Effects of curcumin on mitochondria in neurodegenerative diseases

Neurodegenerative diseases (NDs) result from progressive deterioration of selectively susceptible neuron populations in different central nervous system (CNS) regions. NDs are classified in accordance with the primary clinical manifestations (e.g., parkinsonism, dementia, or motor neuron disease), the anatomic basis of neurodegeneration (e.g., frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations), and fundamental molecular abnormalities (e.g., mutations, mitochondrial dysfunction, and its related molecular alterations). NDs include the Alzheimer disease and Parkinson disease, among others. There is a growing evidence that mitochondrial dysfunction and its related mutations in the form of oxidative/nitrosative stress and neurotoxic compounds play major roles in the pathogenesis of various NDs. Curcumin, a polyphenol and nontoxic compound, obtained from turmeric, has been shown to have a therapeutic beneficial effect in various disorders especially on the CNS cells. It has been shown that curcumin has considerable neuro‐ and mitochondria‐protective properties against broad‐spectrum neurotoxic compounds and diseases/injury‐associating NDs. In this article, we have reviewed the various effects of curcumin on mitochondrial dysfunction in NDs.


| INTRODUCTION
Turmeric (Curcuma longa L.) is a common golden-colored spice from a member of the ginger family (Zingiberaceae), which is a rhizomatous herbaceous perennial flowering plant (Angiosperms). 1,2 The powdered rhizome of turmeric has been used in traditional medicine as a curative compound as well as in Asian cuisines as a food additive and in beverage industries as a coloring agent. 2 Curcuminoids are biologically active and are one of the main components of turmeric, which based on soil conditions and origins, containing 2-9% of the turmeric compounds. Curcuminoids consist of curcumin/diferuloylmethane (the major component), demethoxycurcumin, bis-demethoxycurcumin, and cyclic curcumin (the minor component). 2,3 Over the past half a century, curcuminoids, in particular curcumin, have displayed a growing interest in a broad range of biological/pharmacological research. The antibacterial properties of curcumin were reported for the first time in 1949. 3,4 Since then, growing number of studies have focused on the potential therapeutic properties of curcumin in a myriad conditions and shown to have antioxidant, 5 antitumor and chemosensitizing, 1,6-10 lipid-modifying, 11,12 hepatoprotective, 13,14 vasculoprotective, 15 cardioprotective, 16 pulmonoprotective, 17 neuroprotective, 18 antithrombotic, 19 immunomodulatory, 20,21 antidiabetic, 22 analgesic, 23 antiinflammatory especially antineuroinflammatory, [23][24][25][26] as well as microglia-activation inhibitory 2 properties.
Curcumin (1,7-bis-[hydroxy-3-methoxyphenyl]-1,6heptadiena-3,5-dione; C 21 H 20 O 6 ) is a natural polyphenol compound with a molecular weight of 368.38 g/mol. It contains two ferulic acid residues joined by a methylene bridge. 3,27 It is a hydrophobic molecule, mostly insoluble in water, poorly soluble in hydrocarbon solvents (e.g., cyclohexane and hexane), and easily soluble in polar solvents (e.g., ethanol, methanol, DMSO, acetonitrile, chloroform, and ethyl acetate). 3 Biological activities and therapeutic properties of curcumin take place in three functional groups: an aromatic o-methoxy phenolic group, α, β-unsaturated β-diketo moiety, and a seven carbon linker. 27 In addition to its various therapeutic properties, owing to the hydrophobic tendency, presence of an active methylene group and a β-diketone moiety, curcumin has poor bioavailability/pharmacokinetics and degraded easily via aldo-keto reductase in the liver. 2,28 Numerous studies are being conducted to improve the bioavailability and pharmacokinetics property of curcumin.
