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Therapeutic Potentials of Curcumin in Parkinson’s Disease
C H A P T E R
18 Therapeutic Potentials of Curcumin in Parkinson’s Disease Akhlaq A. Farooqui1 and Tahira Farooqui2 1
Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, United States 2Department of Entomology, The Ohio State University, Columbus, OH, United States
INTRODUCTION Parkinson’s disease (PD) is the second-most common neurodegenerative disease that affects 2% 3% of the population $ 65 years of age. It is characterized by the deficiency of dopamine in striatum and loss of dopaminergic neurons in the substantia nigra leading to abnormal dopaminergic neurotransmission in the basal ganglia motor circuit causing resting tremor, rigidity, bradykinesia, posture, and ambulating difficulty. PD does not manifest clinically until 80% of striatal dopamine is depleted, thus most neuronal damage occurs before the patient presents clinical symptoms. PD is accompanied by the accumulation of intracellular inclusions containing aggregates of α-synuclein, a 140-amino acid protein (mol mass 14 kDa), which is the neuropathological hallmarks of this neurodegenerative disease.1 In addition, studies on postmortem substantia nigral tissue from PD patients not only show increased levels of reduced iron and monoamine oxidase B activity, oxidative stress, neuroinflammation, glutamatergic excitotoxicity, and nitric oxide synthesis but also reduction in the expression of trophic factors, depletion of glutathione (GSH), and alterations in calcium homeostasis.2 It is proposed that iron accumulation in PD, dementia with Parkinson’s disease (PDD), and Lewy body dementia (LBD) may contribute to the oxidative stressinduced apoptosis.3 Furthermore, adenosine triphosphate (ATP) depletion or lipid and protein peroxidation induced by reactive oxygen species (ROS) are also implicated in PD, PDD, LBD, and can kill neurons
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by necrotic processes.4 Despite these finding, the molecular mechanisms contributing to the pathogenesis of PD remain unknown. However, it is proposed that multiple pathways and mechanisms (mitochondrial dysfunction, oxidative stress, apoptosis, axonal transport, calcium homeostasis, and induction of inflammation) either separately or cooperatively induce neurodegeneration in PD.5
EPIDEMIOLOGY AND PATHOGENESIS OF PARKINSON’S DISEASE Epidemiological studies have indicated that approximately 90% of the PD cases have a sporadic origin, which may be caused by unknown environmental factors together with genetic susceptibility. The remaining 10% of PD cases represent familial forms of the disease.6 Out of the six gene mutations responsible for monogenic PD, two are accountable for autosomal dominant PD forms (SNCA and LRRK2) and the remaining four for autosomal recessive PD (PARK2, PINK1, DJ-1, and ATP13A2).7 Sporadic PD cases may be mediated by the environmental and genetic risk factors provoking oxidative stress, excitotoxicity, mitochondrial dysfunction, energy failure, neuroinflammation, misfolding and aggregation of α-synuclein, impairment of protein clearance pathways, cell-autonomous mechanisms, and deficits in proteasomal function or autophagy lysosomal degradation of defective proteins (e.g., α-synuclein).8 10 Epidemiological studies in humans, as well as molecular studies in toxin-induced and genetic animal models of PD, have indicated that mitochondrial dysfunction contributes to the pathogenesis of both sporadic and familial PD. Mitochondrial dynamics (fission, fusion, migration) play an important role not only in neurotransmission but also in synaptic maintenance and neuronal survival. Recent studies have shown that PINK1 and Parkin play crucial roles in the regulation of mitochondrial dynamics and function. Mutations in DJ-1 and Parkin render animals more susceptible to oxidative stress and mitochondrial toxins implicated in sporadic PD, lending support to the hypothesis that some PD cases may be caused by gene environmental factor interactions.8 10 Induction of oxidative stress in dopaminergic neurons of substantia nigra pars compacta is mediated by monoamine oxidase mediated abnormal dopamine metabolism. These enzymes are bound to the outer mitochondrial membrane and catalyze the oxidation of biogenic amine neurotransmitters such as norepinephrine, dopamine, and 5-hydroxytryptamine (serotonin), but they generate free radicals (H2O2) during their action. Induction of excessive oxidative stress causes the oxidative modification of macromolecules (lipids, proteins,
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and DNA) leading to cell damage and even cell death. The pathological effects of ROS also contribute to reduction in ATP production, in an increase of iron levels, and in an increase of intracellular calcium levels along with alterations in mitochondrial respiratory chain complexes function. Apart from dopamine depletion, a profound reduction in specific neurochemical markers such as tyrosine hydrolase (TH), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) has been reported in PD.11,12 The risk of PD is increased by exposure to neurotoxins and pesticides and through oxidative damage to neurons by a decrease in the mitochondrial complex I activity and GSH levels.13 Recently, increased risk for PD has been reported in amphetamine users. It is proposed that like other neurotoxins, amphetamine acts by depleting dopamine to induce PD-like symptoms.14 Furthermore, amphetamine neurotoxicity also involves mitochondrial dysfunction and oxidative stress. Therefore dopamine and related oxidative stress, as well as mitochondrial dysfunction, seem to be common links between PD and amphetamine neurotoxicity.14 In addition to induction of mitochondrial dysfunction and oxidative stress, misfolding of α-synuclein and its aggregation also contributes to the pathogenesis of PD.15,16 α-Synuclein is primarily localized at the presynaptic terminals of neurons.17 Very little is known about the role of α-synuclein in the brain. However, it is suggested that this protein plays an important role in the regulation of synaptic vesicle release and trafficking, maintenance of synaptic vesicle pools, fatty acid binding, neurotransmitter release, synaptic plasticity, and neuronal survival (Fig. 18.1).18 Oxidative stress upregulates the expression of α-synuclein and promotes its fibrillization and aggregation.19 Conversely, a high degree of fibrillization and aggregation of α-synuclein results in an increase of ROS and neurotoxicity.20
FIGURE 18.1
Potential roles of α-synuclein in the brain.
