Curcumin: Historical Background, Chemistry, Pharmacological Action, and Potential Therapeutic Value

C H A P T E R

2 Curcumin: Historical Background, Chemistry, Pharmacological Action, and Potential Therapeutic Value 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 Curcumin [diferuloylmethane (DFM)] is present in 31 species of curcuma plants, including Curcuma longa, L. (Zingiberaceae), the rhizomes of which provide the spice turmeric.1 Curcumin, an orange-yellow component of turmeric, is a hydrophobic polyphenol, which has been the subject of numerous studies over the past decades for the identification and characterization of its pharmacokinetic, pharmacodynamic, and clinical pharmacological properties. Because of polyphenolic nature, curcumin modulates multiple signaling pathways and exerts a wide spectrum of pharmacological activities, such as antiinflammatory,2 antioxidant,3,4 immunomodulatory,5
7 anticarcinogenic,8
10 antitumor,11 antidiabetic,12,13 antibacterial,14,15 and neuroprotective16
21 activities. Curcumin has long been used in traditional Indian and Chinese medicines to treat a variety of diseases, including jaundice and hepatic disorders, ulcers, fever, trauma-rheumatism, anorexia, and diabetic wounds as well as skin diseases such as psoriasis.22 However, the clinical applications of curcumin are limited owing to its poor aqueous solubility due to its hydrophobic nature resulting in poor absorption; rapid

Curcumin for Neurological and Psychiatric Disorders DOI: https://doi.org/10.1016/B978-0-12-815461-8.00002-5

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metabolism, rapid systemic elimination due to glucuronidation/sulfation reactions; and issue regarding the pharmacokinetic parameters exists because of the low levels of curcumin in plasma and tissue. Many approaches have been undertaken to overcome the limitation of the poor bioavailability of curcumin by (1) the use of piperine, a known inhibitor hepatic and intestinal glucuronidation, (2) the use of liposomal curcumin, (3) curcumin-loaded nanoparticles, (4) the use of curcumin
phospholipid complex (curcumin-phytosome), and (5) the use of structural analogues of curcumin. In contrast to commercially available drugs, curcumin is believed to be devoid of any major side effects. In human clinical trials, no dose-limiting toxicity (no increase in adverse effects over placebo) has been reported when administered at doses up to 12 g/day, implicating extreme safety of curcumin.9,23,24 Due to the empirical beneficial health effect of turmeric, the consumption of curcumin as a dietary supplement has markedly increased worldwide. Now curcumin has been “generally recognized as safe” by Food and Drug Administration of the United States. In this review, we at first briefly revisit the historical aspects of curcumin as well as its pharmacological principles, update the current understanding of curcumin’s molecular mechanism, and then shed a light on its therapeutic potential to be relevant for treating various chronic conditions, such as neurological and psychological disorders.

HISTORICAL BACKGROUND As stated above, turmeric (powder of dried rhizome of C. longa Linn) is the ingredient that gives curry powder its characteristic yellow color, which is used extensively in foods for both its flavor and color.25 Turmeric contains bioactive compounds with powerful medicinal properties; therefore it has been used for centuries as far back as 5000 years ago in Indian Traditional Medicine (Ayurveda) and Traditional Chinese Medicine.26 Even today, its regular use in Asian food as a spice is continued. Turmeric was introduced as a coloring agent for food and fabric, which dates as far back as 600 BC. It probably reached China by AD 700, East Africa by AD 800, West Africa by AD 1200, and Jamaica in the 18th century. In 1280 Marco Polo has described turmeric in his notes during his travel in China “a vegetable that has all the properties of true saffron, as well as the smell and the color, yet it is not really saffron.” According to Susruta’s Ayurvedic Compendium, turmeric’s use dates back to 250 BC, where it was added in an ointment to relieve the effects of poisoned food. In Southeast Asia, turmeric has been used as a principal spice,