Neurodegenerative diseases (NDs) are a heterogeneous group of disorders that are characterized by the progressive deterioration of the function and structure of the selectively vulnerable neuron populations in the central nervous system (CNS). 29 NDs are showing a growing trend worldwide as well as worsening mortality and morbidity especially in the elderly. 30 The individual NDs can be classified by their clinical presentations and symptoms, with pyramidal and extrapyramidal movement impairments (also known as ataxias) and cognitive or behavioral impairments (also known as dementia) being the most common. 31,32 NDs comprise Alzheimer disease (AD), Parkinson disease (PD), PD-related disorders, Huntington disease (HD), Spinal muscular atrophy, amyotrophic lateral sclerosis [ALS; also known as motor neuron diseases (MND)], dementia with Lewy bodies (DLB), spinocerebellar ataxia, corticobasal degeneration, frontotemporal dementia (FTD) and its variants, progressive supranuclear palsy, Prion disease, and other dementia/ataxiarelated NDs. 33 NDs are mostly incurable and the current therapeutic strategies are aimed at symptomatic relief and/or restraining the disease progression. 34 NDs not only reduce the life expectancy and health-related quality of life (HRQoL) in patients but also take a heavy toll on family members and impose striking financial strains on global health-care systems. 35,36 Hence, it is an urgent necessity to develop more effective therapeutic strategies to cope with the growing burden and health-related consequences of NDs.
NDs are characterized by many microprocesses resulting in progressive neuronal dysfunction and death. These include specific protein accumulations, mitochondrial dysfunction, oxidative/nitrosative stress, proteotoxic stress, and its related abnormalities in ubiquitin proteasomal and autophagosomal/ lysosomal systems, excitotoxicity, apoptosis (also known as programmed cell death), and uncontrolled neuroinflammation. [37][38][39][40][41][42][43][44] There is an overwhelming evidence of mitochondrial dysfunction and mutations in the pathogenesis of various NDs. Mutations in the mitochondrial DNA (mtDNA), impaired mitochondria dynamics (e.g., shape, size, distribution, fission-fusion, movement), abnormalities in complexes of the electron transport chain (ETC), and partial inhibition of mitochondrial ATP production give rise to overproduction of free radicals. This will lead to damage of the biomolecules (e.g., lipids, proteins, and DNA), neuroinflammation, tissue damage, and consequent cellular apoptosis in CNS which are the major hallmarks of NDs. 39,45 It has been reported that native curcumin and its micellized 46 /micronized 47 /hybridized 48 /nano-sized 49 forms, as well as its derivatives 50 /synthetic analogs 51 and its synergistic combination with other compounds 52 have the excellent capacity for scavenging intracellular reactive oxygen species (ROS) and reactive nitrogen species (RNS). 53,54 In addition, it protects the mitochondrial dysfunctions/impairments by (a) retaining mitochondrial membrane potential (ΔΨm)/the activities of all four mitochondrial complexes (complex I, II, III, and IV) 51 and Bax/Bcl-2 ratio 55 , (b) enhancing/increasing mitochondrial fusion activity, mitochondrial biogenesis, and synaptic proteins 56 , (c) reducing fission machinery, 56 mitochondrial swelling, lipid peroxidation, protein carbonylation, 47 levels of oxidized lipids 52 neuroinflammation, 57 apoptosis, 58-60 cytochrome c, caspase-3 and -9 activation, and mitochondrial depolarization 61 , (d) modulating/targeting the phospho-cAMP response element-binding (CREB)-brainderived neurotrophic factor (BDNF) signaling 57 and the nuclear factor (erythroid-derived 2)-like 2 (also known as Nrf2 or NFE2L2; a transcription factor) 62 , and (e) restoring the glutathione (GSH) levels and superoxide dismutase (SOD). 47 These findings suggest that utilizing curcumin and its related compounds as a neuroprotective agent with modulatory/protective effects on mitochondrial impairments and mitophagy 63 could be a promising approach for the treatment of NDs. Due to the association between NDs and mitochondrial dysfunction, we review in detail about the effects and underlying mechanisms of curcumin on the mitochondria in NDs in vitro, in vivo, and in clinical trials.

