earliest stage of the aggregation process, as well as the fibrillation of the globular protein hen egg-white lysozyme (HEWL) [START_REF] Ahmad | Understanding curcumin-induced modulation of protein aggregation[END_REF]. Both proteins are known to form amyloid-like fibrils. These results have suggested that curcumin might be a potential therapeutic agent for preventing protein aggregation in Alzheimer's, and Parkinson's diseases [START_REF] Ahmad | Understanding curcumin-induced modulation of protein aggregation[END_REF]. Recent in vitro and in vivo investigations of curcumin's activities in neurodegenerative disease models [START_REF] Sarkar | Curcumin revitalizes Amyloid beta (25-35)-induced and organophosphate pesticides pestered neurotoxicity in SH-SY5Y and IMR-32 cells via activation of APE1 and Nrf2[END_REF][START_REF] Zhang | Curcumin exerts effects on the pathophysiology of Alzheimer's disease by regulating PI(3,5)P2 and transient receptor potential mucolipin-1 expression[END_REF][START_REF] Liaquat | Naringenin-induced enhanced antioxidant defense system meliorates cholinergic neurotransmission and consolidates memory in male rats[END_REF][START_REF] Nguyen | Curcumin effectively rescued Parkinson's disease-like phenotypes in a novel drosophila melanogaster model with dUCH Knockdown[END_REF][START_REF] Wang | Protective effect of curcumin against oxidative stress-induced injury in rats with Parkinson's disease through the Wnt/β-catenin signaling pathway[END_REF][START_REF] Snigdha | Intranasal mucoadhesive microemulsion for neuroprotective effect of curcumin in mPTP induced Parkinson model[END_REF][START_REF] Hickey | Improvement of neuropathology and transcriptional deficits in CAG 140 knock-in mice supports a beneficial effect of dietary curcumin in Huntington's disease[END_REF][START_REF] Sevastre-Berghian | Curcumin reverses the diazepam-induced cognitive impairment by modulation of oxidative stress and ERK 1/2/NF-κB pathway in brain[END_REF][START_REF] Motaghinejad | Curcumin confers neuroprotection against alcohol-induced hippocampal neurodegeneration via CREB-BDNF pathway in rats[END_REF][START_REF] Motaghinejad | The neuroprotective effect of curcumin against nicotine-induced neurotoxicity is mediated by CREB-BDNF signaling pathway[END_REF] are summarized in Table 33.2.

Alcohol-induced neurodegeneration

In vivo: rat, oral supplementation Decrease of the reduced form of GSH, 5 SOD, 9 GPx, 3 GR, 13 1 Poly [ADP-ribose] polymerase 1; 2 Aβ-amyloid; 3 Glutathione Peroxidase; 4 Catalase; 5 Glutathione; 6 Acetylcholine; 7 Ubiquitin carboxy-terminal hydrolase; 8 6-Hydroxydopamine; 9 Superoxide dismutase; 10 Malondialdehyde; 11 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 12 Induced nitric oxide synthase; 13 Glutathione reductase.

Clinical Trials and Curcumin Limits

A serious obstacle to the pharmaceutical application of curcumin has arisen from its limited watersolubility and low bioavailability. In addition, this compound is chemically instable, which may cause a loss of biological activities. The failure of free curcumin in clinical trials is likely due to its limited bioavailability. For instance, curcumin has been delivered in doses between 1 and 4 g/per day as capsules or as powder mixed with food in trials for treatment of Alzheimer's disease patients. The performed 6month treatment study found no differences in the Aβ-amyloid levels between the treatment groups or in the Mini Mental State Examination (MMSE) scores [START_REF] Baum | Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease[END_REF]. Similarly, oral curcumin in a 24-week, randomized, double blind, and placebo-controlled study for AD treatment has shown no detectable differences in the measured biomarkers from the different treatment groups [START_REF] Ringman | Oral curcumin for Alzheimer's disease: Tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study[END_REF]. A clinical study with three single cases of patients receiving curcumin (100 mg/day) reported that only one patient increased his MMSE score from 12/30 to 17/30 after 12 weeks of treatment (improved calculation, concentration, transcription of the figure, and spontaneous writing). Two of the patients were on donepezil treatment before starting the curcumin trial [START_REF] Hishikawa | Effects of turmeric on Alzheimer's disease with behavioral and psychological symptoms of dementia[END_REF]. Based on all performed trials with AD patients, it was, however, difficult to conclude if curcumin has positive effects on the AD symptoms [START_REF] Mazzanti | Curcumin and resveratrol in the management of cognitive disorders: What is the clinical evidence?[END_REF].