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as well as a component in religious ceremonies. Indonesians have used turmeric to dye their bodies as part of their wedding ritual. Because of its brilliant yellow color, turmeric is known as “Indian Saffron” in medieval Europe. Turmeric has been used medicinally throughout Asia to treat stomach and liver ailments and has been used externally to help the healing of wounds and bruises, and still applied to all sorts of skin conditions—from smallpox and chickenpox to blemishes, shingles, minor cuts, and burns. In China, turmeric is ingested orally, as well as applied topically for urticaria, inflammatory conditions of joints, and treating skin allergies.27 As an Ayurvedic medicine, it can also be given orally, topically, and via inhalation for treating conditions, such as acne, eczema, parasitic infections, and many skin diseases such as herpes zoster and pemphigus.28,29 Turmeric powder is taken with boiled milk to cure cough and related respiratory ailments. Moreover, in North India, Indian women are given a tonic made out of fresh turmeric paste with dried ginger root powder and honey in a glass of hot milk to drink twice a day after childbirth.30 Now even the West has begun to recognize its importance. Johnson & Johnson (The American pharmaceutical company) makes turmeric Band-Aidst for the Indian market.31 The discovery of curcumin dates back to around two centuries ago. In 1815 Vogel and Pelletier first reported the isolation of “yellow coloring-matter” from the rhizomes of C. longa (turmeric) and named it curcumin.32 In 1842 Vogel Jr. obtained a pure preparation of curcumin.33 In 1910 Milobedzka and Lampe identified the chemical structure of curcumin as DFM or 1,6-heptadiene-3,5-dione-1,7-bis(4hydroxy-3-methoxyphenyl)-(1E, 6E).34 In 1913 the synthesis of this compound was published.35 Subsequently, the curcuminoids in C. longa were separated and quantified by chromatography.36 The first study on the use of curcumin in human diseases was published in 1937 in the Lancet.37 Curcumin’s antibacterial effect and ability to decrease blood sugar levels in human subjects were documented in 1949 and 1972, respectively.12,14 In the 1970s, diverse characteristics of curcumin, such as cholesterol-lowering,38 antidiabetic,12 antiinflammatory,2 and antioxidant3 activities, were discovered. However, in the 1980s, the anticancer activity of curcumin was demonstrated both in vitro and in vivo models.8 In 1995 Singh and Aggarwal were the first to demonstrate the molecular mechanism underlying curcuminmediated suppression of proinflammatory transcription factor nuclear factor (NF)-κB activation, exhibiting antiinflammatory activity.39 Due to interest in the therapeutic use, many attempts have been made on the chemistry and respective roles of curcumin associated with its potential medicinal benefits.

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CHEMISTRY OF CURCUMIN As stated above, curcumin is a low molecular weight (368.37 g/mol) polyphenolic compound with a melting temperature of approximately 183 C. The IUPAC name of curcumin is 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (1E-6E). Curcumin has two ferulic acid moieties bound together with an additional carbon (methane) to abridge the carboxyl groups. Curcumin has a seven carbon linker and three major functional groups including an α,β-unsaturated β-diketone moiety and an aromatic O-methoxy-phenolic group.40 The occurrence of intramolecular hydrogen atoms transfer at the β-diketone chain of curcumin leads to the existence of keto and enol tautomeric conformations in equilibrium (Fig. 2.1). These keto
enol tautomers also exist in several cis and trans forms. The relative concentrations of keto
enol tautomers may vary depending on the temperature, pH, solvent polarity, and O

O OCH3

H3CO

OH

HO DFM (Di-keto form) (In neutral and acidic conditions)

Hydrogen bonding

H O

O OCH3

H3CO

OH

HO DFM (enol form) (Predominantly in alkaline conditions)

FIGURE 2.1 Curcumin (DFM) exists in an equilibrium between keto and enol tautomers. Curcuminoids has a seven carbon linker, three major functional groups (an α,β-unsaturated β-diketone moiety and an aromatic O-methoxy-phenolic group). DFM, Diferuloylmethane.

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aromatic ring substitution.41
43 The keto
enol
enolate level of the heptadienone moiety in equilibrium plays a crucial role in the physicochemical properties and antioxidant activities of curcumin.44 The keto form dominates at pH 3
7, when curcumin acts as an extraordinary potent H-atom donor. However, in alkaline solution (above pH 8), the enolate form of heptadienone link predominates. As a consequence, orthomethoxy-substituted phenoxyl radical shows only moderate electron-donating ability. In another study, the antioxidant activity of curcumin was determined by estimating inhibition of controlled initiation of styrene oxidation.45 Synthetic nonphenolic curcuminoids exhibited no antioxidant activity, implicating that curcumin is a classical phenolic chain breaking antioxidant, which donates H atoms from the phenolic groups (not the CH2 group). Moreover, the antioxidant activities of O-methoxyphenols decrease in hydrogen bond accepting media.45 Due to its hydrophobic nature, curcumin is poorly soluble in water. However, its solubility is improved slightly in basic conditions. Curcumin is readily soluble in organic solvents, including ethanol, methanol, isopropanol, acetone, and dimethylsulfoxide; however, it shows moderate solubility in hexane, cyclohexane, tetrahydrofuran, and dioxane.46,47 Curcumin degrades more rapidly at physiological pH or greater, suggesting that its decomposition is pH dependent,48 which becomes a significant disadvantage for its therapeutic use. Turmeric is composed of constituents such as volatile oils (such as tumerone, atlantone, and zingiberone), sugars, proteins, and resins, as well as a polyphenolic ingredient named curcuminoids consisting (1) curcumin also known as DFM; (2) demethoxycurcumin (DMC); and (3) bisdemethoxycurcumin (BDMC). The pharmacological activity of turmeric is mainly attributed to these curcuminoids.29,49 DFM is the principal constituent (B77%), most active, and responsible for its vibrant yellow color, whereas DMC (B17%) and BDMC (B3%) are present at lower concentration.47,50 The chemical structures of turmeric curcuminoids (DFM, DMC, and BDMC) are shown in Fig. 2.2. All three curcuminoids share the same structure with two benzenemethoxy rings, joined by an unsaturated chain. Among these curcuminoids, the main components in Curcuma species is curcumin, which is the most studied and active component of turmeric that exerts a broad range of pharmacological activities. Curcumin is nearly insoluble in water; however, it is quite stable at the acidic pH of the stomach.48 Therefore for exerting its physiological activities, the maintenance of its stability is very crucial. Curcumin is sensitive to light and rapidly decolorizes upon exposure to UV light.51 The presence or absence of phenolic hydroxyl groups does not play any distinctive role in curcumin photodegradation. However, β-diketone moiety involvement has been suggested in