| Neurodegenerative diseases
At present, there is no definitive treatment for curing the NDs. The current therapeutic strategies are just capable of symptomatic relief and/or managing the overall symptoms as well as restraining the disease progression such as dopaminergic treatments for parkinsonism (e.g., PD, PD-related disorders, and movement impairments), 64 cholinesterase inhibitors for cognitive disorders, 65 antipsychotic drugs (also known as neuroleptics or major tranquilizers) for behavioral and psychological symptoms of dementia, 66 analgesics for pain reduction, 67 antiinflammatory medications for ameliorating disease progression, 2 and deep-brain stimulation, a medical device, to stop tremor and refractory movement disorders. 68 Although recent advances have shed more light into the pathophysiology of NDs, the exact etiology of NDs remain to be fully elucidated. The etiology of NDs could be multifactorial and heterogeneous, albeit credible evidence has emphasized that aging, genetic background, accumulated/misfolded proteins, and environmental/external factors (e.g., lifestyle and chemical exposure) are potentially linked with the onset of these diseases. 69,70 The NDs are typically described by specific misfolded and aggregated proteins 71 ; however, the affected neuron populations and disease severity differ for each NDs. 42 However, NDs share many substantial microprocesses associated with gradual neuronal dysfunction and death such as proteotoxic stress and its related abnormalities in ubiquitinproteasomal and autophagosomal/lysosomal systems, synaptic toxicity, excitotoxicity, oxidative stress, apoptosis, cell-deathrelated signaling pathways, and neuroinflammation. 32,57 AD is the most common form of dementia with a growing impact on NDs-related global health challenges affecting more than 50 million individuals. It is projected that AD cases in 2030 and 2050 will rise to 82 and 152 million, respectively. 72 Aβ peptides accumulation and their deposition into β-amyloid plaques (also known as Aβ plaques), as well as the neurofibrillary tangles aggregation into misfolded and hyperphosphorylated tau protein, are the leading causes and the accelerator of AD and AD-related pathology. 42 Neurotoxic metals (e.g., lead, mercury, aluminum, cadmium, and arsenic), as well as metal-based nanoparticles and some pesticides, are reported to increase Aβ peptides and the neurofibrillary tangles aggregation. This leads to Aβ plaques and hyperphosphorylation of Tau protein and the consequent onset of AD and AD-related pathology. 70 Energy deficiency due to mitochondrial dysfunction is a crucial characteristic of AD and AD-related dementias.
PD and PD-related disorders are the second-most common NDs with more than 6 million cases or 1-2 individual per 1,000 of the population worldwide affected. 73 This group of disorders predominately affect dopaminergic (dopamine-producing) neurons in a specific area of the brain called substantia nigra. 42 The exposure to several metals (e.g., lead and manganese), industrial chemicals and pollutants, 74 solvents, and some pesticides 75 are significantly associated with the mitochondrial dysfunction, metal homeostasis alterations, and proteins aggregation such as a-synuclein, which is a key constituent of DLB and a pivotal factor in PD pathogenesis. 70 Moreover, nuclear genome mutations in the PINK1 and Parkin genes have been implicated in PD-related ND pathology. 76 DLB is the second-most common dementia, which is characterized by progressive cognitive impairment, psychiatric and behavioral disturbances, and parkinsonian motor symptoms. 77 HD is an autosomal dominant neurodegenerative disorder with choreoathetosis, behavioral as well as psychiatric disturbances, and dementia that is caused by excessive CAG repeats in the short arm of chromosome 4p16.3 in the Huntingtin gene. The more the CAG repeats (36 CAG repeats or more), the earlier will be the onset of the disease. 78,79 Prion disease is a group of rare NDs that can affect both humans and animals. 80 Prion is a type of protein that can fold abnormally leading to the onset of prion disease, which is also known as transmissible spongiform encephalopathies.
FTD is an umbrella term given to a heterogeneous group of clinical syndromes and is the leading cause of early-onset dementia in patients under 65. It results from neurodegeneration within the frontal and anterior temporal lobes, insular cortex, and subcortical structures. The major hallmarks of FTD are early changes in emotion and behavior, language, and motor skills. 30 ALS/MND is a fatal motor neuron disorder that is characterized by progressive deterioration of the upper and lower motor neurons at the spinal or bulbar level. 81 The exact etiology of ALS/MND remains to be elucidated. Mutations of SOD 1 have been proposed as the most common cause of this fatal motor neuron disorder. 82

| The roles of mitochondria in NDs
Although the adult brain is about 2% of the body mass, it consumes more than 20% of energy supply in the form of ATP. Most of the brain energy is consumed for synaptic transmission, which is crucial for synaptic plasticity. 83 Mitochondria are dynamic organelles and the powerhouses of cells. The mitochondria are not only responsible for the production of the majority of energy currency represented by ATP but also have a variety of crucial roles including regulation of calcium homeostasis, biogenesis of heme, fatty acid synthesis, biogenesis of iron-sulfur (Fe-S) proteins, apoptosis, and population maintenance through fission and fusion. 84,85 There is overwhelming evidence that mitochondrial dysfunction and mutations play major roles in the aging and pathogenesis of various NDs. 45,86 BDNF pathway is a fundamental pathway for regulating the synaptic transmission and plasticity of neurons. These processes require a high amount of energy consumption and ca 2+ -buffering. For ca 2+ -buffering, mitochondria must be moved to the proper locations. The role of the BDNF pathway in mitochondrial movement and distribution has been increasingly recognized. This suggests that mitochondrial movement and distribution play a crucial role in BDNFmediated synaptic transmission and plasticity. 87 Hence, impairment of mitochondria could affect the synaptic transmission and synaptic plasticity, which are the important neurochemical foundation of learning and memory. Intensifying the BDNF pathway could be associated with a higher mitochondrial movement and distribution.