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This vicious cycle between α-synuclein and oxidative stress may contribute to the progression of loss of substantia nigra pars compactal dopaminergic neurons in PD. It is also reported that aggregation of α-synuclein causes α-synuclein to switch from its physiological role to a pathological toxic gain of function. It is well known that under physiological conditions, monomeric α-synuclein improves ATP synthase efficiency. However, aggregation of α-synuclein generates aggregates that localize to the mitochondria in close proximity to several mitochondrial proteins including ATP synthase. Oligomeric α-synuclein not only impairs complex I dependent respiration but also promotes selective oxidation of the ATP synthase β-subunit and induces mitochondrial lipid peroxidation.21,22 These oxidation events increase the probability of permeability transition pore opening, triggering mitochondrial swelling, and ultimately neuronal cell death.21,22 Collective evidence suggests that similar to misfolded β-amyloid protein (Aβ) inclusion in Alzheimer’s disease, in the intracellular spaces of substantia nigra pars compacta, neurons in LBD and PD contain aggregated α-synuclein, which may contribute to neurodegebneration.9,23,24
CURCUMIN AND ITS BIOLOGICAL PROPERTIES Curcumin (C21H20O6) or diferuloylmethane (bis-α,β-unsaturated β-diketone) is a hydrophobic polyphenolic compound (mol mass of 368.38), which is present in the Indian spice turmeric (curry powder). It is derived from the rhizomes of Curcuma longa, which belongs to family Zingiberaceae.25 It has been used for centuries in Chinese traditional medicine and Indian medicine (Ayurvedic medicine) systems as a nociceptive, antiinflammatory, and antishock drug to relieve pain and inflammation in muscles, and for the treatment of many pathological conditions, such as rheumatism, digestive and inflammatory disorders, intermittent fevers, urinary discharges, leukoderma, and amenorrhea as part of traditional medicine.25 The chemical structure of curcumin consists of two methoxyl groups, two phenolic hydroxyl groups, and three double conjugated bonds. The two aryl rings containing ortho-methoxy phenolic OH2 groups are symmetrically linked to a β-diketone moiety. At the equilibrium, the presence of intramolecular hydrogen atoms at the β-diketone chain results in the existence of keto and enol tautomeric conformations of curcumin. Keto enol tautomers of curcumin also exist in several cis and trans forms. The relative concentrations of cis and trans forms vary according to temperature, polarity of solvent, pH, and substitution of the aromatic rings.26,27 Thus a predominant keto form occurs in acidic and neutral solutions and as a stable enol form occurs in alkaline media.
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The antioxidant properties of curcumin are due to the presence of phenol moiety. It is suggested that the donation of H-atom from β-diketone moiety to lipid alkyl or lipid peroxyl radical contributes antioxidant activity. For instances, the donation of H-atom to a linoleic acid (bis-allylic radical) results in resonance stabilized β-oxo-alkyl curcumin radical with unpaired electron density distributed between three carbon and two oxygen atoms. The resonant curcumin radical undergoes molecular reorganization of rapid intramolecular H-shift to generate the phenoxyl radical.28 The α,β-unsaturated β-diketone moiety also has ability to covalently bind with protein thiols through Michael reaction.29 In addition, the β-diketo group of curcumin is capable of chelating transition metals, thereby reducing the metal induced toxicity.29 Curcumin also mediates its antioxidant effects through the modulation of KEAP1-NRF2-ARE system. This endogenous antioxidant system is present in cytoplasm. It is activated by mild-to-moderate levels of stress induced by free radicals (ROS).30 Curcumin interacts with the KEAP1-NRF2-ARE antioxidant system through its electrophilic properties and promotes the dissociation of KEAP1 freeing nuclear factor E2related factor 2 (NRF2), which then migrates to the nucleus, where it binds to antioxidant response elements (ARE).31 The binding of NRF2 with ARE not only induces the expression of antioxidant enzymes but also increases detoxification enzymes production.32 34. Thus treatment of neural cell with curcumin significantly enhances the levels of heme oxygenase-1 (HO-1) in brain cells.35 HO-1 is a ubiquitous and redoxsensitive inducible protein, responsible for the protection of various tissues from cellular stress. Curcumin also interacts with other targets including transcription factors (NF-κB, AP-1, HIF-1α, NRF2, PPAR-γ, STAT3), growth factors (VEGF, EGF, FGF), and their receptors, cytokines (TNF-α, IL-1β, IL-6), enzymes [cyclooxygenase-2 (COX-2), lipoxygenase (LOX), inducible nitric oxide synthase (iNOS), and various kinases], and adhesion molecules (ELAM-1, ICAM-1, VCAM-1) (Figs. 18.2 and 18.3).36 Antiinflammatory effects of curcumin are not only mediated by its ability to inhibit COX-2, LOX, and iNOS but are also due to the inhibition of NF-κB release in the cytoplasm. This inhibition prevents the translocation of NF-κB to the nucleus, where it is known to promote the expression of proinflammatory cytokines (TNFα, IL-1β, and IL-6). In addition, chronic treatment with curcumin (200 and 400 mg/kg) not only results in significant improvement in spatial learning and memory in a dose-dependent manner but also decreases corticosterone levels indicating stress alleviation. In addition, curcumin supplementation improves mitochondrial enzymes (complexes I V) and redox state indicators such as reduced GSH, catalase, superoxide dismutase, malonaldehyde, and nitrite.37
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FIGURE 18.2 Interactions of curcumin with transcription factors.
