- Email: [email protected]
Summary, Perspective, and Direction for Future Research
C H A P T E R
26 Summary, Perspective, and Direction for Future Research Tahira Farooqui1 and Akhlaq A. Farooqui2 1
Department of Entomology, The Ohio State University, Columbus, OH, United States 2Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, United States
INTRODUCTION Neurological disorders are devastating pathological conditions characterized by structural, neurochemical, and electrophysiological abnormalities in the brain, spinal cord, and nerves. These abnormalities lead to neurodegeneration, which is accompanied by paralysis, muscle weakness, poor coordination, seizures, confusion, pain, and loss of memory.1,2 Neurodegeneration in neurological disorders is a complex multifactorial process that causes neuronal death and brain dysfunction. The molecular mechanisms contributing to neurodegeneration in neurological disorders include oxidative stress, axonal transport deficits, protein misfolding and aggregation, calcium deregulation, mitochondrial dysfunction, abnormal neuron glial interactions, and neuroinflammation.1,2 Although oxidative stress and neuroinflammation are instigators of neurological disorders, in reality oxidative stress and neuroinflammation are key features of redox balance (status) of neural cells and immune system functioning to maintain cellular homeostasis, which defends and preserves the integrity of brain tissue and maintains normal cellular function. Distinct biochemical processes contribute to the induction of oxidative stress and neuroinflammation in the brain. These biochemical pathways are closely intertwined (Fig. 26.1). The major sources of oxidative stress (ROS production) in brain include mitochondrial respiratory chain, xanthine/xanthine oxidase, myeloperoxidase, uncontrolled arachidonic acid cascade, and activation of NADPH
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FIGURE 26.1 Enzymic pathways contributing to oxidative stress and neuroinflammation in the brain. ARA, arachidonic acid; COX-2, cyclooxygenase-2; cPLA2, cytosolic phospholipase A2; 4-HNE, 4-hydroxynonenal; IL-1β, interleukin-1beta; IL-6, interleukin-6; iNOS, inducible nitric oxide synthase; LTs, leukotrienes; lyso-PtdCho, lysophosphatidylcholine; MDA, malondialdehyde; MMP, matrix metalloproteinase; NF-κB, nuclear factor-kappa B; NF-κB-RE, nuclear factor-kappa B response element; NMDA-R, N-methyl-D-aspartate receptors; NO, nitric oxide; ONOO2, peroxynitrite; PAF, platelet activating factor; PGs, prostaglandins; PM, Plasma membrane; PtdCho, phosphatidylcholine; ROS, reactive oxygen species; SOD, superoxide dismutase; sPLA2, secretory phospholipase A2; TNF-α, tumor necrosis factor-alpha; TXs, thromboxanes; VCAM-1, vascular cell adhesion molecule-1.
oxidase. Over 90% of ROS generation occurs in mitochondria during metabolism of oxygen when some of electrons passing “down” the electron transport chain leak away from the main path and go directly to reduce oxygen molecules to the superoxide anion.3,4 At high concentration, ROS activates transcription factors NF-κB, which reside in cytoplasm in an inactive form (complexed with IκB). Activation of NF-κB results in the translocation of free NF-κB from cytoplasm to the nucleus, where it interacts with NF-κB response element to facilitate the expression of proinflammatory enzymes [sPLA2, cyclooxygenase-2 (COX-2), iNOS], cytokines (TNF-α, IL-1β, IL-6, IL-12), chemokines (MIP-1α, MCPP1), adhesion molecule leading to neuroinflammation (Fig. 26.1). NO is an important second messenger, which is synthesized by the action of nitric oxide synthases (NOS) on arginine. In brain, NO not only functions as vasorelaxant but also plays important roles in synaptic CURCUMIN FOR NEUROLOGICAL AND PSYCHIATRIC DISORDERS
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plasticity (long-term potentiation and long-term depression) and modulation of N-methyl-D-aspartate receptor.5 NO is thermodynamically unstable molecule that reacts with other molecules, resulting in the oxidation, nitrosylation, or nitration of proteins, with the concomitant effects on many cellular mechanisms. Under pathophysiological conditions, NO reacts with superoxide anions to produce highly reactive peroxynitrite (ONOO2). Like ROS, ONOO2 produces oxidative damage proteins, lipids, and nucleic acids.6,7 At high concentrations, peroxynitrite produces NO-mediated damage to biological molecules through oxidative and nitrosative stress, which ultimately lead to apoptotic cell death (Fig. 26.2).6 The complex interplay between markers of oxidative stress (reactive oxygen and nitrogen species) and inflammatory mediators (PGs, TNF-α, IL-1β, and IL-6) induced by the long-term consumption of unhealthy high-calorie diet results in the progression of chronic neurodegeneration
FIGURE 26.2
Hypothetical diagram showing the effects of curcumin on the accumulation of Aβ and tau phosphorylation in AD. Aβ, β-Amyloid; AD, Alzheimer disease; APP, amyloid precursor protein; ARA, arachidonic acid; Bcl-2, B-cell lymphoma 2; COX-2, cyclooxygenase-2; cPLA2, cytosolic phospholipase A2; cyto-c, cytochrome c; Glu, glutamate; I-κB, inhibitory subunit of NF-κB; IL-1β, interleukin-1β; IL-6, interleukin-6; 5-LOX, 5-lipoxygenase; lyso-PtdCho, lysophosphatidylcholine; MCP-1, monocyte chemoattractant protein-1; NF-κB, nuclear factor-κB; NF-κB-RE, nuclear factor-κB-response element; NMDA-R, NMDA receptor; PtdCho, phosphatidylcholine; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α.