The CREB protein is a ubiquitous transcription factor. After phosphorylation, it can promote the transcription of cAMP response element-regulated genes especially mitochondrial genes and it related protein biogenesis. 88 However, dysregulation of the CREB transcriptional cascade is reported that have a direct link with the mitochondrial dysfunction and the progression of NDs. 89 The human mtDNA contains genetic coding information of 13 proteins, which are the core constituents of the mitochondrial ETC complexes I-IV that are embedded in the inner membrane. 90 ETC is one of the major hallmarks of mitochondria for energy production in cells through the redox (reduction and oxidation) reactions. Since the major part of ATP is generated by ETC, the proper functioning of this chain is fundamental for the CNS cells. Dysfunction in ETC complexes via genetic or exogenous factors could contribute greatly to the onset of NDs. It is reported that neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine suppresses the protein NADH-CoQ reductase in Complex I from pumping the protons across the mitochondrial membrane leading to inhibition of the electrochemical gradient formation and subsequent hindering ATP production and energetic failure. 91 In addition to mtDNA mutations, nuclear DNA mutations are also associated with mitochondrial dysfunction and subsequent NDs. It is reported that nuclear genome mutations in genes encoding α-synuclein, parkin, 92 PINK1, 93 and LRRK2 94 lead to a molecular link between mitochondrial dysfunction and subsequent oxidative stress contributing to PD and PDrelated NDs pathology. Mutations in amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) genes cause autosomal dominant forms of early-onset AD. 95 PSEN1 and PSEN2 mutations affect the mitochondrial function by deregulating the ca 2+ signaling leading to mitochondrial metabolic defects. 96 On the other hand, APP mutations lead to a serious reduction in respiratory activity and enhance glycolysis as well as reduce the mtDNA transcripts. 97 ETC is responsible for most of the ROS production in the cells. GSH and SOD are the natural antioxidants in the cells especially in mitochondria responsible for ROS scavenging. Several studies have reported that patients with NDs have a significant reduction of these antioxidants. 98 On the other hand, mitochondria dysfunction leads to an increase in the levels of lipid peroxidation and protein carbonylation, which has been identified as the potential intensifier of ROS and/or free-radical productions. 99,100 Nrf2, a basic leucine zipper protein, is among the most pivotal cell defense mechanisms against exogenous and/or endogenous stressors. Nrf2 targets variety of genes such as a vast range of antioxidant enzymes, proteins bound up in xenobiotic detoxification, repair and damaged-protein elimination, inhibition of neuroinflammation, as well as other targeted transcription factors that have fundamental role in retaining the cellular redox homeostasis by regulation, utilization, and generation of GSH and NADPH. 101 It is reported that Nrf2 defends neurons against mitochondrial neurotoxic compounds, reduced GHS, and imbalanced mitochondrial ROS production as well as improving the function and integrity of mitochondria. Besides, in many mitochondrial-related disorders, especially, NDs, the function of Nrf2 is suppressed by several processes. 62,102 ΔΨm generated by proton pumps of ETC complexes I, III, and IV is a fundamental component of mitochondria. It results from the redox reactions associated with the activity of the Krebs cycle and is responsible for the storage of energy. ΔΨm plays a crucial role in mitochondria homeostasis by eliminating mitochondria dysfunction. The association of proton gradient (ΔpH) and ΔΨm forms the transmembrane potential of hydrogen ions and can harness ATP production. The levels of ΔΨm and ATP production are relatively steady with limited fluctuations leading to normal physiological activity. 103 Alterations of mitochondrial function such as reduction of ΔΨm are highly linked to generating more oxidative stress-inducing early apoptosis. 