FIGURE 18.3 Effects of curcumin on enzymic activities in the brain.
Antiapoptotic effects of curcumin are due to restoration of mitochondrial enzyme complex activities and stabilization of mitochondrial function. These processes prevent the release of cytochrome c leading to retardation of apoptotic cell death.36 Despite its effective antioxidant, antiinflammatory, and antiapoptotic properties, curcumin has poor solubility, instability, and extensive metabolism resulting in poor oral bioavailability. Strategies to enhance curcumin delivery include encapsulating or incorporating curcumin in a nanoparticle or microparticle drug delivery system, synthesizing more stable curcumin analogs that
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make them resistant to metabolism while reserving curcumin’s pharmacological properties.36 Collective evidence suggests that curcumin is a safe and nontoxic compound, which exhibits a wide range of pharmacological activities.25,36
NEUROPROTECTIVE EFFECTS OF CURCUMIN IN PARKINSON’S DISEASE In PD, curcumin may produce beneficial effects by inhibiting monoaminoxidase, preventing mitochondrial dysfunction, inhibiting aggregation of α-synuclein, preventing dopamine deficit, and blocking neuroinflammation (Fig. 18.4). Most of this information is obtained from studies on the effects of curcumin in cell culture and animal models of PD.38 Thus several studies have reported that curcumin produces its action by preventing the aggregation of α-synuclein (Fig. 18.5).39 This suggestion is supported by the observation that in the presence of 1 mM Fe31, curcumin produces a dose-dependent inhibition on α-synuclein aggregation and simultaneously enhances α-synuclein solubility.39 Curcumin also provides neuroprotection against α-synuclein-mediated cell death in SH-SY5Y neuroblastoma cells culture system not only by inhibiting mitochondrial toxicity and blocking the formation of ROS40,41 but also by reducing the intracellular overexpression of α-synuclein and ROS generation.41 Furthermore, the activation of caspase-3 can be effectively inhibited and the signs of apoptosis were lessened by curcumin treatment.41 Curcumin also inhibits neuroinflammation in animal
FIGURE 18.4
Neurochemical effects of curcumin in PD. PD, Parkinson’s disease.
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FIGURE 18.5 A hypothetical signal transduction diagram showing the sites of actions of curcumin on signal transduction processes in Parkinson’s disease. ARA, Arachidonic acid; COX, cyclooxygenase; cPLA2, cytosolic phospholipase A2; DA, dopamine; DA-R, dopamine receptor; I-κB, inhibitory subunit of NF-κB; IL-1β, interleukin1β; IL-6, interleukin-6; LOX, lipoxygenase; NF-κB, nuclear factor-κB; NF-κB-RE, nuclear factor-κB-response element; NO, nitric oxide; NOS, nitric oxide synthase; ONOO2, peroxynitrite; PM, plasma membrane; PtdCho, phosphatidylcholine; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α; blocked arrow indicates sites of curcumin action.