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not only in healthy subjects8 but also in many neurotraumatic and neurodegenerative diseases including stroke, Alzheimer’s disease (AD), and Parkinson’s disease (PD).2,9 Long-term consumption of high-calorie diet, genetic abnormalities, immune system problems, and environmental factors not only produce oxidative stress and neuroinflammation but also result in accumulation of misfolded proteins [amyloid β (Aβ) and tau in AD, α-synuclein in PD, huntingtin (Htt) in Huntington disease (HD), and TAR DNA-binding protein 43 in ALS] and increase in levels of proinflammatory cytokines (TNF-α, IL-1β, and IL-6). These processes may be associated with neurodegeneration in neurological disorders.9 Collective evidence suggests that most neurodegenerative diseases are age-related pathological conditions, which involve a multitude of causative factors, including neuroinflammation, oxidative damage, and deposition of misfolded protein aggregates. These events can occur separately or together or in causing neuronal degeneration, which leads to perturbation of neuronal communications, resulting in long-term cognitive and motor dysfunction.9
Curcumin and Neurotraumatic Diseases In neurotraumatic diseases (stroke, traumatic brain injury, and spinal cord injury), curcumin not only acts by reducing oxidative stress and neuroinflammation but also by reversing the behavioral deficits mediated by metabolic and traumatic injuries. The mechanism associated with the maintenance of behavioral deficits by curcumin is not fully understood. However, curcumin acts not only by modulating hypothalamus pituitary adrenal disturbances but also by promoting and restoring memory deficits in a dose-dependent manner.10,11 In addition, curcumin also modulates levels of norepinephrine, dopamine, and serotonin and enhances neurogenesis, notably in the frontal cortex and hippocampal regions of the brain.12 14 These processes may contribute to the beneficial effects of curcumin in animal models of neurotraumatic diseases. Among neurotraumatic diseases, stroke is a metabolic trauma caused by reduction or block in blood flow due to formation of a clot leading to reversible and irreversible alterations in normal cellular function.15 Age is the major risk factor for stroke. Other risk factors are high blood pressure, atherosclerosis, diabetes, and metabolic syndrome.15,16 Approximately 85% of strokes are ischemic, the remainder 15% being hemorrhagic. Stroke produces changes in brain not only through the breakdown of cellular and subcellular integrity mediated by stimulation of glutamate receptor, and influx of Ca21, but also by alterations in ionic balance and redox status, and free-radical generation.15 These processes involve stimulation of phospholipases A2, calcium/calmodulin-dependent kinases,
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mitogen-activated protein kinases, NOS, calpains, calcineurin, and endonucleases. Stimulation of these enzymes results in neurodegeneration mechanisms.15 In animal model of stroke, a single injection of curcumin 30 minutes after focal cerebral ischemic/reperfusion injury in rats produces beneficial effects not only by decreasing infarct volume, improving neurological deficit, and reducing mortality but also by reducing the water content of the brain in a dose-dependent manner.17 In cultured astrocytes, curcumin significantly inhibits iNOS expression. Curcumin acts not only by decreasing lipid peroxidation, preventing glial cell activation, but also by inhibiting neuroinflammation and retarding apoptotic cell death.17 Curcumin also induces expression of genes encoding phase II drug-metabolizing enzymes such as NAD(P)H:quinone oxidoreductase 1, glutathione S-transferase, aldo keto-reductase, and heme oxygenase-1.18 20 Collectively, these studies suggest that neuroprotective activity of curcumin in cerebral ischemia is mediated through its antioxidant, antiinflammatory, and apoptotic activities.21
Curcumin and Neurodegenerative Diseases At present, there are no effective treatments for AD. Studies using MRI and PET brain scans have revealed that early signs of AD pathology in patients appear B4 17 years before the onset of dementia.22 Epidemiological studies have revealed that in India, where dietary curcumin is consumed daily in the form of curry than in the United States, the morbidity rate attributed to AD for Indian elders (70 79 years old) is 4.4 times lower compared to the same age group of Americans.23,24 The consumption of curry containing food by healthy elderly individuals results in a better cognitive performance than seniors who did not consume curry.25 For these reasons, curcumin and its derivatives have been extensively investigated for their potential for AD prevention over decades in animal model and cell culture systems.26 28
Effects of Curcumin in Animal Models of Alzheimer’s Disease It is well known that elevated levels of redox active Fe31 and Cu21 in AD generate ROS producing DNA damage in neural cell through the generation of hydroxyl and superoxide radicals via Fenton reaction. Curcumin is a powerful scavenger of the superoxide anion and the hydroxyl radical. Curcumin also has ability to bind Cu21 and Fe31 and form tight and inactive complexes and can protect neural cell DNA against ROS and singlet oxygen-induced strand breaks (Fig. 26.2).29 In the scavenging ability of curcumin, position and the number of phenolic OH groups play a role through donation of a hydrogen atom
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from their hydroxyl groups to radicals, resulting in radical moiety elimination and in formation of inactive complexes with divalent metal ions. Curcumin also acts by decreasing levels of mediators associated with the initiation and maintenance of oxidative stress. In neuronal cell cultures, curcumin suppresses Aβ formation by downregulating BACE-1.30,31 Thus at 30 μM curcumin attenuates, the production of Aβ-mediated ROS formation and 20 μM curcumin blocks structural changes in Aβ toward β-sheet-rich secondary structures.30,31 In aged mice model of AD, curcumin not only reduces the amount of plaque deposition in mice cortex and hippocampus but also decreases levels of proinflammatory cytokines32,33 and increases levels of antiinflammatory cytokine (IL-4) in microglial cell cultures from curcumin-treated mice.34 This cytokine is known to reduce the production of TNF-α and MCP-135 and inhibits microglial cell activation and subsequently inflammation caused by Aβ.36 It is also reported that curcumin-mediated sustained expression of IL-4 not only reduces Aβ oligomerization and deposition but also improves neurogenesis by increasing the expression of BDNF,37 supporting the view that curcumin may retard neuroinflammation and neuronal cell death via IL-4 production. Collective evidence suggests that curcumin reduces oxidative damage, inhibits neuroinflammation, and reverses the amyloid pathology in an AD transgenic mouse.33,38 41 Hypothetical model of curcumin action in animal model of AD is presented in Fig. 26.2. Curcumin has been potentially used for retarding or delaying the onset of AD not only in animal models of AD but also in animal models of other neurological disorders including stroke, spinal cord injury, PD, and depression.27,28 In animal models of abovementioned neurological disorders, curcumin acts by downregulating multiple molecular signaling pathways associated with the pathogenesis of neurotraumatic and neurodegenerative diseases. It exerts antioxidant, antiinflammatory, antiamyloidogenic, antiangiogenic, antiproliferative, and antiapoptotic effects in the brain. As stated above, curcumin can pass through BBB and neural cell membranes and induce its intracellular effects. It inhibits COX-2, 5-lipoxygenase, phospholipases, transcription factors (AP-1 and NF-κB), and other enzymes involved in metabolizing the neural membrane phospholipids into prostaglandins, a group of lipid mediators,42,43 which contribute to neuroinflammation (Fig. 26.2). Furthermore, curcumin suppresses the activation of NF-κB leading to downregulation of proinflammatory cytokines expression (TNF-α and IL-1β).29 In PBM and THP-1 cells, curcumin (12.5 25 μM) retards early growth response-1 activation, which increases the expression of cytokines (TNF-α and IL1β) and chemokines (MIP-1β, MCP-1, and IL-8) in monocytes through the interactions with Aβ or fibrillar Aβ, and reduces the expression of proinflammatory cytokines and chemokines,44 supporting the view that curcumin is a natural antiinflammatory agent.