In fact, the major fraction (35-89%) of orally administered curcumin can be lost due to its low bioavailability. The intestinal mucosa and mucus form a physical barrier to curcumin adsorption. The drug cannot reach the circulation in a bioactive form as it undergoes reduction and metabolism/conjugation in the liver. Reductases enzymatically reduce curcumin to dihydrocurcumin, tetrahydrocurcumin, and hexahydrocurcumin. Furthermore, curcumin may be conjugated to sulfates and glucuronides [START_REF] Ireson | Metabolism of the cancer chemopreventive agent curcumin in human and rat intestine[END_REF][START_REF] Marczylo | Rapid analysis of curcumin and curcumin metabolites in rat biomatrices using a novel ultraperformance liquid chromatography (UPLC) method[END_REF][START_REF] Marczylo | Comparison of systemic availability of curcumin with that of curcumin formulated with phosphatidylcholine[END_REF]. Thus, most of the circulating curcumin is in a conjugated form.

The necessity of the development of a delivery system for the protection of curcumin from rapid metabolism and for the improvement of its bioavailability has become evident [START_REF] Ghalandarlaki | Nanotechnology-applied curcumin for different diseases therapy[END_REF]. A randomized, double-blind, placebo-controlled clinical trial examined the acute administration (effects 1 h and 3 h after a single dose application), chronic (4 weeks) administration, and acute-on-chronic (1 h or 3 h after a single dose followed by a chronic treatment) effects of solid-lipid-nanoparticle (SLNP) loaded by curcumin. The results of the SLNP formulation of curcumin (400 mg in capsules Longvida ® ) on cognitive function, mood, and blood biomarkers were obtained with 60 healthy adults (aged 60-85). SLNP-loaded curcumin significantly improved the performance in sustained attention and working memory tasks one hour after its administration (as compared to placebo). Working memory and mood (general fatigue and change in the calmness state, contentedness, and fatigue induced by psychological stress) were essentially improved following chronic treatment. A significant acute-on-chronic treatment effect on alertness and contentedness was also observed [START_REF] Cox | Investigation of the effects of solid lipid curcumin on cognition and mood in a healthy older population[END_REF].

Nanocarrier-Mediated Curcumin Delivery

Nanotechnology for nanomedicine development employs functional materials with appropriate nanoscale organization that can interact with biological systems and induce desired physiological responses while minimizing undesirable side effects [START_REF] Modi | Advances in the treatment of neurodegenerative disorders employing nanotechnology[END_REF]. Nanotechnology-based delivery systems can influence drug capacity to cross the biological barriers (e.g., the BBB) and reach the targeted brain regions [START_REF] Ghalandarlaki | Nanotechnology-applied curcumin for different diseases therapy[END_REF][START_REF] Cox | Investigation of the effects of solid lipid curcumin on cognition and mood in a healthy older population[END_REF][START_REF] Modi | Advances in the treatment of neurodegenerative disorders employing nanotechnology[END_REF][START_REF] Sahni | Neurotherapeutic applications of nanoparticles in Alzheimer's disease[END_REF]. Therefore, nanocarriers are promising for the development of personalized medicines for the treatment of neurological disorders [START_REF] Craparo | Nanoparticulate systems for drug delivery and targeting to the central nervous system[END_REF][START_REF] Fonseca-Santos | Nanotechnology-based drug delivery systems for the treatment of Alzheimer's disease[END_REF][START_REF] Kanwar | Nanoparticles in the treatment and diagnosis of neurological disorders: Untamed dragon with fire power to heal[END_REF][START_REF] Gao | Progress and perspectives on targeting nanoparticles for brain drug delivery[END_REF][START_REF] Roney | Targeted nanoparticles for drug delivery through the blood-brain barrier for Alzheimer's disease[END_REF][START_REF] Modi | Nanotechnological applications for the treatment of neurodegenerative disorders[END_REF].