models of PD.40 Studies on the effect of chronic and acute curcumin treatment in the Syn-GFP mouse line showing the overexpression of wild-type human α-synuclein protein indicating that curcumin containing diet significantly improves gait impairments and results in an increase in phosphorylated forms of α-synuclein at cortical presynaptic terminals.42 Acute curcumin treatment also results in an increase in phosphorylated α-synuclein in terminals but has no direct effect on α-synuclein aggregation, as measured by in vivo multiphoton imaging and proteinase-K digestion.42 These studies support the view that even at low concentration, dietary curcumin intervention correlates with significant behavioral and molecular changes in a genetic synucleinopathy mouse model that mimics human disease.42 Recently, curcumin derivatives (CNB-001, pyrazole curcumin derivative, and curcumin-bis-α D-glucoside) have been synthesized. These derivatives not only protect dopaminergic neurons against MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) toxicity by regulating various molecular and cellular
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events but also protect against excitotoxicity, glucose-starvation assay,43 and exhibit strong antioxidant and antiapoptotic properties.44 The therapeutic potential of these derivatives is supported by their ability to cross blood brain barrier (BBB), restoration of behavioral impairments, reduction in oxidative stress, restoration of mitochondrial deficits, and enhancement in expressions of TH, DAT, and VMAT2 in animal model of PD.44 47 In 1-methyl-4-phenylpyridinium ion-induced apoptosis in PC12 cells, curcumin also mediates its effect through the modulation of Bcl-2-mitochondria-ROS-iNOS pathway.48 Similarly, in the dopaminergic cell lines MES23.5 and SH-SY5Y, curcumin treatments attenuate the neurotoxicity of 6-OHDA and improve cell viability by inhibiting increases in ROS levels, mitochondrial protection, and reducing p53mediated apoptosis.49,50 It is also reported that curcumin protects against mitochondrial dysfunction and cell death in PINK1 knockdown SH-SY5Y cells.51 Moreover, curcumin had the potential not only to increase life span and locomotor abilities but also to decrease oxidative stress and dopamine neuron degeneration in rotenone-induced and human α-synuclein-expressing Drosophila models of PD.52 There has not been any clinical study to date to provide information on the efficacy of curcumin in PD patients. The information obtained on cell and animal models can be used to demonstrate the efficacy of curcumin for cognitive improvement in PD patients using biomarkers such as α-synuclein, Aβ, and tau proteins along with sensitive behavioral assays. This type of studies can be used for paving road for multicenter, double-blind human trials.
CONCLUSION PD is a progressive neurodegenerative movement disorder characterized by selective loss of dopaminergic neurons, deficiency of dopamine in the striatum, and the presence of Lewy bodies, which are enriched in α-synuclein, a 140-amino acid protein (mol mass 14 kDa) which is the neuropathological hallmark of PD and Lewy bodies dementia. Several studies in humans, as well as molecular studies in toxin-induced and genetic animal models of PD, have shown that mitochondrial dysfunction is the primary defect in the pathogenesis of both sporadic and familial PD. Mitochondrial dynamics (fission, fusion, migration) is important for neurotransmission, synaptic maintenance, and neuronal survival. Among several genes that contribute to the pathogenesis of PD, PINK1 and Parkin play crucial roles in the regulation of mitochondrial dynamics and function. Mutations in DJ-1 and Parkin render animals more susceptible to oxidative stress and mitochondrial toxins
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implicated in sporadic PD, lending support to the hypothesis that some PD cases may be caused by gene environmental factor interactions. Curcumin, a polyphenol, is an easily accessible, inexpensive, and nontoxic bioactive compound. It crosses the BBB and produces neuroprotective effects in brain due to its antioxidant, antiinflammatory, and antiapoptotic properties. Curcumin also promotes neuroprotection not only by chelating Fe21 but also due to its antiamyloidogenic properties in several cell culture and animal models of PD. Curcumin improves motor coordination and cognition in animal models of PD. However, poor water solubility, instability in body fluids, rapid degradation, and limited bioavailability makes its use difficult for treating PD in humans.
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37. Sarker MR, Franks SF. Efficacy of curcumin for age-associated cognitive decline: a narrative review of preclinical and clinical studies. Geroscience 2018;40:73 95. 38. Lee WH, Loo CY, Bebawy M, Luk F, Mason RS, Rohanizadeh R. Curcumin and its derivatives: their application in neuropharmacology and neuroscience in the 21st century. Curr Neuropharmacol 2013;11:338 78. 39. Pandey N, Strider J, Nolan WC, Yan SX, Galvin JE. Curcumin inhibits aggregation of alpha-synuclein. Acta Neuropathol 2008;115:479 89. 40. Liu Z, Yu Y, Li X, Ross CA, Smith WW. Curcumin protects against A53T alphasynuclein-induced toxicity in a PC12 inducible cell model for Parkinsonism. Pharmacol Res 2011;63:439 44. 41. Wang MS, Boddapati S, Emadi S, Sierks MR. Curcumin reduces α-synuclein induced cytotoxicity in Parkinson’s disease cell model. BMC Neurosci 2010;11:57. 42. Spinelli KJ, Osterberg VR, Meshul CK, Soumyanath A, Unni VK. Curcumin treatment improves motor behavior in α-synuclein transgenic mice. PLoS One 2015;10:e0128510. 