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The effect of curcumin on tau metabolism has also been studied. It is reported that curcumin act on tau metabolism by modulating the phosphorylation of tau at serine 202.45 This reaction is independent of anti-Aβ inhibiting activity. It is also reported that curcumin is a potent inhibitor of GSK3β, with an IC50 value of 66.3 nM. It is proposed that curcumin fits within the binding pocket of GSK3β via interactions with key amino acids.46 As GSK3β is one of the kinases associated with the phosphorylation of tau, the inhibition of GSK3β by curcumin may be one possible mechanism by which curcumin reduces tau phosphorylation. It is also reported that curcumin-mediated inhibition of tau phosphorylated correlates with an improved short-term memory. This has been assessed the Y-maze test, in 3xTg-AD mice.47 In AD and PD, curcumin may not only act by inhibiting ER stress48,49 but also by maintaining ER proteostasis through activating autophagy. This process leads to the suppression of ER stress with subsequent improvement of insulin sensitivity. Collectively, these studies indicate that curcumin fulfills the characteristics for an ideal neuroprotective agent with its low toxicity, affordability, and easy accessibility.
Effects of Curcumin in Animal Models of Parkinson’s Disease PD is characterized by degeneration of dopaminergic neurons in substantia nigra, induction of oxidative stress, and neuroinflammation, accumulation of α-synuclein aggregates, and formation of Lewy body inclusions in specific regions of the brain such as substantia nigra, thalamus, and neocortex.50,51 It is proposed that the accumulation of α-synuclein impairs synaptic dopamine release and promotes the death of nigrostriatal neurons.50,52 Under physiological conditions, α-synuclein interacts with and modulates synaptic vesicle proteins and membranes. However, in PD, the aggregation of α-synuclein is compromised and the correct neuronal functioning is lost not only due to the interference with the regulation of synaptic vesicle release and trafficking, maintenance of synaptic vesicle pools, and fatty acid binding but also due to alterations in neurotransmitter release, synaptic plasticity, and neuronal survival.50,52 To this end, detailed investigations have indicated that high levels of α-synuclein alter the size of synaptic vesicle pools and impair their trafficking. α-Synuclein overexpression can either dysregulate or redistribute proteins of the presynaptic SNARE complex. This leads to deficient tethering, docking, priming, and fusion of synaptic vesicles at the active zone (AZ).53 Moreover, α-synuclein inclusions are found within the presynaptic AZ, accompanied by a decrease in AZ protein levels. Furthermore, α-synuclein overexpression reduces the endocytic retrieval of synaptic vesicle membranes during vesicle recycling. These presynaptic alterations, mediated by accumulation of α-synuclein,
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together impair neurotransmitter exocytosis and neuronal communication.53 Finally, α-synuclein pathology spreads into the brain and can affect the peripheral autonomic and somatic nervous system. Indeed, monomeric, oligomeric, and fibrillary α-synuclein can move from cell to cell and can trigger the aggregation of the endogenous protein in recipient neurons. This novel “prion-like” behavior can further contribute to synaptic failure in PD.52 In animal models of PD, curcumin and curcumin-glucoside analog act not only by inhibiting oxidative stress and neuroinflammation but also by inhibiting α-synuclein aggregation in a dose-dependent manner (Fig. 26.3). Curcumin also enhances the solubility of α-synuclein.54 Detailed investigations have indicated that in animal models, curcumin
FIGURE 26.3 Hypothetical diagram showing the effects of curcumin on the accumulation of α-synuclein in PD. ARA, arachidonic acid; COX, cyclooxygenase; cPLA2, cytosolic phospholipase A2; DA, dopamine; DA-R, dopamine receptor; I-κB, inhibitory subunit of NF-κB; IL-1β, interleukin-1β; IL-6, interleukin-6; Keap1, Kelch-like-ECH-associated protein1; LOX, lipoxygenase; NF-κB, nuclear factor-κB with its subunits (p65 and p50); NF-κB-RE, nuclear factor-κB-response element; Nrf2, nuclear factor (erythroid-derived 2)-like 2; lyso-PtdCho, lysophosphatidylcholine; PAF, platelet activating factor; PD, Parkinson’s disease; PM, plasma membrane; PtdCho, phosphatidylcholine; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α. Blocked arrow indicates sites of curcumin action. Positive sign indicates stimulation.
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acts by preventing the formation of both oligomer and fibril formation of α-synuclein.54,55 Furthermore, curcumin and its analogs also solubilize the oligomeric form of α-synuclein and prevent the onset of PD by disintegrating the α-synuclein fibrils.55 In Drosophila model of PD, curcumin monoglucoside (CMG) not only shows improved bioavailability but also protects against rotenone-induced toxicity in N27 dopaminergic neuronal cells. CMG prevents rotenone-mediated neurotoxicity by exerting antioxidant effects and by replenishing cellular glutathione levels. These processes significantly decrease levels of ROS. CMG pretreatment also restores rotenone-mediated inhibition of mitochondrial complex I and IV. Furthermore, CMG treatment not only retards rotenone-induced nuclear damage but also prevents apoptotic cell death by decreasing the phosphorylation of JNK3 and c-jun, which in turn decreases the cleavage of pro-caspase 3.56
Curcumin in Animal Models of Huntington Disease HD is a fatal progressive neurodegenerative disorder caused by an expansion of CAG tract beyond 35 repeats in exon 1 of the IT15 gene encoding Htt, a large 350 kDa protein which is expressed ubiquitously and normally carries a repeat of B8 25 glutamines in its N-terminal portion.57,58 Htt is present in the nucleus, cell body, dendrites, and nerve terminals of neurons and is also associated with a number of organelles including the Golgi apparatus, endoplasmic reticulum, and mitochondria. Htt forms part of the dynactin complex, colocalizing with microtubules and interacting directly with β-tubulin, which suggests a role in vesicle transport and/or cytoskeletal anchoring. Htt plays an important role in clathrin-mediated endocytosis, neuronal transport, and postsynaptic signaling. Furthermore, Htt can protect neuronal cells from apoptotic stress and therefore may have a prosurvival role.59 Symptoms of HD include midlife onset of involuntary movements; cognitive, physical, and emotional deterioration; personality changes; and dementia leading to premature death. At the genetic level, HD is caused by an expanded CAG repeat encoding a polyglutamine tract in exon 1 of the HD gene, which encodes for Htt. Normal HD alleles have 37 or fewer glutamines in this polymorphic tract, more than 37 of these residues may contribute to the onset of HD.60 Insoluble aggregates containing Htt occur in cytosol and nuclei of HD patients, transgenic animal, and cell culture models of HD. The molecular mechanism involved in aggregate formation is not fully understood. However, it is proposed that interactions of Htt with other proteins may promote its own polymerization to form insoluble aggregates. These Htt aggregates promote neurodegeneration by modulating gene transcription, protein interactions, protein transport inside the nucleus and cytoplasm as well as