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2. HISTORICAL BACKGROUND, CHEMISTRY, PHARMACOLOGICAL ACTION O

O

H3CO

OCH3

HO

OH

Curcumin or diferuloylmethane (DFM, ~ 77%)

OH

O OCH3

HO

OH

Demethoxycurcumin (DMC, ~ 17%)

O

HO

O

OH Bis-demethoxycurcumin (BDMC, ~ 3%)

FIGURE 2.2 Structures of curcuminoids: curcumin (DFM) and its two related compounds DMC, and BDMC, which are the main secondary metabolites of Curcuma longa and other Curcuma spp. BDMC, Bisdemethoxycurcumin; DFM, diferuloylmethane; DMC, demethoxycurcumin.

scavenging of the hydroxyl radical and redox reactions, resulting in the formation of smaller phenolic compounds47 such as ferulic aldehyde, ferulic acid, 4-vinylguaiacol, vanillin, and vanilic acid (Fig. 2.3).51,52 Moreover, other by-products such as benzaldehyde, cinnamaldehyde, 20 -hydroxy-50 ,60 -benzochalcone, flavanone (Fig. 2.4), and some unknown photoproducts have also been identified from the photodegradation of nonphenolic curcuminoids.53

CURCUMIN METABOLISM Curcumin and its two related compounds (DMC and BDMC) known as curcuminoids are the main secondary metabolites of C. longa and other Curcuma spp.54 Phase I metabolism comprises the reduction of the four double bonds of the heptadiene-3,5-dione structure, namely, curcumin-dihydrocurcumin (DHC)-tetrahydrocurcumin (THC)-hexahydrocurcumin (HHC)-octahydrocurcumin (OHS) (Fig. 2.5). In animals

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CURCUMIN METABOLISM OCH3 OH

HO

OCH3

HO

H3CO

O O Curcumin

HO 4-Vinylguaicol

Ferulic aldehyde OCH3

OCH3

OH Feruloylmethane H

O

HO

OH HO

O

OCH3 Ferulic acid

OCH3

OH Vanillic acid

OCH3

OH

OH

Vanillin

FIGURE 2.3 Curcumin degradative products as a result of photochemical reactions. O

O H

Benzaldehyde

H

Cinnamaldehyde

O HO

O O

2′-hydrosy-5′,6′-benzochalcone

Flavanonoe

FIGURE 2.4 Other by-products of curcumin.

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2. HISTORICAL BACKGROUND, CHEMISTRY, PHARMACOLOGICAL ACTION OH

O OCH3

H3CO

Curcumin HO

OH

OH

O

OCH3

H3CO

Dihydrocurcumin OH

HO OH

O

H3CO

OCH3

Tetrahydrocurcumin HO

OH

O

H3CO

OH OCH3

Hexahydrocurcumin OH

HO OH

O

H3CO

OCH3

Octahydrocurcumin (Hexahydoxycurcuminol) HO

OH

FIGURE 2.5 Major metabolites of curcumin.

out of four reduction products, THC and HHC are major products, whereas DHC and OHS are minor ones.55
59 Animal studies have indicated that rapid curcumin metabolism occurs through glucuronidation and sulfation (Fig. 2.6), or it is reduced to HHC in liver and intestine.60 Thus during phase II, curcumin and its reduced metabolites are conjugated with a monoglucuronide, a monosulfate, and a mixed sulfate/glucuronide, namely, conjugated curcumin-conjugated DHC-conjugated THC-conjugated HHCconjugated OHS (Fig. 2.6). Glucuronidation and sulfation of curcumin are catalyzed by uridine-50 -diphosphoglucuronosyl transferase and sulfotransferases in liver and intestine.61,62 The major biliary metabolites of curcumin are glucuronides of THC and HHC in rats.63 Secondary metabolites, a group of bioactive substances, having diverse classes of compounds such as alkaloids, terpenoids, phenols, flavonoids, tannins, saponins, etc., are produced through secondary metabolism in different plants. The medicinal value of plants lies in the chemical substances that have definite physiological action on the human body.64 Phytochemical screening of the ethanolic extract of six different species of genus Curcuma has demonstrated the presence of

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FIGURE 2.6 Curcumin metabolism through glucuronidation and sulfation.

phenols, flavonoids, alkaloids, terpenoids, tannins, and saponins.64 These bioactive substances which are responsible for their possible medicinal benefits (such as antioxidant and antiinflammatory properties) vary in Curcuma samples based on their geographical origin or curcuma species.