Lipid-based nanoparticles, including solid lipid nanoparticles (SLNPs), nanostructured lipid carriers (NLC), liposomes and liquid crystalline nanocarriers (LCN), as well as polymer-based nanoparticles (Fig. 33.3), have been developed to overcome the poor solubility, stability, and bioavailability of curcumin, and to promote its utilization as a drug in disease treatments . Lipid-based nanoparticles have the advantage of being the least toxic carriers for in vivo applications. The lipids used to prepare biocompatible and biodegradable nanoparticles are usually naturally occurring molecules with low acute and chronic toxicity. In the case of polymeric nanoparticles, the in vivo degradation of the polymer matrices might cause toxic effects [START_REF] Ganesan | Lipid nanoparticles: Different preparation techniques, characterization, hurdles, and strategies for the production of solid lipid nanoparticles and nanostructured lipid carriers for oral drug delivery[END_REF]. The biocompatibility and the physicochemical diversity of lipids and their capacity to enhance the oral bioavailability of drugs have made this kind of nanocarriers very attractive systems for drug delivery. As a matter of fact, lipid-based formulations may positively influence drug absorption in several ways, e.g., by influencing the solubilization properties, preventing the drug precipitation upon intestinal dilution, increasing the membrane permeability, inhibiting the efflux transporters, reducing the CYP enzymes, or enhancing the lymphatic transport [START_REF] Ganesan | Lipid nanoparticles: Different preparation techniques, characterization, hurdles, and strategies for the production of solid lipid nanoparticles and nanostructured lipid carriers for oral drug delivery[END_REF]122]. Among the lipid-based nanoparticles, SLNPs have been intensively developed because they combine the advantages of different carrier systems like liposomes and polymeric particles. Similar to liposomes, SLNPs are composed of physiologically biocompatible excipients (lipids and fatty acids). In the same way to polymeric NPs, their solid matrix core can efficiently protect the loaded active pharmaceutical ingredient against chemical degradation under the harsh conditions of biological milieux. Therefore, SLNPs provide controlled release profiles of the encapsulated drugs [START_REF] Sadegh-Malvajerd | Brain delivery of curcumin using solid lipid nanoparticles and nanostructured lipid carriers: Preparation, optimization, and pharmacokinetic evaluation[END_REF]. In addition to the above advantages, liposomes can encapsulate and transport both lipophilic and hydrophilic drugs. They have a high degree of similarity to cell membranes in terms of lipid composition and organization, which facilitates the bioavailability of the pharmaceutical compounds [102]. Liquid crystalline nanocarriers (LCN) such as cubosomes and hexosomes (Fig. 33.3) involve multiple compartments for encapsulation of either lipophilic or hydrophilic drugs. They display structural advantages which enable high encapsulation efficacy for molecules of various sizes and hydrophilicity [113,116]. LCNs are formed by self-assembly of lyotropic lipids such as unsaturated monoglycerides, phospholipids, glycolipids, and other amphiphilic molecules. For example, monoolein, which is a nontoxic, biodegradable, and biocompatible lipid, is classified as a GRAS (Generally Recognized As Safe), and ω-3 polyunsaturated fatty acids (n-3 PUFA) have been shown to be highly beneficial in various disease models of neurodegeneration [123, 124]. In the following section, we summarize recently reported works on curcumin delivery to in vitro and in vivo models of neurodegenerative diseases.

Curcumin Delivery by Polymeric Nanoparticles

Polymeric nanoparticles of a biocompatible and biodegradable nature are of essential interest as drug delivery nanocarriers. The release of the encapsulated drug can be modulated by altering the polymer composition and amphiphilicity. Poly(lactic-co-glycolic acid) (PLGA) is one of the most commonly used biodegradable synthetic polymers. It is a FDA-(US) and EMA-approved platform for the delivery of drugs to humans. PLGA-derived nanoparticles have been successfully used for the encapsulation of different hydrophobic compounds (such as curcumin) by nanoprecipitation or by single emulsion techniques [START_REF] Song | Curcumin-loaded PLGA-PEG-PLGA triblock copolymeric micelles: Preparation, pharmacokinetics and distribution in vivo[END_REF]. Hydrophilic molecules can be encapsulated by means of double emulsions or by two-step nanoprecipitation methods. On the other site, polymeric micelles have been studied towards site-specific drug delivery [START_REF] Ma | Micelles of poly(ethyleneoxide)-bpoly(epsilon-caprolactone) as vehicles for the solubilization, stabilization, and controlled delivery of curcumin[END_REF][START_REF] Yu | Structure of modified epsilon-polylysine micelles and their application in improving cellular antioxidant activity of curcuminoids[END_REF][START_REF] Podaralla | Synthesis of novel biodegradable methoxypoly (ethylene glycol)-zein micelles for effective delivery of curcumin[END_REF].