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vesicular transport along with proteosomal dysfunction, axonal transport deficit, and excitotoxicity.61 64 In CAG140 KI mice model, dietary supplementation of curcumin for several months ameliorates three aspects of HD with the most notable effect on the Htt aggregates. Curcumin supplementation not only leads to partially behavioral changes but also improves transcriptional deficits observed in HD. It is proposed that behavioral improvements may be related to improvements in the level of the striatal transcripts for the D1 dopaminergic receptor and DARRP-32.65,66
Curcumin and Neuropsychiatric Diseases Neuropsychiatric diseases include depression, schizophrenia, posttraumatic stress disorders, obsessive-compulsive disorders, bipolar disorders, psychotic disorders, and autism. These diseases are associated with the abnormalities in cerebral cortex and limbic system (thalamus, hypothalamus, hippocampus, and amygdale). Recently, the concept of alterations in circuit connections “connectopathy” has been introduced in both neuropsychiatric as well as neurodegenerative diseases.67 70 It is proposed that in neuropsychiatric diseases, curcumin acts as an antidepressant and neuroprotectant.71 The molecular mechanisms of curcumin action involve stimulation of neurotrophic factors expression and suppression of proinflammatory. In addition to abnormalities in genes and signal transduction processes, neuropsychiatric disorders are also linked to gray matter atrophy caused by decreased neuronal and glial size, increased cellular packing density suggesting a disruption in neuronal connectivity, particularly in the dorsolateral prefrontal cortex, and distortions in neuronal orientation.11,72 74 These findings are supported by neuroimaging studies that indicate a number of anatomical and neurochemical abnormalities in neurocircuits in specific brain area of neuropsychiatric patients. In addition, neuropsychiatric diseases are accompanied by changes in several neurotransmitters within a single microcircuit, and each transmitter system shows circuitry changes in more than one region. Changes in microcircuits and neurotransmitters (synthesis and transport) may not only vary on a region-by-region basis but also from one neuropsychiatric disease to another. In animal models of depression, curcumin acts by modulating levels of neurotransmitters such as serotonin and dopamine.11 In major depressive disorders, curcumin acts by preventing hypothalamus pituitary adrenal disturbances, lowering inflammation and protecting against oxidative stress, preventing mitochondrial damage, and retarding intestinal hyperpermeability.11,75 All these processes are compromised in major depressive disorder. With increasing interest in natural treatments for depression,
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efforts are underway to enhance current treatment outcomes. Curcumin presents itself as a promising novel, adjunctive, or stand-alone natural antidepressant.
CONCLUSION Multiple beneficial effects of curcumin in animal models of neurological disorders are linked with its ability to act as a strong antioxidant, antiinflammatory, and antiapoptotic agent. In animal models of AD, curcumin acts by binding to Aβ plaques to inhibit amyloid accumulation and aggregation in the brain. In addition, curcumin also acts not only by downregulating BACE-1 but also by preventing oxidative stress and neuroinflammation. In animal models of PD, curcumin prevents α-synuclein aggregation and attenuating ROS-induced COX-2 expression. These observations demonstrate that curcumin may be potentially effective therapeutic means to treat neurodegenerative diseases. In neuropsychiatric diseases, curcumin produces its beneficial effects by acting as an antidepressant and neuroprotective agent.
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50. Uversky VN, Eliezer D. Biophysics of Parkinson’s disease: structure and aggregation of α-synuclein. Curr Prot Peptide Sci 2009;10:483 99. 51. Lee JY, Seo SH, Kim YK, Yoo HB, Kim YE, Song IC, et al. Extrastriatal dopaminergic changes in Parkinson’s disease patients with impulse control disorders. J Neurol Neurosurg Psychiatry 2014;85:23 30. 52. Longhena F, Faustini G, Missale C, Pizzi M, Spano P, Bellucci A. The contribution of α-synuclein spreading to Parkinson’s disease synaptopathy. Neural Plast 2017;2017:5012129. 53. Bridi JC, Hirth F. Mechanisms of α-synuclein induced synaptopathy in Parkinson’s disease. Front Neurosci 2018;12:80. 54. Pandey N, Strider J, Nolan WC, Yan SX, Galvin JE. Curcumin inhibits aggregation of alpha-synuclein. Acta Neuropathol 2008;115:479 89. 55. Gadad BS, Subramanya PK, Pullabhatla S, Shantharam IS, Rao KS. Curcuminglucoside, a novel synthetic derivative of curcumin inhibits alpha-synuclein oligomer formation relevance to Parkinson’s disease. Curr Pharm Design 2012;18:76 84. 56. Pandareesh MD, Shrivash MK, Naveen Kumar HN, Misra K, Srinivas Bharath MM. Curcumin monoglucoside shows improved bioavailability and mitigates rotenone induced neurotoxicity in cell and Drosophila models of Parkinson’s disease. Neurochem Res 2016;41:3113 28. 57. Cepeda C, Ariano MA, Calvert CR, Flores-Hernandez J, Chandler SH, Leavitt BR, et al. NMDA receptor function in mouse models of Huntington disease. J Neurosci Res 2001;66:525 39. 58. Landles C, Bates GP. Huntingtin and the molecular pathogenesis of Huntington’s disease. Fourth in molecular medicine review series. EMBO Rep 2004;5:958 63. 59. Rigamonti D, Bauer JH, De-Fraja C, Conti L, Sipione S, Sciorati C, et al. Wild-type huntingtin protects from apoptosis upstream of caspase-3. J Neurosci 2000;20:3705 13. 60. Rubinsztein DC, Leggo J, Coles R, Almqvist E, Biancalana V, Cassiman JJ, et al. Phenotypic characterization of individuals with 30 40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36 39 repeats. Am J Hum Genet 1996;59:16 22. 61. Scherzinger E, Lurz R, Turmaine M, Mangiarini L, Hollenbach B, Hasenbank R, et al. Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell 1997;90:549 58. 62. Bonilla E. Huntington disease. A review. Invest Clin 2000;41:117 41. 63. Cowan CM, Raymond LA. Selective neuronal degeneration in Huntington’s disease. Curr Top Dev Biol 2006;75:25 71. 64. Gil JM, Rego AC. Mechanisms of neurodegeneration in Huntington’s disease. Eur J Neurosci 2008;27:2803 20. 65. Hickey MA, Zhu C, Medvedeva V, Lerner RP, Patassini S, Franich NR, et al. Improvement of neuropathology and transcriptional deficits in CAG 140 knock-in mice supports a beneficial effect of dietary curcumin in Huntington’s disease. Mol Neurodegener 2012;7:12. 66. Svenningsson P, Nishi A, Fisone G, Girault JA, Nairn AC, Greengard P. DARPP-32: an integrator of neurotransmission. Annu Rev Pharmacol Toxicol 2004;2004 (44):269 96. 67. Martin G. Network analysis and the connectopathies: current research and future approaches. Nonlinear Dynamics Psychol Life Sci 2012;16:79 90. 68. Castre´n E. Neuronal network plasticity and recovery from depression. JAMA Psychiatry 2013;70:983 9. 69. Di Benedetto B, Rupprecht R, Cze´h B. Talking to the synapse: how antidepressants can target glial cells to reshape brain circuits. Curr Drug Targets 2013;14:1329 35.