PHARMACOLOGICAL ACTIONS Over the past decades, numerous scientific studies have identified curcumin’s pharmacological properties by using in vitro and in vivo model systems. However, clinical application of curcumin in humans remains limited due to its poor pharmacokinetic characteristics. Curcumin has been shown to possess a wide range of pharmacological

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FIGURE 2.7 Pharmacological properties of curcumin.

properties, including antiinflammatory, anticancer, antioxidant, wound healing, cardioprotective, antimicrobial, antihypertensive, antihyperlipidemic, antiangiogenic, antidiabetic (hypoglycemic), antipsoriasis, antithrombotic, antihepatotoxic, and analgesic uses.3
22,30,65
73 However, specific properties (such as antioxidant, antiinflammatory, immunomodulatory, antiamyloidogenic, antiexcitotoxic, and antiapoptotic) that have been studied worldwide implicate that the combination of these actions (Fig. 2.7) may be involved in curcumin’s neuroprotective activity:

Antioxidant Activity The aerobic organisms undergo complex interactions during normal metabolism, leading to the release of reactive oxygen species (ROS) that are chemically reactive chemical species containing oxygen, such as superoxide anion radical (O22), singlet oxygen, hydrogen peroxide (H2O2), and highly reactive hydroxyl radical (OH•). ROS are harmful mediators that are referred as free radical because of its unpaired electron. ROS can cause oxidative damage to lipids, proteins, and DNA. The OH• is a harmful by-product of oxidative metabolism that can cause molecular damage in living system by reacting with nuclear

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DNA, mitochondrial DNA, proteins, and membrane lipids. Moreover, it can also be generated by the Fenton reaction.74 Copper can induce oxidative stress by catalyzing the formation of ROS via a Fenton-like reaction.75,76 The cupric ion (Cu(II)), in the presence of superoxide anion radical or biological reductants (ascorbic acid or glutathione (GSH)), can be reduced to cuprous ion (Cu(I)) and catalyzes the formation of reactive hydroxyl radicals through the decomposition of H2O2 via the Fenton reaction: CuðIIÞ 1 O2 2 -CuðIÞ 1 O2 CuðIÞ 1 H2 O2 -CuðIIÞ 1 OH 1 OH2 ðFenton reactionÞ The presence of ascorbic acid, copper, oxygen, and hydrogen peroxide is an efficient hydroxyl radical generating system,77 which ultimately leads to oxidative damage of all types of biomolecules. The phenolic groups in the structure of curcumin explain the ability of curcumin to eliminate oxygen-derived free radicals (hydroxyl radical, singlet oxygen, superoxide radical, nitrogen dioxide, and NO).78 The antioxidant activity of curcumin is related to the O-methoxyphenol group and methylenic hydrogen that contributes an electron/hydrogen atom to free radicals (Fig. 2.8). The α,β-unsaturated β-diketone moiety strongly via Michael reaction acts with protein thiols.79 Curcumin
metal complexes modify the physicochemical properties of curcumin as well as decrease metal toxicity.80 Some curcumin
metal complexes (Cu21, Mn21) act as new metal-based antioxidants. Curcumin has been shown to exhibit strong

FIGURE 2.8 Functional groups responsible for curcumin’s antioxidant activity. Curcumin structure showing Michael reaction acceptors (keto form) expressed in dotted boxes, as well as hydroxy group as R1 represent key regions for radical trapping and antioxidant activity. Source: Adapted from Refs. [44,45].

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antioxidant activity, which is comparable to vitamins C and E.81 An in vitro study measuring the effect of curcumin on endothelial heme oxygenase-1 (an inducible stress protein that degrades heme to the vasoactive molecule carbon monoxide and the antioxidant biliverdin) was conducted utilizing bovine aortic endothelial cells.82 This study demonstrated that increased heme oxygenase activity by curcumin is responsible for cellular resistance to oxidative damage.82 Moreover, curcumin’s ability to scavenge various ROS produced by macrophages, such as superoxide anions, hydrogen peroxide, and nitrite radicals, may be the major mechanism by which curcumin exhibits its antioxidant activities. Recently, a chemical-molecular paradigm has been reported relating the structure of curcumin and its autoxidative/antioxidant behavior to its antiinflammatory activity.69 This group has provided the evidence that the electrophilic metabolites, rather than parent curcumin or the final bicyclopentadione, adduct covalently to cellular protein, and specifically to IκB kinase (IKK) β of the NF-κB pathway, suggesting that metabolic bioactivation of curcumin is necessary to exert its antiinflammatory activity.69 Moreover, curcumin can induce the expression of Phase II antioxidant enzymes, such as glutamate
cysteine ligase, which is a rate-limiting enzyme in GSH (an important endogenous antioxidant) synthesis.