Micelles are formed by amphiphilic macromolecules, which self-assemble into nano-sized (10-100 nm in diameter) core/shell structures in excess aqueous media (Fig. 33.3, top). The core-shell organization facilitates the incorporation of curcumin inside the hydrophobic core, while the water solubility of the nanocarriers is ensured by their hydrophilic corona [START_REF] Ma | Micelles of poly(ethyleneoxide)-bpoly(epsilon-caprolactone) as vehicles for the solubilization, stabilization, and controlled delivery of curcumin[END_REF]. Amphiphilic co-polymers selfassemble into micelles in aqueous solutions due to the hydrophobic interactions among their waterinsoluble segments. Curcumin-loaded polymeric micelles have received attention due to various features (Table 33.3), like (i) the enhanced solubility of the drug; (ii) the sustained CU release profile; and (iii) the small size of the PEG-decorated carriers (<200 nm), which stabilizes them in biological fluids [START_REF] Kanwar | Nanoparticles in the treatment and diagnosis of neurological disorders: Untamed dragon with fire power to heal[END_REF][START_REF] Gao | Progress and perspectives on targeting nanoparticles for brain drug delivery[END_REF][START_REF] Roney | Targeted nanoparticles for drug delivery through the blood-brain barrier for Alzheimer's disease[END_REF]. Micelles formed by the PLGA-PEG-PLGA synthetic copolymer have shown potential in modifying the pharmacokinetics and tissue distribution of curcumin. Evaluation of pharmacokinetics and biodistribution has demonstrated a prolonged half-life of the CU-micelles and a more efficient drug delivery to brain areas as compared to the carrier-free CU administration [START_REF] Song | Curcumin-loaded PLGA-PEG-PLGA triblock copolymeric micelles: Preparation, pharmacokinetics and distribution in vivo[END_REF]. Solid lipid nanoparticles (SLNPs) are submicron colloidal lipid carriers (from 50 nm to 1000 nm in diameter) which maintain a solid, spherical shape at room temperature. They possess a solid lipid core matrix stabilized by emulsifiers that can solubilize lipophilic molecules. The CU-SLNPs are usually small, ranging from 100 to 300 nm in diameter. The total drug content can reach up to 92% when the SLNPs are manufactured using the micro-emulsification technique [START_REF] Kakkar | Curcumin loaded solid lipid nanoparticles: An efficient formulation approach for cerebral ischemic reperfusion injury in rats[END_REF]. In an experimental rat model of cerebral ischemic reperfusion injury, animals fed with CU-loaded SLNPs have had a 90% improvement in their cognitive function along with a 52% inhibition of the acetyl cholinesterase activity [START_REF] Kakkara | Proof of concept studies to confirm the delivery of curcumin loaded solid lipid nanoparticles (C-SLNs) to brain[END_REF]. The investigated formula has been shown to increase the levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and the activities of mitochondrial enzymes, while decreasing the lipid peroxidation and the peroxynitrite levels. Furthermore, this formulation showed a 16.4 to 30-fold improvement in the bioavailability of CU in the brain upon oral and intravenous (IV) administrations, respectively [START_REF] Kakkara | Proof of concept studies to confirm the delivery of curcumin loaded solid lipid nanoparticles (C-SLNs) to brain[END_REF]. The product Longvida ® (Verdure Sciences Inc.) is a SLNP-formulation of curcumin which can yield from 0.1 to 0.2 µM plasma levels of CU with associated 1-2 µM brain levels of free CU in animals [START_REF] Maiti | Comparative neuroprotective effects of dietary curcumin and solid lipid curcumin particles in cultured mouse neuroblastoma cells after exposure to Abeta42[END_REF][START_REF] Maiti | A comparative study of dietary curcumin, nanocurcumin, and other classical amyloid-binding dyes for labeling and imaging of amyloid plaques in brain tissue of 5x-familial Alzheimer's disease mice[END_REF][START_REF] Maiti | Solid lipid curcumin particles provide greater anti-amyloid, antiinflammatory and neuroprotective effects than curcumin in the 5xFAD mouse model of Alzheimer's disease[END_REF]. This formula was later optimized as "lipidated Cur," which can yield more than 5 µM CU in mouse brain [START_REF] Dadhaniya | Safety assessment of a solid lipid curcumin particle preparation: Acute and subchronic toxicity studies[END_REF].

Other formulations of CU-loaded SLNPs, tested in Alzheimer's disease models, are outlined in Table 33 Nanostructured lipid carriers (NLC) are referred to as the "second generation" of SLNPs. NLCs are composed of mixtures of sterically different amphiphilic molecules. Often, mixtures of liquid-phase lipids and solid-phase lipids yield matrices with imperfections, which may incorporate increased quantities of drug molecules as compared to the SLNPs. Despite of the presence of the liquid-phase lipid, the NLC matrix appears to be in a solid state at room and body temperatures. The solid state is controlled by the fraction of the included liquid-phase lipid [START_REF] Ganesan | Lipid nanoparticles: Different preparation techniques, characterization, hurdles, and strategies for the production of solid lipid nanoparticles and nanostructured lipid carriers for oral drug delivery[END_REF]. Sadegh-Malvajerd et al. have reported an enhanced entrapment efficiency of curcumin in NLCs (94% ± 0.74) as compared to SLNPs (82% ± 0.49). The pharmacokinetic studies, performed after intravenous (IV) administration of 4 mg/kg dose of curcumin in rats, have indicated that the amount of curcumin available in the brain was significantly higher for curcumin-loaded NLCs (AUC0-t = 505.76 ng/g h) as compared to free curcumin (AUC0-t = 0.00 ng/g h) and curcumin-loaded SLNs (AUC0-t = 116.31 ng/g h) (P < 0.005) [START_REF] Sadegh-Malvajerd | Brain delivery of curcumin using solid lipid nanoparticles and nanostructured lipid carriers: Preparation, optimization, and pharmacokinetic evaluation[END_REF]. The outcomes of other recent investigations of CU-loaded NLCs in models of neurodegenerative diseases are summarized in Table 33.4.