43. Liu Y, Dargusch R, Maher P, Schubert D. A broadly neuroprotective derivative of curcumin. J Neurochem 2008;105:1336 45. 44. Jayaraj RL, Tamilselvam K, Manivasagam T, Elangovan N. Neuroprotective effect of CNB-001, a novel pyrazole derivative of curcumin on biochemical and apoptotic markers against rotenone-induced SK-N-SH cellular model of Parkinson’s disease. J Mol Neurosci 2013;51:863 70. 45. Gadad BS, Subramanya PK, Pullabhatla S, Shantharam IS, Rao KS. Curcuminglucoside, a novel synthetic derivative of curcumin, inhibits α-synuclein oligomer formation: relevance to Parkinson’s disease. Curr Pharm Des 2012;18:76 84. 46. Jayaraj RL, Elangovan N, Manigandan K, Singh S, Shukla S. CNB-001 a novel curcumin derivative, guards dopamine neurons in MPTP model of Parkinson’s disease. Biomed Res Int 2014;2014:236182. 47. Ahsan N, Mishra S, Jain MK, Surolia A, Gupta S. Curcumin pyrazole and its derivative N-(3-nitrophenylpyrazole) curcumin inhibit aggregation, disrupt fibrils and modulate toxicity of wild type and mutant α-synuclein. Sci Rep 2015;5:9862. 48. Chen J, Tang XQ, Zhi JL, Cui Y, Yu HM, Tang EH, et al. Curcumin protects PC12 cells against 1-methyl-4-phenylpyridinium ion-induced apoptosis by Bcl-2-mitochondriaROS-iNOS pathway. Apoptosis 2006;11:943 53. 49. Wang J, du XX, Jiang H, Xie JX. Curcumin attenuates 6-hydroxydopamine-induced cytotoxicity by anti-oxidation and nuclear factor-kappa B modulation in MES23.5 cells. Biochem Pharmacol 2009;78:178 83. 50. Jaisin Y, Thampithak A, Meesarapee B, et al. Curcumin I protects the dopaminergic cell line SH-SY5Y from 6-hydroxydopamine-induced neurotoxicity through attenuation of p53-mediated apoptosis. Neurosci Lett 2011;489:192 6. 51. van der Merwe C, van Dyk HC, Engelbrecht L, et al. Curcumin rescues a PINK1 knock down SH-SY5Y cellular model of Parkinson’s disease from mitochondrial dysfunction and cell death. Mol Neurobiol 2017;54:2752 62. 52. Siddique YH, Naz F, Jyoti S. Effect of curcumin on lifespan, activity pattern, oxidative stress, and apoptosis in the brains of transgenic Drosophila model of Parkinson’s disease. BioMed Res Int 2014;2014:6.
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18 Therapeutic Potentials of Curcumin in Parkinson’s Disease Akhlaq A. Farooqui1 and Tahira Farooqui2 1
Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, United States 2Department of Entomology, The Ohio State University, Columbus, OH, United States
INTRODUCTION Parkinson’s disease (PD) is the second-most common neurodegenerative disease that affects 2% 3% of the population $ 65 years of age. It is characterized by the deficiency of dopamine in striatum and loss of dopaminergic neurons in the substantia nigra leading to abnormal dopaminergic neurotransmission in the basal ganglia motor circuit causing resting tremor, rigidity, bradykinesia, posture, and ambulating difficulty. PD does not manifest clinically until 80% of striatal dopamine is depleted, thus most neuronal damage occurs before the patient presents clinical symptoms. PD is accompanied by the accumulation of intracellular inclusions containing aggregates of α-synuclein, a 140-amino acid protein (mol mass 14 kDa), which is the neuropathological hallmarks of this neurodegenerative disease.1 In addition, studies on postmortem substantia nigral tissue from PD patients not only show increased levels of reduced iron and monoamine oxidase B activity, oxidative stress, neuroinflammation, glutamatergic excitotoxicity, and nitric oxide synthesis but also reduction in the expression of trophic factors, depletion of glutathione (GSH), and alterations in calcium homeostasis.2 It is proposed that iron accumulation in PD, dementia with Parkinson’s disease (PDD), and Lewy body dementia (LBD) may contribute to the oxidative stressinduced apoptosis.3 Furthermore, adenosine triphosphate (ATP) depletion or lipid and protein peroxidation induced by reactive oxygen species (ROS) are also implicated in PD, PDD, LBD, and can kill neurons
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by necrotic processes.4 Despite these finding, the molecular mechanisms contributing to the pathogenesis of PD remain unknown. However, it is proposed that multiple pathways and mechanisms (mitochondrial dysfunction, oxidative stress, apoptosis, axonal transport, calcium homeostasis, and induction of inflammation) either separately or cooperatively induce neurodegeneration in PD.5
EPIDEMIOLOGY AND PATHOGENESIS OF PARKINSON’S DISEASE Epidemiological studies have indicated that approximately 90% of the PD cases have a sporadic origin, which may be caused by unknown environmental factors together with genetic susceptibility. The remaining 10% of PD cases represent familial forms of the disease.6 Out of the six gene mutations responsible for monogenic PD, two are accountable for autosomal dominant PD forms (SNCA and LRRK2) and the remaining four for autosomal recessive PD (PARK2, PINK1, DJ-1, and ATP13A2).7 Sporadic PD cases may be mediated by the environmental and genetic risk factors provoking oxidative stress, excitotoxicity, mitochondrial dysfunction, energy failure, neuroinflammation, misfolding and aggregation of α-synuclein, impairment of protein clearance pathways, cell-autonomous mechanisms, and deficits in proteasomal function or autophagy lysosomal degradation of defective proteins (e.g., α-synuclein).8 10 Epidemiological studies in humans, as well as molecular studies in toxin-induced and genetic animal models of PD, have indicated that mitochondrial dysfunction contributes to the pathogenesis of both sporadic and familial PD. Mitochondrial dynamics (fission, fusion, migration) play an important role not only in neurotransmission but also in synaptic maintenance and neuronal survival. Recent studies