Antiinflammatory Activity Inflammation is a common phenomenon of living tissues induced by microbial infection or tissue injury,83 which can lead to the destruction of microbes and host tissue. This process involves an enormous expenditure of metabolic energy, damage and destruction of host tissues, and even the risk of sepsis, multiple organ failure, and death. The main function of inflammation is to resolve the infection or repair the damage and return to a state of homeostasis. Curcumin has a rich history as an antiinflammatory agent in traditional Asian medicine.84 It can suppress the acute and chronic inflammation. Curcumin can reduce inflammation by lowering histamine levels and possibly by increasing the production of natural cortisone by the adrenal glands.85 In human vascular cells in vitro system, curcumin has shown its antiinflammatory action by attenuating inflammatory response of tumor necrosis factor α (TNF-α)
stimulated human endothelial cells by interfering with NF-κB.86 Its antiinflammatory properties may be attributed to its ability to inhibit both biosynthesis of inflammatory prostaglandins from arachidonic acid and neutrophil function during inflammatory states.87 Curcumin and its metabolites (THC, HHC, and OHS) have been shown to significantly inhibit various lipopolysaccharide-induced responses of RAW 264.7

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macrophage cells, suggesting that the antiinflammatory mechanism of curcumin and its metabolites may proceed via the inhibition of IκB-α protein degradation, which in turn prevent the translocation of NF-κB to the nucleus.85 Following treatment with curcumin and its three metabolites, nitric oxide overproduction was potently inhibited.85 Curcumin and THC have been reported to significantly inhibit the release of prominent cytokines, including TNF-α and interleukin-6 (IL-6), but HHC and OHS do not significantly alter cytokine release.85 The feeding of curcumin to aged mice with advanced plaques deposits has been reported to result in reduction of plaques deposition in cortex and hippocampus as well as decreased proinflammatory cytokines.88,89 In another study, primary cultures of mice microglia showed increased expression of the cytokines IL-4 and IL-2, whereas THC treatment weakly reduced phosphorylated Tau protein and failed to significantly alter plaque burden and cytokine expression.90 In contrast, the optimized turmeric extract (HSS-888) significantly reduced brain levels of soluble and insoluble Aβ as well as phosphorylated Tau protein, implicating that Alzheimer’s progression can be attenuated by inhibiting plaque burden, Tau phosphorylation, and microglial inflammation.90

Immunomodulatory Effect The immune system plays a vital role in the defense against infections. Immunomodulators help regulate or normalize the immune system by weakening or modulating the activity of the immune system, resulting in the reduction of the inflammatory response. Various flavonoids show significant pharmacological and biochemical activity, affecting the normal functions of immune cells, such as B and T cells, macrophages, neutrophils, basophils, and mast cells.91 Curcumin has been shown to downregulate the expression of various proinflammatory cytokines, including TNF, IL-1, IL-2, IL-6, IL-8, IL-12, and chemokines, most likely through inactivation of the transcription factor NF-κB. However, at low doses curcumin can also enhance antibody responses,92 implicating that curcumin’s beneficial effects in treating chronic diseases (arthritis, allergy, asthma, atherosclerosis, heart disease, AD, diabetes, and cancer) may be partly due to modulation of the immune system. Curcumin has demonstrated to exert an inhibitory response on the production of inflammatory cytokines by human monocytes. In animal model of multiple sclerosis (MS) such as experimental autoimmune encephalomyelitis, curcumin decreases IL-12 production, and signal transducer and activator of transcription 4 (STAT4) activation.93 The effect of curcumin on STAT4 activation dependent upon the stimulus to which the T cells have been exposed. For treating various

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cancers and inflammation-mediated diseases, the molecular mechanisms underlying the targets of curcumin are diverse and may involve combinations of multiple signaling pathways, including NF-κB and STAT3 signaling.94 Several preclinical and clinical trials have revealed immunomodulatory actions of curcumin, which arise from its effects on immune cells and mediators involved in the immune response (e.g., various T-lymphocyte subsets and dendritic cells, as well as different inflammatory cytokines), implicating that curcumin can affect different immune cells,95,96 warranting that further consideration of curcumin is required as a therapy for immune diseases.