Liposomes

Liposomes are lipid bilayer-based, self-assembled, closed colloidal structures, typically 25 nm to 5 µm in diameter [START_REF] Lazar | Curcumin-conjugated nanoliposomes with high affinity for Aβ deposits: Possible applications to Alzheimer disease[END_REF]. They usually have a spherical shape comprising an aqueous core surrounded by a hydrophobic lipid membrane (Fig. 33.3). The lipid bilayer can be loaded with hydrophobic or amphiphilic molecules, whereas the hydrophilic molecules can be encapsulated in the aqueous reservoir of the liposomes. Often, liposomes are composed of phospholipids (e.g., phosphatidylcholines) or mixtures of phospholipids with co-lipids. Various liposome architectures can form depending on the preparation methods; for instance, multilamellar vesicles (MLV, involving a stack of several lipid bilayers), small unilamellar vesicles (SUV, constituted by a single lipid bilayer), large unilamellar vesicles (LUV), tubular vesicles, and cochleate vesicles.

Curcumin encapsulated in liposomes has been proven to be a safe formulation, which enhances the CU solubility and its cellular uptake [START_REF] Lazar | Curcumin-conjugated nanoliposomes with high affinity for Aβ deposits: Possible applications to Alzheimer disease[END_REF][START_REF] Sancini | Functionalization with TAT-peptide enhances blood-brain barrier crossing in vitro of nanoliposomes carrying a curcumin-derivative to bind amyloid-β peptide[END_REF][START_REF] Mourtas | Curcumin-decorated nanoliposomes with very high affinity for amyloid beta1-42 peptide[END_REF][100][101]. Liposomes deliver CU into the cells via membrane fusion or endocytosis process. Liposomal formulations with a PEG surface coating provide a longer circulation time for the encapsulated drug. Biomolecular ligands can be anchored to the liposome surface in order to enhance the receptor targeting capacity, and hence, the permeability across the blood-brain barrier (BBB) [102,103]. The outcomes of the investigated CU-loaded liposomes in models of neurodegenerative diseases are summarized in Table 33.4.

Liquid crystalline nanoparticles with internal structure

Liquid crystalline nanoparticles (LCNPs) are self-assembled architectures of lyotropic lipids, colipids (surfactants or oils), and water. They are typically formed upon dispersion and fragmentation of bulk lyotropic liquid crystalline phases (e.g., bicontinuous cubic, sponge, or inverted hexagonal phases) [104-106]. The amphiphilic molecules spontaneously organize into compartments with hydrophobic and hydrophilic domains (Fig. 33.3), which can encapsulate lipophilic or hydrosoluble guest compounds. The structures formed by this self-assembly process are thermodynamically stable. The initial liquid crystalline phases are usually viscous and have a short-range order in comparison to solids, but longrange order in comparison to liquids. A typical example of a lyotropic liquid crystalline phase is the inverted bicontinuous cubic phase formed upon mixing of unsaturated monoglyceride lipids with water [105]. Cubosomes are produced upon dispersion of the bicontinuous cubic liquid crystalline phases in excess aqueous medium. Their periodic structures comprise folded bicontinuous lipid bilayer membranes and periodic networks of aqueous channels (Fig. 33.3). The latter enable high encapsulation capacity for hydrophilic guest macromolecules [106][107][108][109][110][111]. Lipid nanocarriers of liquid crystalline internal structures have received considerable attention as delivery vehicles through the BBB [111,112].

Curcumin has been successfully entrapped into monolein-based LCNPs with almost 100% encapsulation efficiency [113]. LCNPs dispersion was very stable in terms of nanocarrier sizes and surface charge upon storage. LCNPs were efficiently taken up by cultures cells following the sustained release of curcumin. In addition, they provided inhibition of the cell proliferation and apoptosis induction in an anticancer study [113]. A recent investigation of an inverse hexagonal (HII) liquid crystalline phase encapsulating curcumin has demonstrated that the release of curcumin was a concentration-diffusion controlled process in the early stages, whereas multiple diffusion mechanisms coexisted in the later stages of drug release. Radical scavenging experiments have shown that curcumin-loaded LCNPs exert the desired antioxidant activity [114]. Thus, curcumin-loaded LCNPs may be promising for neurodegenerative disease treatments using sustained-release nanoformulations for combination therapies [115,116]. Further results obtained with lipid-based LCNPs in models of neurodegenerative disease are presented in Table 33.4.