have shown that PINK1 and Parkin play crucial roles in the regulation of mitochondrial dynamics and function. Mutations in DJ-1 and Parkin render animals more susceptible to oxidative stress and mitochondrial toxins implicated in sporadic PD, lending support to the hypothesis that some PD cases may be caused by gene environmental factor interactions.8 10 Induction of oxidative stress in dopaminergic neurons of substantia nigra pars compacta is mediated by monoamine oxidase mediated abnormal dopamine metabolism. These enzymes are bound to the outer mitochondrial membrane and catalyze the oxidation of biogenic amine neurotransmitters such as norepinephrine, dopamine, and 5-hydroxytryptamine (serotonin), but they generate free radicals (H2O2) during their action. Induction of excessive oxidative stress causes the oxidative modification of macromolecules (lipids, proteins,
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and DNA) leading to cell damage and even cell death. The pathological effects of ROS also contribute to reduction in ATP production, in an increase of iron levels, and in an increase of intracellular calcium levels along with alterations in mitochondrial respiratory chain complexes function. Apart from dopamine depletion, a profound reduction in specific neurochemical markers such as tyrosine hydrolase (TH), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) has been reported in PD.11,12 The risk of PD is increased by exposure to neurotoxins and pesticides and through oxidative damage to neurons by a decrease in the mitochondrial complex I activity and GSH levels.13 Recently, increased risk for PD has been reported in amphetamine users. It is proposed that like other neurotoxins, amphetamine acts by depleting dopamine to induce PD-like symptoms.14 Furthermore, amphetamine neurotoxicity also involves mitochondrial dysfunction and oxidative stress. Therefore dopamine and related oxidative stress, as well as mitochondrial dysfunction, seem to be common links between PD and amphetamine neurotoxicity.14 In addition to induction of mitochondrial dysfunction and oxidative stress, misfolding of α-synuclein and its aggregation also contributes to the pathogenesis of PD.15,16 α-Synuclein is primarily localized at the presynaptic terminals of neurons.17 Very little is known about the role of α-synuclein in the brain. However, it is suggested that this protein plays an important role in the regulation of synaptic vesicle release and trafficking, maintenance of synaptic vesicle pools, fatty acid binding, neurotransmitter release, synaptic plasticity, and neuronal survival (Fig. 18.1).18 Oxidative stress upregulates the expression of α-synuclein and promotes its fibrillization and aggregation.19 Conversely, a high degree of fibrillization and aggregation of α-synuclein results in an increase of ROS and neurotoxicity.20
FIGURE 18.1
Potential roles of α-synuclein in the brain.
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This vicious cycle between α-synuclein and oxidative stress may contribute to the progression of loss of substantia nigra pars compactal dopaminergic neurons in PD. It is also reported that aggregation of α-synuclein causes α-synuclein to switch from its physiological role to a pathological toxic gain of function. It is well known that under physiological conditions, monomeric α-synuclein improves ATP synthase efficiency. However, aggregation of α-synuclein generates aggregates that localize to the mitochondria in close proximity to several mitochondrial proteins including ATP synthase. Oligomeric α-synuclein not only impairs complex I dependent respiration but also promotes selective oxidation of the ATP synthase β-subunit and induces mitochondrial lipid peroxidation.21,22 These oxidation events increase the probability of permeability transition pore opening, triggering mitochondrial swelling, and ultimately neuronal cell death.21,22 Collective evidence suggests that similar to misfolded β-amyloid protein (Aβ) inclusion in Alzheimer’s disease, in the intracellular spaces of substantia nigra pars compacta, neurons in LBD and PD contain aggregated α-synuclein, which may contribute to neurodegebneration.9,23,24
CURCUMIN AND ITS BIOLOGICAL PROPERTIES Curcumin (C21H20O6) or diferuloylmethane (bis-α,β-unsaturated β-diketone) is a hydrophobic polyphenolic compound (mol mass of 368.38), which is present in the Indian spice turmeric (curry powder). It is derived from the rhizomes of Curcuma longa, which belongs to family Zingiberaceae.25 It has been used for centuries in Chinese traditional medicine and Indian medicine (Ayurvedic medicine) systems as a nociceptive, antiinflammatory, and antishock drug to relieve pain and inflammation in muscles, and for the treatment of many pathological conditions, such as rheumatism, digestive and inflammatory disorders, intermittent fevers, urinary discharges, leukoderma, and amenorrhea as part of traditional medicine.25 The chemical structure of curcumin consists of two methoxyl groups, two phenolic hydroxyl groups, and three double conjugated bonds. The two aryl rings containing ortho-methoxy phenolic OH2 groups are symmetrically linked to a β-diketone moiety. At the equilibrium, the presence of intramolecular hydrogen atoms at the β-diketone chain results in the existence of keto and enol tautomeric conformations of curcumin. Keto enol tautomers of curcumin also exist in several cis and trans forms. The relative concentrations of cis and trans forms vary according to temperature, polarity of solvent, pH, and substitution of the aromatic rings.26,27 Thus a predominant keto form occurs in acidic and neutral solutions and as a stable enol form occurs in alkaline media.