Antiapoptotic Effect Apoptosis is a highly regulated mechanism by which cells undergo programmed cell death.97 In cancer, curcumin’s chemopreventive properties are used mainly due to its ability to arrest cell cycle and to induce apoptosis of cancer cells by intrinsic and extrinsic apoptosis pathways, the NF-kB-mediated pathway, PI3K/Akt signaling pathway, as well as sensitization of cells to TNF-related apoptosis-inducing ligand-induced apoptosis pathway.98 However, neuroprotective effects of curcumin have been reported in the treatment of focal cerebral ischemic injury. It involves the expression of caspase-3, and mitochondrial Bcl-2 protein in rats.99 β-Amyloid is known to induce apoptosis in neuronal cells, therefore antiapoptotic activity of curcumin was studied by this group using nanoparticles.100 It was reported that curcumin activity was enhanced in ApoE3-mediated poly(butyl) cyanoacrylate (ApoE3-C-PBCA) nanoparticles compared to plain curcumin.100 ApoE3 also possesses both antioxidant and antiamyloidogenic activity; therefore ApoE3 itself has activity against β-amyloid-induced cytotoxicity along with curcumin, suggesting that ApoE3-C-PBCA offers great advantage in the treatment of β-amyloid-induced cytotoxicity in AD.100 Another independent group investigated the protective effect of a pyrazole derivative of curcumin (CNB-001) on rotenone-induced toxicity in neuroblastoma SK-N-SH cells.101 Rotenone insult results in decreased cell viability due to significant apoptosis by altering Bcl-2, Bax, caspase-3, and cytochrome C expression, oxidative stress, and mitochondrial dysfunction. However, pretreatment with CNB-001 before rotenone exposure increased cell viability, decreased ROS formation, maintained normal physiological mitochondrial membrane potential, and reduced apoptosis.101 CNB-001 also inhibited downstream apoptotic cascade by increasing the expression of vital antiapoptotic protein Bcl-2 and decreased the expression of Bax, caspase-3, and cytochrome C, implicating that CNB-001 protects neuronal cell against toxicity through antioxidant and antiapoptotic properties through its action on mitochondria.101 Moreover, CNB-001 has been

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shown to mitigate motor impairments associated with neurodegeneration via suppression of neuroinflammatory and apoptotic response in experimental Parkinson’s disease (PD) mice,102 which suggests its potential as a therapeutic candidate for treatment of PD.

Antiexcitotoxic Activity Excitotoxicity is the pathological process for neuronal killing.103 Glutamate-induced excitotoxicity is produced by excessive glutamate. It leads to neuronal injury by inducing an influx of calcium, which causes neuronal injury through the stimulation of Ca21-dependent enzymes. Glutamate-induced excitotoxicity may contribute to neurodegeneration in chronic neurodegenerative disorders such as amyotrophic lateral sclerosis, MS, PD, and others.104 Glutamate-induced excitotoxicity may also contribute to the pathogenesis of major depressive disorder (MDD) in animal models.105
107 Curcumin also exerts antidepressant-like effects in animal models of MDD.108 Persistent and excessive glutamate insults triggering Ca21 influx through N-methyl-D-aspartic acid (NMDA) receptor in SH-SY5Y human neuroblastoma cells is considered as the key toxic mechanism of neurologic diseases (such as MDD, brain trauma, and AD). Due to its polyphenolic nature, curcumin is known to exert antiexcitotoxicity effects. Curcumin protects both retinal and hippocampal neurons against NMDA-induced cell death in a dose- and timedependent manner.109 The stimulation of α-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid (AMPA) as well as its downstream pathways is also considered as potential central mediators in antidepressant mechanisms.110 Curcumin protects neurons from glutamate-mediated neurotoxicity not only by decreasing Ca21 influx but also by inhibiting the translocation of A-kinase anchoring protein 79 (AKAP79) from cytomembrane to cytoplasm. Moreover, pretreatment of cells with protein kinase A (PKA) anchoring inhibitor Ht31 disassociates PKA from AKAP79, no neuroprotective effects are observed, suggesting that curcumin acts by enhancing the phosphorylation of AMPA receptor and its downstream pathways in PKA-dependent manner.110 These observations suggest that curcumin protects neurons from glutamate-induced excitotoxicity by interacting with AKAP79-PKA network. According to another group that explored the effect of curcumin against glutamatemediated excitotoxicity mainly by focusing on the neuroprotective effects of curcumin on the expression of brain-derived neurotrophic factor (BDNF),111 the exposure of rat cortical neurons to glutamate significantly decreases BDNF level, reduction in cell viability, and enhancement in cellular apoptosis. In contrast, pretreatment of neurons with curcumin enhances the BDNF expression and cell viability in a dose- and time-dependent manner. However, a Trk receptor inhibitor

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(K252a) not only suppresses the neuroprotective effect of curcumin and increase in BDNF expression but also retards TrkB signaling pathway.111

Antiamyloidogenic Activity One of the key features of a brain affected by AD is the accumulation of amyloid plaques in the brain. In a healthy brain, these protein fragments are broken down and eliminated. However, in AD, these fragments accumulate to form hard, insoluble plaques called as β-amyloid that is toxic to neurons in the brain and causes cell death. Curcumin has been reported to exert potent antiamyloidogenic activity in vitro and in vivo.72,89,112 Curcumin can cross the blood
brain barrier and can reverse existing amyloid pathology and associated neurotoxicity in a mouse model of AD.113 Curcumin-mediated inhibition of the accumulation of amyloid β-peptide (Aβ), the prevention of β-amyloid fibrils (fAbeta) formation in vitro and in vivo, and the destabilization of preformed fAbeta in the brain support the rationale for curcumin potential use of curcumin for AD treatment.114 Collectively, above findings strongly support the view that pleiotropic actions of curcumin may be responsible for neuroprotective efficacy of curcumin in clinical trials.