Conclusions

The naturally occurring compound curcumin is increasingly studied in neurodegenerative disease models due to its neurogenesis-stimulating properties and its anti-amyloid and anti-tau potential. Nanotechnology-based delivery systems of curcumin have been developed with the purpose of improving its solubility, stability, and bioavailability in potential treatment strategies of neurodegenerative disorders. We summarized recent advances in research on safe liquid crystalline lipid-based nanocarriers (cubosome, spongosome, hexosome, and liposome particles) and solid lipid nanoparticles, as well as on selected biodegradable polymer-based nanocarriers. The emphasis is given on the observed biological outcomes of the curcumin nanoformulations in in vitro and in vivo models of the multifactor neurodegenerative (AD, PD, HD and ALS). Despite the difficulty of overcoming biological barriers, promising results on the enhancement of the permeability of the BBB and receptor-mediated delivery across the BBB have been reported with liposome and cubosome nanocarriers. Further investigations will be required in order to understand the involved mechanisms of action of curcumin nanoformulations in the proposed neurodegenerative disease models, and to optimize the delivery systems and strategies towards translation into clinics.

Abbreviations

Figure 33 . 1

 331 Figure 33.1 Neurodegeneration is triggered and boosted by a vicious circle involving neurotoxic protein accumulation, oxidative stress, mitochondrial damage, DNA damage, and impairment of the calcium (Ca 2+ ) homeostasis, neurotrophin deficiency, neuroinflammation, genetic, and environmental factors.

Figure 33 . 2

 332 Figure 33.2 Summary of the curcumin activities and suggested mechanisms of action, which can be exploited for treatment of neurodegenerative diseases.

Figure 33 . 3

 333 Figure 33.3 Schematic presentation of amphiphilic nanocarriers enabling the encapsulation and protection of hydrophobic and hydrophilic molecules of therapeutic significance.

Table 33 .

 33

		1 Pathological characteristics, genetic factors and clinical symptoms of Alzheimer's disease (AD),
	Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) [1-30]
	Diseases	Characteristics	Genetics factors	Symptoms	Actual treatments
	AD	Senile plaques from	Inherited form (70%	Progressive memory	Anticholinergics
		extracellular	of patients):	loss, Decision	(tacrine,
		amyloid-Aβ	mutations of APP,	judgment loss,	rivastigmine,
		accumulation,	PSEN1 or PSEN2;	Autonomy loss	galantamine and
		Intracellular	Sporadic form		donepezil),
		neurofibrillary	(30%): presence of		Memantine,

Table 33

 33

	Disease	Model/administration	Mechanism	Outcomes
		route
	AD	In vitro: human	Enhancement of the	Revitalization of the
		neuroblastoma SH-SY5Y	expression of DNA	neuronal cells from Aβ 2 -
		and IMR-32 cells	repair enzymes (APE1,	induced oxidative stress
			pol β, and PARP1 1 ) to	[41]
			halt the oxidative DNA
			base damage via base
			excision repair (BER)
			pathway; Activation of
			the antioxidant
			response element (ARE)
			via Nrf2 upregulation
	AD	In vitro: mouse	Decrease of the	Neuronal cell growth,
		hippocampal clone	autophagosomes	Protective role of CU on
		neuronal cell line HT-22	number, Increase of the	memory and cognition
		cells treated with Aβ 1-42,	lysosomal Ca 2+	impairments [42]
		In vivo: mice with	regulation of PI(3,5)P2
		APP/PS1 transgenes	and Transient Receptor
			Potential Mucolipin-1
			Expression (TRPME)
	AD	In vivo: rat, oral	Increase of GPx, 3 CAT, 4	Improving memory and
		supplementation	GSH 5 activities, and Ach 6	cognitive abilities [43]
			levels
	PD	In vivo: Drosophila model	Effects on dUCH 7	Decrease of ROS levels,
		of PD with dUCH 7	knockdown, a homolog	Improved locomotive
		knockdown	of human UCH-L1	abilities, Reduction of
				dopaminergic neurons
				degeneration [44]
	PD	In vivo: male Sprague-	Activation of the Wnt/β-	Protective effect of CU
		Dawley rats injured by 6-	catenin signaling	against oxidative stress-
		OHDA 8 in the left striatum	pathway, Higher Wnt3a	induced injury,
			and β-catenin mRNA	Enhanced viability,
			and protein expressions,	survival, and adhesion,
			c-myc and cyclin D1	attenuated apoptosis of
			mRNA expression,	deutocerebrum primary
			enhanced SOD 9 and	cells [45]
			GPx 3 contents,
			decreased MDA 10
			content and elevated
			mitochondrial
			membrane potential
	PD	In vivo: MPTP 11 mice,	Increase of dopamine	Improvement in motor
		intranasal mode of	concentration in brain,	performance,
		administration of CU	which improves	Symptomatic
		(mucoadhesive system)	muscular coordination	neuroprotection against
			and gross behavioral	MPTP-induced
			activities of the test	neurodegeneration in
			animal, Significant	the striatum [46]
			reduction of the
			MPTP 11 -mediated
			dopamine depletion
	HD	In vivo: CAG140 mice, a	Decreased huntingtin	Partial improvement of
		knock-in (KI) mouse	aggregates, increased	transcriptional deficits,
		model of HD	striatal DARPP-32 and	partial behavioral
			D1 receptor mRNAs	improvement [47]