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The antioxidant properties of curcumin are due to the presence of phenol moiety. It is suggested that the donation of H-atom from β-diketone moiety to lipid alkyl or lipid peroxyl radical contributes antioxidant activity. For instances, the donation of H-atom to a linoleic acid (bis-allylic radical) results in resonance stabilized β-oxo-alkyl curcumin radical with unpaired electron density distributed between three carbon and two oxygen atoms. The resonant curcumin radical undergoes molecular reorganization of rapid intramolecular H-shift to generate the phenoxyl radical.28 The α,β-unsaturated β-diketone moiety also has ability to covalently bind with protein thiols through Michael reaction.29 In addition, the β-diketo group of curcumin is capable of chelating transition metals, thereby reducing the metal induced toxicity.29 Curcumin also mediates its antioxidant effects through the modulation of KEAP1-NRF2-ARE system. This endogenous antioxidant system is present in cytoplasm. It is activated by mild-to-moderate levels of stress induced by free radicals (ROS).30 Curcumin interacts with the KEAP1-NRF2-ARE antioxidant system through its electrophilic properties and promotes the dissociation of KEAP1 freeing nuclear factor E2related factor 2 (NRF2), which then migrates to the nucleus, where it binds to antioxidant response elements (ARE).31 The binding of NRF2 with ARE not only induces the expression of antioxidant enzymes but also increases detoxification enzymes production.32 34. Thus treatment of neural cell with curcumin significantly enhances the levels of heme oxygenase-1 (HO-1) in brain cells.35 HO-1 is a ubiquitous and redoxsensitive inducible protein, responsible for the protection of various tissues from cellular stress. Curcumin also interacts with other targets including transcription factors (NF-κB, AP-1, HIF-1α, NRF2, PPAR-γ, STAT3), growth factors (VEGF, EGF, FGF), and their receptors, cytokines (TNF-α, IL-1β, IL-6), enzymes [cyclooxygenase-2 (COX-2), lipoxygenase (LOX), inducible nitric oxide synthase (iNOS), and various kinases], and adhesion molecules (ELAM-1, ICAM-1, VCAM-1) (Figs. 18.2 and 18.3).36 Antiinflammatory effects of curcumin are not only mediated by its ability to inhibit COX-2, LOX, and iNOS but are also due to the inhibition of NF-κB release in the cytoplasm. This inhibition prevents the translocation of NF-κB to the nucleus, where it is known to promote the expression of proinflammatory cytokines (TNFα, IL-1β, and IL-6). In addition, chronic treatment with curcumin (200 and 400 mg/kg) not only results in significant improvement in spatial learning and memory in a dose-dependent manner but also decreases corticosterone levels indicating stress alleviation. In addition, curcumin supplementation improves mitochondrial enzymes (complexes I V) and redox state indicators such as reduced GSH, catalase, superoxide dismutase, malonaldehyde, and nitrite.37
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FIGURE 18.2 Interactions of curcumin with transcription factors.
FIGURE 18.3 Effects of curcumin on enzymic activities in the brain.
Antiapoptotic effects of curcumin are due to restoration of mitochondrial enzyme complex activities and stabilization of mitochondrial function. These processes prevent the release of cytochrome c leading to retardation of apoptotic cell death.36 Despite its effective antioxidant, antiinflammatory, and antiapoptotic properties, curcumin has poor solubility, instability, and extensive metabolism resulting in poor oral bioavailability. Strategies to enhance curcumin delivery include encapsulating or incorporating curcumin in a nanoparticle or microparticle drug delivery system, synthesizing more stable curcumin analogs that
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make them resistant to metabolism while reserving curcumin’s pharmacological properties.36 Collective evidence suggests that curcumin is a safe and nontoxic compound, which exhibits a wide range of pharmacological activities.25,36
NEUROPROTECTIVE EFFECTS OF CURCUMIN IN PARKINSON’S DISEASE In PD, curcumin may produce beneficial effects by inhibiting monoaminoxidase, preventing mitochondrial dysfunction, inhibiting aggregation of α-synuclein, preventing dopamine deficit, and blocking neuroinflammation (Fig. 18.4). Most of this information is obtained from studies on the effects of curcumin in cell culture and animal models of PD.38 Thus several studies have reported that curcumin produces its action by preventing the aggregation of α-synuclein (Fig. 18.5).39 This suggestion is supported by the observation that in the presence of 1 mM Fe31, curcumin produces a dose-dependent inhibition on α-synuclein aggregation and simultaneously enhances α-synuclein solubility.39 Curcumin also provides neuroprotection against α-synuclein-mediated cell death in SH-SY5Y neuroblastoma cells culture system not only by inhibiting mitochondrial toxicity and blocking the formation of ROS40,41 but also by reducing the intracellular overexpression of α-synuclein and ROS generation.41 Furthermore, the activation of caspase-3 can be effectively inhibited and the signs of apoptosis were lessened by curcumin treatment.41 Curcumin also inhibits neuroinflammation in animal
FIGURE 18.4
Neurochemical effects of curcumin in PD. PD, Parkinson’s disease.