CONCLUSION Curcumin, an active ingredient of turmeric, is known to exert strong antioxidant, antiinflammatory, immunomodulatory, antiapoptotic, antiexitotoxic actions, and cognitive-enhancing properties. Many of the abovementioned effects of curcumin may not be achievable in target tissues in vivo with oral dosing. Despite of our concerns about its poor oral bioavailability, curcumin has at least 10 known neuroprotective actions, and many of these may be realized later in vivo. Accumulating cell culture and animal model data suggest that dietary curcumin is a strong candidate for use in the prevention or treatment of major agerelated neurodegenerative diseases such as AD and PD. Therefore more extensive and well-controlled clinical trials are required to check its bioefficacy for treating neurodegenerative diseases in humans.

References 1. Borra SK, Mahendra J, Gurumurthy P, Jayamathi, Iqbal SS, Mahendra L. Effect of curcumin against oxidation of biomolecules by hydroxyl radicals. J Clin Diagn Res 2014;8 (10):CC01
5.

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REFERENCES

39

2. Srimal RC, Dhawan BN. Pharmacology of diferuloyl methane (curcumin), a nonsteroidal anti-inflammatory agent. J Pharm Pharmacol 1973;25:447
52. 3. Sharma OP. Antioxidant activity of curcumin and related compounds. Biochem Pharmacol 1976;25:1811
12. 4. Sandur SK, Ichikawa H, Pandey MK, Kunnumakkara AB, Sung B, Sethi G, et al. Role of pro-oxidants and antioxidants in the anti-inflammatory and apoptotic effects of curcumin (diferuloylmethane). Free Radic Biol Med 2007;43(4):568
80. 5. Antony S, Kuttan R, Kuttan G. Immunomodulatory activity of curcumin. Immunol Invest 1999;28(5
6):291
303. 6. Trivedi MK, Mondal SC, Gangwar M, Jana S. Immunomodulatory potential of nanocurcumin-based formulation. Inflammopharmacology 2017;25(6):609
19. 7. Adapala N, Chan MM. Long-term use of an antiinflammatory, curcumin, suppressed type 1 immunity and exacerbated visceral leishmaniasis in a chronic experimental model. Lab Invest 2008;88:1329
39. 8. Kuttan R, Bhanumathy P, Nirmala K, George MC. Potential anticancer activity of turmeric (Curcuma longa). Cancer Lett 1985;29:197
202. 9. Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 2003;23(1A):363
98. 10. Aggarwal S, Ichikawa H, Takada Y, Sandur SK, Shishodia S, Aggarwal BB. Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IkappaBalpha kinase and Akt activation. Mol Pharmacol 2006;69(1):195
206. 11. Ono M, Higuchi T, Takeshima M, Chen C, Nakano S. Differential anti-tumor activities of curcumin against Ras- and Src-activated human adenocarcinoma cells. Biochem Biophys Res Commun 2013;436(2):186
91. 12. Srinivasan M. Effect of curcumin on blood sugar as seen in a diabetic subject. Indian J Med Sci 1972;26:269
70. 13. Sharma S, Kulkarni SK, Chopra K. Curcumin, the active principle of turmeric (Curcuma longa), ameliorates diabetic nephropathy in rats. Clin Exp Pharmacol Physiol 2006;33:940
5. 14. Schraufstatter E, Bernt H. Antibacterial action of curcumin and related compounds. Nature 1949;164:456. 15. Teow SY, Liew K, Ali SA, Khoo AS, Peh SC. Antibacterial action of curcumin against Staphylococcus aureus: a brief review. J Trop Med 2016;2016:2853045. 16. Cole GM, Teter B, Frautschy SA. Neuroprotective effects of curcumin. Adv Exp Med Biol 2007;595:197
212. 17. Singh S, Kumar P. Neuroprotective activity of curcumin in combination with piperine against quinolinic acid induced neurodegeneration in rats. Pharmacology 2016;97 (3
4):151
60. 18. Kuttan R, Binitha PP. Neuroprotective activity of curcumin and Emblica officinalis extract against carbofuran-induced neurotoxicity in Wistar rats. In: Farooqui T, Farooqui AA, editors. Neuroprotective effects of phytochemicals in neurological disorders. New York: John Wiley & Sons, Inc; 2017. p. 581
94 (ed). 19. Farooqui AA. Therapeutic potentials of curcumin for Alzheimer disease. New York: Springer; 2016. 20. Ghosh S, Banerjee S, Sil PC. The beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease: a recent update. Food Chem Toxicol 2015;83: 111
24. 21. Goozee KG, Shah TM, Sohrabi HR, Rainey-Smith SR, Brown B, Verdile G, et al. Examining the potential clinical value of curcumin in the prevention and diagnosis of Alzheimer’s disease. Br J Nutr 2016;115(3):449
65. 22. Singh S. From exotic spice to modern drug? Cell 2007;130(5):765
8.