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70. Bredt DS, Furey ML, Chen G, Lovenberg T, Drevets WC, Manji HK. Translating depression biomarkers for improved targeted therapies. Neurosci Biobehav Rev 2015;59:1 15. 71. Farioli Vecchioli S, Sacchetti S, Nicolis di Robilant V, Cutuli D. The role of physical exercise and Omega-3 fatty acids in depressive illness in the elderly. Curr Neuropharmacol 2018;16:308 26. 72. Arnold SE, Trojanowski JQ. Human fetal hippocampal development: II. The neuronal cytoskeleton. J Comp Neurol 1996;367:293 307. 73. Blitzer RD, Iyengar R, Landau EM. Postsynaptic signaling networks: cellular cogwheels underlying long-term plasticity. Biol Psychiatry 2005;57:113 19. 74. Tizabi Y, Hurley LL, Qualls Z, Akinfiresoye L. Relevance of the anti-inflammatory properties of curcumin in neurodegenerative diseases and depression. Molecules 2014;19:20864 79. 75. Lopresti AL. Curcumin for neuropsychiatric disorders: a review of in vitro, animal and human studies. J Psychopharmacol 2017;31:287 302.
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26 Summary, Perspective, and Direction for Future Research Tahira Farooqui1 and Akhlaq A. Farooqui2 1
Department of Entomology, The Ohio State University, Columbus, OH, United States 2Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, United States
INTRODUCTION Neurological disorders are devastating pathological conditions characterized by structural, neurochemical, and electrophysiological abnormalities in the brain, spinal cord, and nerves. These abnormalities lead to neurodegeneration, which is accompanied by paralysis, muscle weakness, poor coordination, seizures, confusion, pain, and loss of memory.1,2 Neurodegeneration in neurological disorders is a complex multifactorial process that causes neuronal death and brain dysfunction. The molecular mechanisms contributing to neurodegeneration in neurological disorders include oxidative stress, axonal transport deficits, protein misfolding and aggregation, calcium deregulation, mitochondrial dysfunction, abnormal neuron glial interactions, and neuroinflammation.1,2 Although oxidative stress and neuroinflammation are instigators of neurological disorders, in reality oxidative stress and neuroinflammation are key features of redox balance (status) of neural cells and immune system functioning to maintain cellular homeostasis, which defends and preserves the integrity of brain tissue and maintains normal cellular function. Distinct biochemical processes contribute to the induction of oxidative stress and neuroinflammation in the brain. These biochemical pathways are closely intertwined (Fig. 26.1). The major sources of oxidative stress (ROS production) in brain include mitochondrial respiratory chain, xanthine/xanthine oxidase, myeloperoxidase, uncontrolled arachidonic acid cascade, and activation of NADPH
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FIGURE 26.1 Enzymic pathways contributing to oxidative stress and neuroinflammation in the brain. ARA, arachidonic acid; COX-2, cyclooxygenase-2; cPLA2, cytosolic phospholipase A2; 4-HNE, 4-hydroxynonenal; IL-1β, interleukin-1beta; IL-6, interleukin-6; iNOS, inducible nitric oxide synthase; LTs, leukotrienes; lyso-PtdCho, lysophosphatidylcholine; MDA, malondialdehyde; MMP, matrix metalloproteinase; NF-κB, nuclear factor-kappa B; NF-κB-RE, nuclear factor-kappa B response element; NMDA-R, N-methyl-D-aspartate receptors; NO, nitric oxide; ONOO2, peroxynitrite; PAF, platelet activating factor; PGs, prostaglandins; PM, Plasma membrane; PtdCho, phosphatidylcholine; ROS, reactive oxygen species; SOD, superoxide dismutase; sPLA2, secretory phospholipase A2; TNF-α, tumor necrosis factor-alpha; TXs, thromboxanes; VCAM-1, vascular cell adhesion molecule-1.
oxidase. Over 90% of ROS generation occurs in mitochondria during metabolism of oxygen when some of electrons passing “down” the electron transport chain leak away from the main path and go directly to reduce oxygen molecules to the superoxide anion.3,4 At high concentration, ROS activates transcription factors NF-κB, which reside in cytoplasm in an inactive form (complexed with IκB). Activation of NF-κB results in the translocation of free NF-κB from cytoplasm to the nucleus, where it interacts with NF-κB response element to facilitate the expression of proinflammatory enzymes [sPLA2, cyclooxygenase-2 (COX-2), iNOS], cytokines (TNF-α, IL-1β, IL-6, IL-12), chemokines (MIP-1α, MCPP1), adhesion molecule leading to neuroinflammation (Fig. 26.1). NO is an important second messenger, which is synthesized by the action of nitric oxide synthases (NOS) on arginine. In brain, NO not only functions as vasorelaxant but also plays important roles in synaptic CURCUMIN FOR NEUROLOGICAL AND PSYCHIATRIC DISORDERS
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plasticity (long-term potentiation and long-term depression) and modulation of N-methyl-D-aspartate receptor.5 NO is thermodynamically unstable molecule that reacts with other molecules, resulting in the oxidation, nitrosylation, or nitration of proteins, with the concomitant effects on many cellular mechanisms. Under pathophysiological conditions, NO reacts with superoxide anions to produce highly reactive peroxynitrite (ONOO2). Like ROS, ONOO2 produces oxidative damage proteins, lipids, and nucleic acids.6,7 At high concentrations, peroxynitrite produces NO-mediated damage to biological molecules through oxidative and nitrosative stress, which ultimately lead to apoptotic cell death (Fig. 26.2).6 The complex interplay between markers of oxidative stress (reactive oxygen and nitrogen species) and inflammatory mediators (PGs, TNF-α, IL-1β, and IL-6) induced by the long-term consumption of unhealthy high-calorie diet results in the progression of chronic neurodegeneration
FIGURE 26.2
Hypothetical diagram showing the effects of curcumin on the accumulation of Aβ and tau phosphorylation in AD. Aβ, β-Amyloid; AD, Alzheimer disease; APP, amyloid precursor protein; ARA, arachidonic acid; Bcl-2, B-cell lymphoma 2; COX-2, cyclooxygenase-2; cPLA2, cytosolic phospholipase A2; cyto-c, cytochrome c; Glu, glutamate; I-κB, inhibitory subunit of NF-κB; IL-1β, interleukin-1β; IL-6, interleukin-6; 5-LOX, 5-lipoxygenase; lyso-PtdCho, lysophosphatidylcholine; MCP-1, monocyte chemoattractant protein-1; NF-κB, nuclear factor-κB; NF-κB-RE, nuclear factor-κB-response element; NMDA-R, NMDA receptor; PtdCho, phosphatidylcholine; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α.