104 In short, long-term decline or the rise of ΔΨm levels may promote adverse effects on cell viability and could be a reason for generating various pathologies especially NDs in CNS. 105 Mitochondria also play a prominent role in the extrinsic/ death receptor and intrinsic/mitochondrial apoptosis pathway, which is a fundamental process for growth, homeostasis, and immunomodulation in mammalian cells. Apoptosis is initiated by multiple forms of cellular stress stimuli/DNA damage including oxidative stress/ROS/RNS and endoplasmic reticulum stress, radiation, and drugs (e.g., chemotherapeutic agents). 39,106 In this process, proapoptotic Bcl-2 homology domain 3 only (BH3-only) proteins (e.g., Bad, Bid, Bim, and NOXA) activate Bcl-2 pro-apoptotic family members (e.g., Bax and Bak), and consequently, they translocate to the mitochondria. Bax and Bak also induce the cytochrome c release into the cytosol. This promotes the assembling of apoptosome (Apaf-1 and caspase-9) and subsequent activation of executioner caspase-3, -6, -7 initiating the cell death. Moreover, Bcl-2 family has a group of antiapoptotic members such as Bcl-2, Bcl-xL, Mcl-1, and Bcl-w. For the proper functioning of the cells, the ratio between antiapoptotic (e.g., Bcl-2, Bcl-xL) and proapoptotic (e.g., Bax and Bak) members of Bcl-2 family proteins must be steady. Unbalancing the antiapoptotic and proapoptotic members of Bcl-2 family proteins leads to neuronal damage/death and NDs. 107,108 Moreover, the extrinsic pathway can also crosstalk to the intrinsic apoptosis pathway by an amplification induced by caspase-dependent activation of Bid protein. 109 Microglial cells are the innate immune system cells residing in the CNS. In circumstances such as an invasion of pathogens and the formation of Aβ plaques, microglial cells are converted into the activated state. To defend against the pathogenic invaders and eliminate the Aβ plaques, activated-microglia have the capability of generating neuroinflammation by releasing broad-range of compounds such as inflammatory mediators and neurotoxic compounds. These compounds are a doubleedged sword for defending the neurons or affecting the neurons viability and CNS integrity. The chronic expression of several compounds such as TNF-α, IL-1β, PGE2, IL-6, IFN-γ, ROS, and RNS could be destructive to cells. 2,110 Long-standing neuroinflammation and chronic expression of several compounds will strikingly affect the neuronal viability and the survival of neural precursor cells by unbalancing the antiapoptotic and proapoptotic members of Bcl-2 family proteins and targeting mitochondria as well as extrinsic and intrinsic apoptosis pathway. 111,112 Moreover, astrocytic mitochondrial dysfunction including change in intracellular calcium, GSH, SOD, and specific neurotoxic compounds production has been implicated by various studies to be associated with the onset of NDs. 113 In short, mitochondrial impairment/dysfunction in the CNS neurons results in mitochondrial depolarization and reduction of mitochondrial dynamics/movements, distribution and fission, as well as releasing cytochrome c/ROS/RNS and subsequent neuronal damage and apoptosis. Moreover, many genetic alterations and related suppression on proteins production are associated with a higher incidence of mitochondrial dysfunction and its molecular consequences. Hence, mitochondrion and its related abnormalities are promising therapeutic targets for neurological disorders and NDs (Figure 1).

| Molecular targets of curcumin on mitochondria in NDs
It has been shown that many exogenous and endogenous factors, such as aging, nuclear-and mt-DNA mutations, drugs, neurotoxic compounds, and misfolded/aggregated proteins, lead to mitochondria dysfunction, which is markedly linked to the onset and pathogenesis of NDs. 29 NDs have a significant effect on the life expectancy and HRQoL 36 ; however, the existing medications are just capable of symptomatic relief or managing the overall symptoms. It is a priority to develop more effective drugs to face the growing trend of mortality and morbidity of NDs. Curcumin is a natural polyphenol and nontoxic compound stemmed from Curcuma longa L., which has a highly pleiotropic and broad range of targets in cells especially the cell relating to NDs. Moreover, curcumin's structure makes it possible to cross the blood-brain barrier (BBB). 2 There is growing evidence on the beneficial therapeutic properties of curcumin on various aspects of cells associated with NDs especially for their dysfunctional/impaired mitochondria (Table 2). In this section, we discuss the molecular targets of curcumin on mitochondria in NDs.