.2 Recently reported curcumin (CU) activities in in vitro and in vivo models of neurodegenerative diseases

[START_REF] Sarkar | Curcumin revitalizes Amyloid beta (25-35)-induced and organophosphate pesticides pestered neurotoxicity in SH-SY5Y and IMR-32 cells via activation of APE1 and Nrf2[END_REF][START_REF] Zhang | Curcumin exerts effects on the pathophysiology of Alzheimer's disease by regulating PI(3,5)P2 and transient receptor potential mucolipin-1 expression[END_REF][START_REF] Liaquat | Naringenin-induced enhanced antioxidant defense system meliorates cholinergic neurotransmission and consolidates memory in male rats[END_REF][START_REF] Nguyen | Curcumin effectively rescued Parkinson's disease-like phenotypes in a novel drosophila melanogaster model with dUCH Knockdown[END_REF][START_REF] Wang | Protective effect of curcumin against oxidative stress-induced injury in rats with Parkinson's disease through the Wnt/β-catenin signaling pathway[END_REF][START_REF] Snigdha | Intranasal mucoadhesive microemulsion for neuroprotective effect of curcumin in mPTP induced Parkinson model[END_REF][START_REF] Hickey | Improvement of neuropathology and transcriptional deficits in CAG 140 knock-in mice supports a beneficial effect of dietary curcumin in Huntington's disease[END_REF][START_REF] Sevastre-Berghian | Curcumin reverses the diazepam-induced cognitive impairment by modulation of oxidative stress and ERK 1/2/NF-κB pathway in brain[END_REF][START_REF] Motaghinejad | Curcumin confers neuroprotection against alcohol-induced hippocampal neurodegeneration via CREB-BDNF pathway in rats[END_REF][START_REF] Motaghinejad | The neuroprotective effect of curcumin against nicotine-induced neurotoxicity is mediated by CREB-BDNF signaling pathway[END_REF]

Table 33 . 3

 333 Curcumin-loaded polymeric nanoparticles studied in in vitro and in vivo models of neurodegenerative diseases

	Disease	Nanoformulation Type	Model/administration	Outcomes
			route
	AD	PLGA 1 nanoparticles	In vitro: SK-N-SH human	Protection against H2O2-
			neuroblastoma cells	induced oxidative
				damage [70]
	AD	PLGA nanoparticles	In vitro: Neural stem cells,	Expression of genes
			In vivo: Aβ 2 -amyloid	involved in neuronal
			induced rat model of AD-	proliferation and
			like phenotypes	differentiation, Reverse
				learning and memory
				impairments [73]
	AD	PLGA nanoparticles	In vitro	Anti-amyloid activity
		conjugated with Tet-1		unchanged, decrease of
		peptide		aggregates size [74],
				Diminution of anti-
				oxidant activity
	AD	PLGA nanoparticles	In vitro: in SK-N-SH cells	Neuronal uptake,
		functionalized with		Enhanced curcumin
		glutathione		action [75, 76]
	AD	PLGA nanoparticles	In vivo: Rat, IV, oral	Increased CU
				bioavailability and
				plasma concentration
				[77]
	AD	PLGA nanoparticles	In vivo: Rat	Prolonged CU retention
				time in cerebral cortex
				and hippocampus [78]
	AD	Apolipoprotein E3-	In vitro: SH-SY5Y cells	Protection against Aβ-
		mediated		induced cytotoxicity [79]
		poly(butyl)cyano
		acrylate nanoparticles
	AD	Pegylated poly(alkyl	In vitro	Inhibition of Aβ
		cyanoacrylate)		aggregation [80]
		nanoparticles with anti-
		Aβ 1-42 antibody at the
		surface
	AD	Spherical (SPNs) or	In vitro: Raw 264.7 cells,	Decrease of the pro-
		Discoidal (DPNs)	In vitro production of Aβ	inflammatory cytokines
		polymeric nanocontructs	fibers	in macrophages
		PLGA, DSPE-PEG 3		stimulated via Aβ fibers
				[81]
	AD	Polymeric nanoparticles	In vitro: SK-N-SH	Protection against H2O2-
		(NanoCurc TM )	differentiated cells, In	induced oxidative stress,
			vivo: Mice, parenteral	Downregulation of
			injection	caspase 3 and 7
				activities, mediators of
				the apoptotic pathway,
				Increased glutathione
				levels [82]
	AD	Nanocurcumin CU within	In vivo: AD model Tg2576	Higher curcumin
		polyethylene glycol-	mice	concentration in plasma,
		polylactide diblock		6 times higher area
		polymer micelles		under the curve and
				mean residence time in
				brain than ordinary CU,

1

Poly(lactic-co-glycolic acid); 2 Aβ-amyloid; 3 Distearoyl phosphatidylethanolamine-polyethylene glycol.