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not only in healthy subjects8 but also in many neurotraumatic and neurodegenerative diseases including stroke, Alzheimer’s disease (AD), and Parkinson’s disease (PD).2,9 Long-term consumption of high-calorie diet, genetic abnormalities, immune system problems, and environmental factors not only produce oxidative stress and neuroinflammation but also result in accumulation of misfolded proteins [amyloid β (Aβ) and tau in AD, α-synuclein in PD, huntingtin (Htt) in Huntington disease (HD), and TAR DNA-binding protein 43 in ALS] and increase in levels of proinflammatory cytokines (TNF-α, IL-1β, and IL-6). These processes may be associated with neurodegeneration in neurological disorders.9 Collective evidence suggests that most neurodegenerative diseases are age-related pathological conditions, which involve a multitude of causative factors, including neuroinflammation, oxidative damage, and deposition of misfolded protein aggregates. These events can occur separately or together or in causing neuronal degeneration, which leads to perturbation of neuronal communications, resulting in long-term cognitive and motor dysfunction.9
Curcumin and Neurotraumatic Diseases In neurotraumatic diseases (stroke, traumatic brain injury, and spinal cord injury), curcumin not only acts by reducing oxidative stress and neuroinflammation but also by reversing the behavioral deficits mediated by metabolic and traumatic injuries. The mechanism associated with the maintenance of behavioral deficits by curcumin is not fully understood. However, curcumin acts not only by modulating hypothalamus pituitary adrenal disturbances but also by promoting and restoring memory deficits in a dose-dependent manner.10,11 In addition, curcumin also modulates levels of norepinephrine, dopamine, and serotonin and enhances neurogenesis, notably in the frontal cortex and hippocampal regions of the brain.12 14 These processes may contribute to the beneficial effects of curcumin in animal models of neurotraumatic diseases. Among neurotraumatic diseases, stroke is a metabolic trauma caused by reduction or block in blood flow due to formation of a clot leading to reversible and irreversible alterations in normal cellular function.15 Age is the major risk factor for stroke. Other risk factors are high blood pressure, atherosclerosis, diabetes, and metabolic syndrome.15,16 Approximately 85% of strokes are ischemic, the remainder 15% being hemorrhagic. Stroke produces changes in brain not only through the breakdown of cellular and subcellular integrity mediated by stimulation of glutamate receptor, and influx of Ca21, but also by alterations in ionic balance and redox status, and free-radical generation.15 These processes involve stimulation of phospholipases A2, calcium/calmodulin-dependent kinases,
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mitogen-activated protein kinases, NOS, calpains, calcineurin, and endonucleases. Stimulation of these enzymes results in neurodegeneration mechanisms.15 In animal model of stroke, a single injection of curcumin 30 minutes after focal cerebral ischemic/reperfusion injury in rats produces beneficial effects not only by decreasing infarct volume, improving neurological deficit, and reducing mortality but also by reducing the water content of the brain in a dose-dependent manner.17 In cultured astrocytes, curcumin significantly inhibits iNOS expression. Curcumin acts not only by decreasing lipid peroxidation, preventing glial cell activation, but also by inhibiting neuroinflammation and retarding apoptotic cell death.17 Curcumin also induces expression of genes encoding phase II drug-metabolizing enzymes such as NAD(P)H:quinone oxidoreductase 1, glutathione S-transferase, aldo keto-reductase, and heme oxygenase-1.18 20 Collectively, these studies suggest that neuroprotective activity of curcumin in cerebral ischemia is mediated through its antioxidant, antiinflammatory, and apoptotic activities.21
Curcumin and Neurodegenerative Diseases At present, there are no effective treatments for AD. Studies using MRI and PET brain scans have revealed that early signs of AD pathology in patients appear B4 17 years before the onset of dementia.22 Epidemiological studies have revealed that in India, where dietary curcumin is consumed daily in the form of curry than in the United States, the morbidity rate attributed to AD for Indian elders (70 79 years old) is 4.4 times lower compared to the same age group of Americans.23,24 The consumption of curry containing food by healthy elderly individuals results in a better cognitive performance than seniors who did not consume curry.25 For these reasons, curcumin and its derivatives have been extensively investigated for their potential for AD prevention over decades in animal model and cell culture systems.26 28
Effects of Curcumin in Animal Models of Alzheimer’s Disease It is well known that elevated levels of redox active Fe31 and Cu21 in AD generate ROS producing DNA damage in neural cell through the generation of hydroxyl and superoxide radicals via Fenton reaction. Curcumin is a powerful scavenger of the superoxide anion and the hydroxyl radical. Curcumin also has ability to bind Cu21 and Fe31 and form tight and inactive complexes and can protect neural cell DNA against ROS and singlet oxygen-induced strand breaks (Fig. 26.2).29 In the scavenging ability of curcumin, position and the number of phenolic OH groups play a role through donation of a hydrogen atom
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from their hydroxyl groups to radicals, resulting in radical moiety elimination and in formation of inactive complexes with divalent metal ions. Curcumin also acts by decreasing levels of mediators associated with the initiation and maintenance of oxidative stress. In neuronal cell cultures, curcumin suppresses Aβ formation by downregulating BACE-1.30,31 Thus at 30 μM curcumin attenuates, the production of Aβ-mediated ROS formation and 20 μM curcumin blocks structural changes in Aβ toward β-sheet-rich secondary structures.30,31 In aged mice model of AD, curcumin not only reduces the amount of plaque deposition in mice cortex and hippocampus but also decreases levels of proinflammatory cytokines32,33 and increases levels of antiinflammatory cytokine (IL-4) in microglial cell cultures from curcumin-treated mice.34 This cytokine is known to reduce the production of TNF-α and MCP-135 and inhibits microglial cell activation and subsequently inflammation caused by Aβ.36 It is also reported that curcumin-mediated sustained expression of IL-4 not only reduces Aβ oligomerization and deposition but also improves neurogenesis by increasing the expression of BDNF,37 supporting the view that curcumin may retard neuroinflammation and neuronal cell death via IL-4 production. Collective evidence suggests that curcumin reduces oxidative damage, inhibits neuroinflammation, and reverses the amyloid pathology in an AD transgenic mouse.33,38 41 Hypothetical model of curcumin action in animal model of AD is presented in Fig. 26.2. Curcumin has been potentially used for retarding or delaying the onset of AD not only in animal models of AD but also in animal models of other neurological disorders including stroke, spinal cord injury, PD, and depression.27,28 In animal models of abovementioned neurological disorders, curcumin acts by downregulating multiple molecular signaling pathways associated with the pathogenesis of neurotraumatic and neurodegenerative diseases. It exerts antioxidant, antiinflammatory, antiamyloidogenic, antiangiogenic, antiproliferative, and antiapoptotic effects in the brain. As stated above, curcumin can pass through BBB and neural cell membranes and induce its intracellular effects. It inhibits COX-2, 5-lipoxygenase, phospholipases, transcription factors (AP-1 and NF-κB), and other enzymes involved in metabolizing the neural membrane phospholipids into prostaglandins, a group of lipid mediators,42,43 which contribute to neuroinflammation (Fig. 26.2). Furthermore, curcumin suppresses the activation of NF-κB leading to downregulation of proinflammatory cytokines expression (TNF-α and IL-1β).29 In PBM and THP-1 cells, curcumin (12.5 25 μM) retards early growth response-1 activation, which increases the expression of cytokines (TNF-α and IL1β) and chemokines (MIP-1β, MCP-1, and IL-8) in monocytes through the interactions with Aβ or fibrillar Aβ, and reduces the expression of proinflammatory cytokines and chemokines,44 supporting the view that curcumin is a natural antiinflammatory agent.