Various neurotoxic compounds and/or drug are increasingly being recognized as external risk factors linked to the mitochondria-mediated onset of various NDs. For instance, long-term alcohol abuse induces oxidative stress, activates the neuroinflammation pathways, increases the caspase-3, -9, -8, and also changes the Bcl-2/Bax ratio (decreases Bcl-2 and increases Bax proteins). Mitochondria are responsible for regulating the neurotoxicity induced by long-term alcohol abuse; however, these compounds promote the cytochrome c and decrease mitochondria biogenesis. [114][115][116] Curcumin has neuro-and mitochondria-protective effects by reversing the withdrawal effects of the alcohol-induced neurodegeneration and also improves neuronal survival by reducing apoptosis, oxidative stress, neuroinflammation, and perturbation in phospho-CREB-BDNF signaling. Moreover, curcumin improves the alcohol-induced reduction in the SOD, GSH, oxidized GSH, and GSH reductase activity. Curcumin also decreases the levels of TNF-α and IL-1β as well as reduces the Bax and Bax/Bcl-2 ratio. 57 Oxaliplatin, a platinum-based anticancer chemotherapy drug has dose-limiting side effects on the mitochondria by mediating the oxidative stress leading to damage the neurons. 117,118 Combination of curcumin and quercetin has demonstrated neuro-and mitochondrial-protective effects against oxaliplatin side effects by significantly reducing the mitochondrial lipid peroxidation levels, protein carbonyl content, and subsequent oxidative stress. It also improves the altered nonenzymatic and enzymatic antioxidants and ETC complex enzymes of mitochondria. 118 Exposure of tert-butyl hydroperoxide (t-BHP) to neurons leads to ΔΨm loss and cytochrome c release and subsequent activation of caspase-3 and PARP cleavage and cell apoptosis. Curcumin has neuro-and mitochondrial-protective effects by abrogating the ΔΨm loss and cytochrome c release, suppressing the caspase-3 activation and altering the Bcl-2 family expression as well as preventing the cellular GSH and decreasing intracellular ROS generation. In short, curcumin has the potential to attenuate tBHP-induced apoptosis in cortical neurons. 119 Aβ and APP can impair the mitochondria by localizing in the mitochondria membrane, interacting with mitochondrial proteins, disrupting the ETC and following synaptic activity reduction, increasing ROS production, reducing the mitochondrial biogenesis and fusion activity, and leading to mitochondrial and neuronal damage and consequent NDs. 52,120 It has been reported that curcumin can reverse the Aβ-withdrawal (and maybe APP-withdrawal) effects by reducing the mitochondrial dysfunction and its fission machinery, improving mitochondrial fusion activity and maintaining cell viability and mitochondrial dynamics, mitochondrial biogenesis, synaptic activity, and synaptic proteins. 56 Rotenone, an insecticide and pesticide, has the potential to impair the cognitive function, affect the oxidative defense (e.g., by increasing lipid peroxidation and nitrite concentration, and decreasing the activity of SOD, catalase, and reduced GSH level), and also influence the mitochondrial complex (II and III) enzymes activities. 40,[121][122][123][124][125] It is reported that curcumin has the neuro-and mitochondrial-protective against rotenone-withdrawal effects by improving the behavioral alterations and mitochondrial ETC complex enzyme activities, reducing ROS production and oxidative damage, preventing apoptosis as well as restoring the motor deficits and ΔΨm, and enhancing the antioxidant enzymes. 51,123 D-galactose, a reducing sugar, have the potential of inducing oxidative stress resulting in an alteration in mitochondrial F I G U R E 1 Genetic alterations (e.g., mutations) and environmental/external factors as well as their synergistic effects can induce the formation of reactive oxygen species (ROS), reactive nitrogen species (RNS), and other neurotoxic compounds, leading to accumulated/misfolded proteins and subsequent mitochondrial dysfunction. Mitochondrial dysfunction can contribute to neurodegeneration through several mechanisms including interference with cell signaling, redox state, microglial activation, and lipid peroxidation. Curcumin can mitigate the destructive effects of ROS, RNS, and other neurotoxic compounds by several mechanisms that result in blunted neurodegeneration. ETC, electron transport chain; GSH, reduced glutathione; SOD, superoxide dismutase dynamics and apoptosis of neurons. Additionally, D-galactose can impair the activity of the mitochondrial ETC complexes I-III. It also significantly increases the lipid/protein oxidation, diminishes the levels of GSH, and activates the caspase-3. 