33.4.2 Curcumin Delivery by Lipid Nanoparticles

33.4.2.1 Solid lipid nanoparticles and nanostructured lipid carriers

  .4.

	AD	Solid lipid curcumin particle (SLCP), Longvida ®	In vitro: lipopolysaccharide (LPS)-stimulated RAW 264.7	degeneration of Aβ Improved solubility insulted neurons over unformulated curcumin, Decreased [101]
	AD	WGA 3 -conjugated and cardiolipin-incorporated liposomes carrying NGF 4 and CU	cultured murine macrophages In vitro: Human astrocytes and to protect SK-N-MC cells Apoptosis induced by β-amyloid 1-42 (A β 1-42) fibrils	LPS induced pro-Increased entrapment inflammatory efficiency of NGF and mediators NO, PGE2, CU, of NGF release and IL-6 by inhibiting and cell viability, the activation of NF-Decreased release of kB [92] CU, Permeability of
	AD	Solid lipid particles with CU (SLCP)	In vivo: one-year-old 5xFAD-and age-matched wild-type mice,	NGF and CU across Decrease in Aβ the blood-brain plaque loads in dentate gyrus of barrier [102]
	AD	Liposomes	intraperitoneal injections of CU/SLCP In vivo: Mice, stereotaxic injection in the right neocortex hippocampus and	hippocampus, More Decrease in Aβ anti-amyloid, anti-secretion and toxicity inflammatory, and neuroprotective [91] [97]
	AD AD	Solid lipid nanoparticles Liposomes decorated with anti-transferrin	In vivo: Rat, oral In vivo injection, hippocampus and	Effective delivery Decrease in Aβ 1-42 across the BBB 2 [88] aggregation,
	HD	Solid lipid nanoparticles (CU-receptor mAb	In vivo: (3-NP)-induced HD in rats neocortex	Internalization in the Restored glutathione levels and superoxide BBB model [99]
	AD	SLNs) Liposomes derivative TREG curcumin-alkyne functionalized with a	Human biological fluids syndrome subjects patients and down from sporadic AD	dismutase activity, Sequestration of Aβ Activation of nuclear Reduction in antioxidant pathway, factor-erythroid 2 1-42 [100, 101]
	Neuronal loss	Liquid-crystalline lipid nanoparticles carrying curcumin and DHA	In vitro: SH-SY5Y cells	mitochondrial Neuronal viability swelling, lipid and neurite peroxidation, protein outgrowth by carbonyls and activation of the TrkB reactive oxygen receptor signaling, species [89] and promotion of
	CNS disorders	Solid lipid nanoparticles (CU-SLNs) and	In vivo: male Sprague-Dawley rats 6-8 weeks old, oral	phosphorylated CREB Enhanced curcumin protein expression brain uptake, Cur-NLCs enhance the [118]
	AD	nanostructured lipid carriers (CU-NLCs) Lipopeptide: a short microtubule-stabilizing peptide conjugated to a	In vitro: Neuro-2a cells, PC-12 differentiated cells	absorption of brain Neurite outgrowth in curcumin more than absence of external 4-folds in comparison growth factors, with Cur-SLNs [95] Neural cells
	AD	Lipoprotein (LDL)-mimic nanostructured lipid carrier (NLC) hydrophobic palmitic acid chain	In vivo: Rat, oral	morphology and Cellular uptake health amelioration mediated by the Lf receptor, [120, 121]
	modified with lactoferrin (Lf) and 1 Aβ-amyloid; 2 blood-brain barrier; 3 wheat germ agglutinins; 4 nerve growth factor.	Permeability through the BBB and
		loaded with CU		preferentially
				accumulation in the
				brain, Efficacy in
				controlling the
				damage associated
				with AD [96]
	Disease AD	Nanoformulation type Liposomes functionalized with	Model/administration In vitro route	Outcomes Permeability across the BBB enhanced
		TAT-peptide		[98]
	AD	Solid lipid	In vitro: Mouse	Decreased ROS
	AD	nanoparticles Liposomes containing	neuroblastoma cells after In vitro: SK-N-MC cells	production, Inhibition of the
		cardiolipin	Aβ 1 exposure	Prevented apoptotic phosphorylation of
				death, Inhibition of p38, JNK, and tau
				Tau formation [89,90] protein, Protection
				against serious

Disclosures and Conflict of Interest

This work is supported by the "IDI 2017" project funded by the IDEX Paris-Saclay, ANR-11-IDEX-0003-02. The authors declare no conflict of interest.

Corresponding Author

Dr. Angelina Angelova Institut Galien Paris-Sud CNRS UMR 8612 LabEx LERMIT, Univ Paris-Sud, Univ Paris-Saclay F-92296 Châtenay-Malabry, France Email: angelina.angelova@u-psud.fr