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The effect of curcumin on tau metabolism has also been studied. It is reported that curcumin act on tau metabolism by modulating the phosphorylation of tau at serine 202.45 This reaction is independent of anti-Aβ inhibiting activity. It is also reported that curcumin is a potent inhibitor of GSK3β, with an IC50 value of 66.3 nM. It is proposed that curcumin fits within the binding pocket of GSK3β via interactions with key amino acids.46 As GSK3β is one of the kinases associated with the phosphorylation of tau, the inhibition of GSK3β by curcumin may be one possible mechanism by which curcumin reduces tau phosphorylation. It is also reported that curcumin-mediated inhibition of tau phosphorylated correlates with an improved short-term memory. This has been assessed the Y-maze test, in 3xTg-AD mice.47 In AD and PD, curcumin may not only act by inhibiting ER stress48,49 but also by maintaining ER proteostasis through activating autophagy. This process leads to the suppression of ER stress with subsequent improvement of insulin sensitivity. Collectively, these studies indicate that curcumin fulfills the characteristics for an ideal neuroprotective agent with its low toxicity, affordability, and easy accessibility.
Effects of Curcumin in Animal Models of Parkinson’s Disease PD is characterized by degeneration of dopaminergic neurons in substantia nigra, induction of oxidative stress, and neuroinflammation, accumulation of α-synuclein aggregates, and formation of Lewy body inclusions in specific regions of the brain such as substantia nigra, thalamus, and neocortex.50,51 It is proposed that the accumulation of α-synuclein impairs synaptic dopamine release and promotes the death of nigrostriatal neurons.50,52 Under physiological conditions, α-synuclein interacts with and modulates synaptic vesicle proteins and membranes. However, in PD, the aggregation of α-synuclein is compromised and the correct neuronal functioning is lost not only due to the interference with the regulation of synaptic vesicle release and trafficking, maintenance of synaptic vesicle pools, and fatty acid binding but also due to alterations in neurotransmitter release, synaptic plasticity, and neuronal survival.50,52 To this end, detailed investigations have indicated that high levels of α-synuclein alter the size of synaptic vesicle pools and impair their trafficking. α-Synuclein overexpression can either dysregulate or redistribute proteins of the presynaptic SNARE complex. This leads to deficient tethering, docking, priming, and fusion of synaptic vesicles at the active zone (AZ).53 Moreover, α-synuclein inclusions are found within the presynaptic AZ, accompanied by a decrease in AZ protein levels. Furthermore, α-synuclein overexpression reduces the endocytic retrieval of synaptic vesicle membranes during vesicle recycling. These presynaptic alterations, mediated by accumulation of α-synuclein,
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together impair neurotransmitter exocytosis and neuronal communication.53 Finally, α-synuclein pathology spreads into the brain and can affect the peripheral autonomic and somatic nervous system. Indeed, monomeric, oligomeric, and fibrillary α-synuclein can move from cell to cell and can trigger the aggregation of the endogenous protein in recipient neurons. This novel “prion-like” behavior can further contribute to synaptic failure in PD.52 In animal models of PD, curcumin and curcumin-glucoside analog act not only by inhibiting oxidative stress and neuroinflammation but also by inhibiting α-synuclein aggregation in a dose-dependent manner (Fig. 26.3). Curcumin also enhances the solubility of α-synuclein.54 Detailed investigations have indicated that in animal models, curcumin
FIGURE 26.3 Hypothetical diagram showing the effects of curcumin on the accumulation of α-synuclein in PD. ARA, arachidonic acid; COX, cyclooxygenase; cPLA2, cytosolic phospholipase A2; DA, dopamine; DA-R, dopamine receptor; I-κB, inhibitory subunit of NF-κB; IL-1β, interleukin-1β; IL-6, interleukin-6; Keap1, Kelch-like-ECH-associated protein1; LOX, lipoxygenase; NF-κB, nuclear factor-κB with its subunits (p65 and p50); NF-κB-RE, nuclear factor-κB-response element; Nrf2, nuclear factor (erythroid-derived 2)-like 2; lyso-PtdCho, lysophosphatidylcholine; PAF, platelet activating factor; PD, Parkinson’s disease; PM, plasma membrane; PtdCho, phosphatidylcholine; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α. Blocked arrow indicates sites of curcumin action. Positive sign indicates stimulation.