52,126 Curcumin can markedly reduce the D-galactose effects on CNS cells by restoring the activity of the mitochondrial ETC complexes I-III, decreasing the levels of malondialdehyde, advanced oxidation protein products and protein carbonylation, increasing the GSH and oxidized GSH, and reducing the expression of cleaved caspase-3. 52 Various misfolded and aggregated proteins lead to the onset and progression of NDs. α-synuclein, an expressed neuronal protein, is the main protein affected in a group of neurodegenerative disorders called α-synucleinopathies, which are characterized by the presence of intracellular α-synuclein aggregation. α-synuclein can potentially lead to the onset of dementia in DLB, PD, and PD-related disorders. 127,128 α-synuclein aggregation leads to the induction of the cell death, intracellular ROS production, caspase-3 and -9 activations, mitochondrial depolarization, and cytochrome c release. Curcumin has neuro-and mitochondrial-protective properties against the aggregated-α-synuclein neurotoxicity by reducing the cell death, intracellular ROS, caspase-3 and -9 activations, mitochondrial depolarization, and cytochrome c release. 61 Hydrogen peroxide (H 2 O 2 ) is the major source of oxidative stress and is considered to have a major role in various neurological disorders especially NDs. H 2 O 2 has the potential ability to induce ROS production, apoptosis, caspase-3 and -9 activation, and lipid peroxidation, reduce the mitochondrial depolarization, GSH, and GSH peroxidase, and increase the intracellular and extracellular release of ca 2+ . It was reported that curcumin has the neuro-and mitochondrial-protective ability by reversing the detrimental effects of H 2 O 2 . 129 1-methyl-4-phenylpridinium ions (MPP + ), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin, exerts its neurotoxicity by inhibiting ATP production, stimulating superoxide radical formation, and leading to mitochondria dysfunction and consequent CNS cell death. 130 Curcumin significantly protects CNS cells against MPP +induced apoptosis. It also improves the mitochondrial function by attenuating the ΔΨm dysfunction and intracellular ROS production and expression of Bcl-2. 59 Glutamate is the major excitatory neurotransmitter in the CNS. A mounting number of evidence suggests that perturbations in the systems using the excitatory L-glutamate may underlie the pathogenic mechanisms of a myriad of diseases such as epilepsy and chronic NDs. All neurons in the CNS have the N-methyl-d-aspartate subtype of ionotropic L-glutamate receptors mediating the postsynaptic Ca2 + influx. Excitotoxicity resulting from the activation of NMDA receptors leads to the upregulation of GSH peroxidase 1, GSH disulfide, Ca2 + influx, NO/ROS/H 2 O 2 production, cytochrome c release, Bax/Bcl-2 ratio, caspase-3 activity, lactate dehydrogenase, and malondialdehyde. It also downregulates GSH, GSH reductase, SOD, and catalase, thereby promoting cell apoptosis. 131,132 Curcumin has been shown to effectively protect CNS cells by reversing all the described glutamate-induced oxidative toxicity and excitotoxicity. 132 Neurotoxic compounds such as manganese and aluminum have the capability to enhance the ETC activity of NADH dehydrogenase (complex I), succinic dehydrogenase (complex II), and cytochrome oxidize (Complex IV), increase the malondialdehyde, ROS production, as well as induce mitochondria-related apoptosis such as caspase-3 and -9 activations, cytochrome c release, and Bcl-2/Bax ratio (Bax increase, and Bcl-2 decrease). Curcumin exerts its neuro-and mitochondrial-protective effects on CNS cells especially microglial cells by reversing the effects of manganese-and aluminum-induced cytotoxicity/neurocytotoxicity. 60,133 Nrf2 has a pivotal role in defending the CNS cells against the mitochondrial dysfunction and its neurotoxic compounds, reduced GHS, and imbalanced mitochondrial ROS, which is suppressed in NDs. Curcumin activates Nrf2 and Nrf2 target genes in the CNS cells decreases the level of intracellular ROS and attenuates the oxidative damage and mitochondrial dysfunction. 134 Cerebral ischemia can induce a rapid increase in lipid peroxidation and reduction in ΔΨm, and increase cytochrome c release and caspase-3 activation, thereby resulting in apoptosis. Cerebral ischemia also induces extensive neuronal death together with increasing the astrocytes and microglial cells activation. However, it has been reported that curcumin exerts its neuro-and mitochondrial-protective effects against ischemia-induced neurodegeneration by attenuating ischemia-induced neuronal death and glial activation as well as decreasing the lipid peroxidation, mitochondrial dysfunction, and, thereby, apoptosis. 58