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FIGURE 18.5 A hypothetical signal transduction diagram showing the sites of actions of curcumin on signal transduction processes in Parkinson’s disease. ARA, Arachidonic acid; COX, cyclooxygenase; cPLA2, cytosolic phospholipase A2; DA, dopamine; DA-R, dopamine receptor; I-κB, inhibitory subunit of NF-κB; IL-1β, interleukin1β; IL-6, interleukin-6; LOX, lipoxygenase; NF-κB, nuclear factor-κB; NF-κB-RE, nuclear factor-κB-response element; NO, nitric oxide; NOS, nitric oxide synthase; ONOO2, peroxynitrite; PM, plasma membrane; PtdCho, phosphatidylcholine; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α; blocked arrow indicates sites of curcumin action.
models of PD.40 Studies on the effect of chronic and acute curcumin treatment in the Syn-GFP mouse line showing the overexpression of wild-type human α-synuclein protein indicating that curcumin containing diet significantly improves gait impairments and results in an increase in phosphorylated forms of α-synuclein at cortical presynaptic terminals.42 Acute curcumin treatment also results in an increase in phosphorylated α-synuclein in terminals but has no direct effect on α-synuclein aggregation, as measured by in vivo multiphoton imaging and proteinase-K digestion.42 These studies support the view that even at low concentration, dietary curcumin intervention correlates with significant behavioral and molecular changes in a genetic synucleinopathy mouse model that mimics human disease.42 Recently, curcumin derivatives (CNB-001, pyrazole curcumin derivative, and curcumin-bis-α D-glucoside) have been synthesized. These derivatives not only protect dopaminergic neurons against MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) toxicity by regulating various molecular and cellular
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events but also protect against excitotoxicity, glucose-starvation assay,43 and exhibit strong antioxidant and antiapoptotic properties.44 The therapeutic potential of these derivatives is supported by their ability to cross blood brain barrier (BBB), restoration of behavioral impairments, reduction in oxidative stress, restoration of mitochondrial deficits, and enhancement in expressions of TH, DAT, and VMAT2 in animal model of PD.44 47 In 1-methyl-4-phenylpyridinium ion-induced apoptosis in PC12 cells, curcumin also mediates its effect through the modulation of Bcl-2-mitochondria-ROS-iNOS pathway.48 Similarly, in the dopaminergic cell lines MES23.5 and SH-SY5Y, curcumin treatments attenuate the neurotoxicity of 6-OHDA and improve cell viability by inhibiting increases in ROS levels, mitochondrial protection, and reducing p53mediated apoptosis.49,50 It is also reported that curcumin protects against mitochondrial dysfunction and cell death in PINK1 knockdown SH-SY5Y cells.51 Moreover, curcumin had the potential not only to increase life span and locomotor abilities but also to decrease oxidative stress and dopamine neuron degeneration in rotenone-induced and human α-synuclein-expressing Drosophila models of PD.52 There has not been any clinical study to date to provide information on the efficacy of curcumin in PD patients. The information obtained on cell and animal models can be used to demonstrate the efficacy of curcumin for cognitive improvement in PD patients using biomarkers such as α-synuclein, Aβ, and tau proteins along with sensitive behavioral assays. This type of studies can be used for paving road for multicenter, double-blind human trials.
CONCLUSION PD is a progressive neurodegenerative movement disorder characterized by selective loss of dopaminergic neurons, deficiency of dopamine in the striatum, and the presence of Lewy bodies, which are enriched in α-synuclein, a 140-amino acid protein (mol mass 14 kDa) which is the neuropathological hallmark of PD and Lewy bodies dementia. Several studies in humans, as well as molecular studies in toxin-induced and genetic animal models of PD, have shown that mitochondrial dysfunction is the primary defect in the pathogenesis of both sporadic and familial PD. Mitochondrial dynamics (fission, fusion, migration) is important for neurotransmission, synaptic maintenance, and neuronal survival. Among several genes that contribute to the pathogenesis of PD, PINK1 and Parkin play crucial roles in the regulation of mitochondrial dynamics and function. Mutations in DJ-1 and Parkin render animals more susceptible to oxidative stress and mitochondrial toxins
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implicated in sporadic PD, lending support to the hypothesis that some PD cases may be caused by gene environmental factor interactions. Curcumin, a polyphenol, is an easily accessible, inexpensive, and nontoxic bioactive compound. It crosses the BBB and produces neuroprotective effects in brain due to its antioxidant, antiinflammatory, and antiapoptotic properties. Curcumin also promotes neuroprotection not only by chelating Fe21 but also due to its antiamyloidogenic properties in several cell culture and animal models of PD. Curcumin improves motor coordination and cognition in animal models of PD. However, poor water solubility, instability in body fluids, rapid degradation, and limited bioavailability makes its use difficult for treating PD in humans.
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