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acts by preventing the formation of both oligomer and fibril formation of α-synuclein.54,55 Furthermore, curcumin and its analogs also solubilize the oligomeric form of α-synuclein and prevent the onset of PD by disintegrating the α-synuclein fibrils.55 In Drosophila model of PD, curcumin monoglucoside (CMG) not only shows improved bioavailability but also protects against rotenone-induced toxicity in N27 dopaminergic neuronal cells. CMG prevents rotenone-mediated neurotoxicity by exerting antioxidant effects and by replenishing cellular glutathione levels. These processes significantly decrease levels of ROS. CMG pretreatment also restores rotenone-mediated inhibition of mitochondrial complex I and IV. Furthermore, CMG treatment not only retards rotenone-induced nuclear damage but also prevents apoptotic cell death by decreasing the phosphorylation of JNK3 and c-jun, which in turn decreases the cleavage of pro-caspase 3.56
Curcumin in Animal Models of Huntington Disease HD is a fatal progressive neurodegenerative disorder caused by an expansion of CAG tract beyond 35 repeats in exon 1 of the IT15 gene encoding Htt, a large 350 kDa protein which is expressed ubiquitously and normally carries a repeat of B8 25 glutamines in its N-terminal portion.57,58 Htt is present in the nucleus, cell body, dendrites, and nerve terminals of neurons and is also associated with a number of organelles including the Golgi apparatus, endoplasmic reticulum, and mitochondria. Htt forms part of the dynactin complex, colocalizing with microtubules and interacting directly with β-tubulin, which suggests a role in vesicle transport and/or cytoskeletal anchoring. Htt plays an important role in clathrin-mediated endocytosis, neuronal transport, and postsynaptic signaling. Furthermore, Htt can protect neuronal cells from apoptotic stress and therefore may have a prosurvival role.59 Symptoms of HD include midlife onset of involuntary movements; cognitive, physical, and emotional deterioration; personality changes; and dementia leading to premature death. At the genetic level, HD is caused by an expanded CAG repeat encoding a polyglutamine tract in exon 1 of the HD gene, which encodes for Htt. Normal HD alleles have 37 or fewer glutamines in this polymorphic tract, more than 37 of these residues may contribute to the onset of HD.60 Insoluble aggregates containing Htt occur in cytosol and nuclei of HD patients, transgenic animal, and cell culture models of HD. The molecular mechanism involved in aggregate formation is not fully understood. However, it is proposed that interactions of Htt with other proteins may promote its own polymerization to form insoluble aggregates. These Htt aggregates promote neurodegeneration by modulating gene transcription, protein interactions, protein transport inside the nucleus and cytoplasm as well as
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vesicular transport along with proteosomal dysfunction, axonal transport deficit, and excitotoxicity.61 64 In CAG140 KI mice model, dietary supplementation of curcumin for several months ameliorates three aspects of HD with the most notable effect on the Htt aggregates. Curcumin supplementation not only leads to partially behavioral changes but also improves transcriptional deficits observed in HD. It is proposed that behavioral improvements may be related to improvements in the level of the striatal transcripts for the D1 dopaminergic receptor and DARRP-32.65,66
Curcumin and Neuropsychiatric Diseases Neuropsychiatric diseases include depression, schizophrenia, posttraumatic stress disorders, obsessive-compulsive disorders, bipolar disorders, psychotic disorders, and autism. These diseases are associated with the abnormalities in cerebral cortex and limbic system (thalamus, hypothalamus, hippocampus, and amygdale). Recently, the concept of alterations in circuit connections “connectopathy” has been introduced in both neuropsychiatric as well as neurodegenerative diseases.67 70 It is proposed that in neuropsychiatric diseases, curcumin acts as an antidepressant and neuroprotectant.71 The molecular mechanisms of curcumin action involve stimulation of neurotrophic factors expression and suppression of proinflammatory. In addition to abnormalities in genes and signal transduction processes, neuropsychiatric disorders are also linked to gray matter atrophy caused by decreased neuronal and glial size, increased cellular packing density suggesting a disruption in neuronal connectivity, particularly in the dorsolateral prefrontal cortex, and distortions in neuronal orientation.11,72 74 These findings are supported by neuroimaging studies that indicate a number of anatomical and neurochemical abnormalities in neurocircuits in specific brain area of neuropsychiatric patients. In addition, neuropsychiatric diseases are accompanied by changes in several neurotransmitters within a single microcircuit, and each transmitter system shows circuitry changes in more than one region. Changes in microcircuits and neurotransmitters (synthesis and transport) may not only vary on a region-by-region basis but also from one neuropsychiatric disease to another. In animal models of depression, curcumin acts by modulating levels of neurotransmitters such as serotonin and dopamine.11 In major depressive disorders, curcumin acts by preventing hypothalamus pituitary adrenal disturbances, lowering inflammation and protecting against oxidative stress, preventing mitochondrial damage, and retarding intestinal hyperpermeability.11,75 All these processes are compromised in major depressive disorder. With increasing interest in natural treatments for depression,
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efforts are underway to enhance current treatment outcomes. Curcumin presents itself as a promising novel, adjunctive, or stand-alone natural antidepressant.
CONCLUSION Multiple beneficial effects of curcumin in animal models of neurological disorders are linked with its ability to act as a strong antioxidant, antiinflammatory, and antiapoptotic agent. In animal models of AD, curcumin acts by binding to Aβ plaques to inhibit amyloid accumulation and aggregation in the brain. In addition, curcumin also acts not only by downregulating BACE-1 but also by preventing oxidative stress and neuroinflammation. In animal models of PD, curcumin prevents α-synuclein aggregation and attenuating ROS-induced COX-2 expression. These observations demonstrate that curcumin may be potentially effective therapeutic means to treat neurodegenerative diseases. In neuropsychiatric diseases, curcumin produces its beneficial effects by acting as an antidepressant and neuroprotective agent.
References 1. Kovacs GG. Molecular pathological classification of neurodegenerative diseases: turning towards precision medicine. Int J Mol Sci 2016;17:pii: E189. 2. Farooqui AA. Ischemic, traumatic brain, and spinal cord injuries: mechanisms and potential therapies. San Diego, CA: Academic Press; 2018. an imprint of Elsevier. 3. Sun GY, Horrocks LA, Farooqui AA. The role of NADPH oxidase and phospholipases A2 in mediating oxidative and inflammatory responses in neurodegenerative diseases. J Neurochem 2007;103:1 16. 4. Pieczenik SR, Neustadt J. Mitochondrial dysfunction and molecular pathways of disease. Exper Mol Pathol 2007;83:84 92. 5. Prast H, Philippu A. Nitric oxide as modulator of neuronal function. Prog Neurobiol 2001;64:51 68. 6. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev 2007;87:315 424. 7. Radi R. Peroxynitrite and reactive nitrogen species: the contribution of ABB in two decades of research. Arch Biochem Biophys 2009;484:111 13. 8. Francis HM, Stevenson RJ. Higher reported saturated fat and refined sugar intake is associated with reduced hippocampal-dependent memory and sensitivity to interoceptive signals. Behav Neurosci 2011;125:943 55. 9. Farooqui AA. Inflammation and oxidative stress in neurological disorders: effect of lifestyle, genes, and age. Springer, International Publishing Switzerland; 2014. 10. Bergman J, Miodownik C, Bersudsky Y, Sokolik S, Lerner PP, et al. Curcumin as an add-on to antidepressive treatment: a randomized, double-blind, placebo-controlled, pilot clinical study. Clin Neuropharmacol 2013;36:73 7. 11. Lopresti AL, Hood SD, Drummond PD. Multiple antidepressant potential modes of action of curcumin: a review of its anti-inflammatory, monoaminergic, antioxidant, immune-modulating and neuroprotective effects. J Psychopharmacol 2012;26:1512 24.
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