| Curcumin analogs
Despite the myriad therapeutic beneficial effects of curcumin due to its hydrophobic tendency and the presence of an active methylene group and a β-diketone moiety, curcumin has a poor bioavailability/pharmacokinetics and is metabolized easily via aldo-keto reductase in the liver, which hinders its in vivo and clinical trial use in many routes of administration. 2,28 Numerous studies have been looking into mechanisms to circumvent the unstable and poor bioavailability and pharmacokinetic properties of curcumin by designing and characterizing micellized 46 /micronized 47 / hybridized 48 /nano-sized 49 forms of native curcumin as well as its derivatives 50   Modification of curcumin not only enhances its bioavailability status but also amplifies the neuro-and mitochondrialprotective effects of curcumin. For instance, curcumin pyrazole derivatives (e.g., C1-C6 and CNB-001) have significantly more protective properties on mitochondrial dysfunction and it related abnormalities by inhibiting the ΔΨm loss, attenuating intracellular ROS, and enhancing nuclear translocation of Nrf2. 51,62 Curcumin micelles have been shown to have a better bioavailability status by improving solubility in different cells membranes. It has been shown that some micelles considerably improve the curcumin bioavailability up to 40-fold. Moreover, curcumin micelles are more effective in preventing mitochondrial swelling and oxidative stress than native curcumin. 46 Hybridization of compounds to curcumin is another approach to overcome its poor bioavailability and also potentially intensify the neuro-and mitochondrial-protection by another therapeutic compound. It is reported that curcumin and melatonin hybridization (two natural compounds) can potentiate the curcumin bioavailability and its function and can cross the BBB, which could be even more significant and promising in neuroprotective approaches in NDs therapy. 48 Bioconjugates of curcumin such as di-demethylenated piperoyl, di-valinoyl, and di-glutamoyl esters improve neuroprotective effects against nitrosative stress and mitochondrial dysfunction and damage. 50 To compensate for the poor bioavailability of curcumin, curcumin-encapsulated solid lipid nanoparticles (CSLNs) have been shown to significantly increase the activity of mitochondrial ETC complexes and cytochrome levels. Moreover, CSLNs also restore GSH levels and SOD activity. CSLNs markedly reduce the mitochondrial swelling, lipid peroxidation, protein carbonyls, and ROS and also promote the Nrf2 antioxidant pathway. 47 When encapsulated in nano-sized PLGA, curcumin exerts its neuro-and mitochondrial-protective effects through the regulation of NF-κB (p65) and also reduce the caspase-9a expression as well as the apoptosis by ameliorating CSF levels of TNF-α and IL-1β. 49

| The promise of curcumin for NDs therapy
Curcumin has the potential to protect the CNS cells against a myriad of conditions including NDs. It has been shown that curcumin not only protects mitochondrial dysfunction and inhibits neuronal death by targeting wide range of crucial pathways including oxidative stress/ROS/RNS, intrinsic/extrinsic pathway of apoptosis, neuroinflammatory mediators, as well as microglial cells activation and other glial cells, but also attenuates the neuronal loss by many diseases/injuries and neurotoxic compounds. Many conditions such as hypertension, diabetes, atrial fibrillation, ischemic, heart-disease, dyslipidemia, and obesity have the potential to induce stroke especially ischemic stroke, which increases the risk of dementia up to fivefold. 135 It has been shown that curcumin can protect the CNS cell against ischemia-induced mitochondrial dysfunction and the onset of NDs.
Due to curcumin's structural properties, it has poor bioavailability; however, there are an increasing number of studies using nano-/micro-sized and encapsulated form of curcumin to enhance its bioavailability. Developing hybrid medications with curcumin and other natural compounds can potentiate the properties of curcumin even more, which could be assessed in future clinical trials. Hence, the use of curcumin is a promising therapeutic strategy to cope with the growing trend of NDs.

CONFLICT OF INTEREST
The authors declare no potential conflict of interest.