CURCUMIN FOR NEUROLOGICAL AND PSYCHIATRIC DISORDERS

40

2. HISTORICAL BACKGROUND, CHEMISTRY, PHARMACOLOGICAL ACTION

23. Chainani-Wu N. Safety and anti-inflammatory activity of curcumin: a component of turmeric (Curcuma longa). J Altern Complement Med 2003;9(1):161
8. 24. Lao CD, Ruffin 4th MT, Normolle D, Heath DD, Murray SI, Balley JM, et al. Dose escalation of a curcuminoid formulation. BMC Complement Altern Med 2006;6:10. 25. Kc¸hler FE. Ko¨hler’s Medizinal-Pflanzen in naturgetreuen Abbildungen mit kurz erl_uterndem Texte: Atlas zur Pharmacopoea germanica, Gera-Untermhaus. Gera; 1887. 26. Ammon H, Wahl MA. Pharmacology of Curcuma longa. Planta Med 1991;57:1
7. 27. Kapoor LD. Handbook of Ayurvedic medicinal plants. Boca Raton, FL: CRC Press; 1990. 28. WHO. Rhizoma Curcumae Longae, WHO monographs on selected medicinal plants, vol. 1. World Health Organization; 1999. 29. Labban L. Medicinal and pharmacological properties of turmeric (Curcuma longa): a review. Int J Pharm Biomed Sci 2014;5(1):17
23. 30. Hatcher H, Planalp R, Cho J, Torti FM, Torti SV. Curcumin: from ancient medicine to current clinical trials. Cell Mol Life Sci 2008;65:1631
52. 31. MacGregor H. Out of the spice box, into the lab: turmeric, an Indian staple, has long had medicinal uses. Now the West is taking notice. Los Angeles Times, Los Angeles, CA 2006. 32. Vogel H, Pelletier J. Curcumin-biological and medicinal propertie. J Pharmacie 1815;I:289. 33. Vogel Jr. A. Me´moire sur la Curcumine. J de Pharm et Chim 1842;3:20
7. 34. Milobedzka J, Kostanecki S, Lampe V. Zur Kenntnis des Curcumins. Ber Deut Chem Ges 1910;43:2163
70. 35. Lampe V, Milobedzka J. Studien uber Curcumin. Ber Deut Chem Ges 1913;46:2235
7. 36. Srinivasan KR. A chromatographic study of the curcuminoids in Curcuma longa L. J Pharm Pharmacol 1953;5:448
57. 37. Albert O. Turmeric (curcumin) in biliary diseases. Lancet 1937;229:619
21. 38. Patil TN, Srinivasan M. Hypocholesteremic effect of curcumin in induced hypercholesteremic rats. Indian J Exp Biol 1971;9:167
9. 39. Singh S, Aggarwal BB. Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane) [corrected]. J Biol Chem 1995;270:24995
5000. 40. Iqbal M, Sharma SD, Okazaki Y, Fujisawa M, Okada S. Dietary supplementation of curcumin enhances antioxidant and phase II metabolizing enzymes in ddY male mice: possible role in protection against chemical carcinogenesis and toxicity. Pharmacol Toxicol 2003;92(1):33
8. 41. Cornago P, Claramunt RM, Bouissane L, Alkorta I, Elguero J. A study of the tautomerism of beta-dicarbonyl compounds with special emphasis on curcuminoids. Tetrahedron 2008;64:8089
94. 42. Nie D, Bian Z, Yu A, Chen Z, Liu Z, Huang C. Ground and excited state intramolecular proton transfer controlled intramolecular charge separation and recombination: a new type of charge and proton transfer reaction. Chem Phys 2008;348:181
6. 43. Bertolasi V, Ferretti V, Gilli P, Yao X, Li C-J. Substituent effects on keto-enol tautomerization of β-diketones from X-ray structural data and DFT calculations. New J Chem 2008;32:694
704. 44. Jovanovic SV, Steenkens S, Boone CW, Simic MG. H-atom transfer is a preferred antioxidant mechanism of curcumin. J Am Chem Soc 1999;121(41):9677
81. 45. Barclay LRC, Vinqvist MR, Mukai M, Goto H, Hashimoto Y, Tokuunaga A, et al. On the antioxidant mechanism of curcumin: classical methods are needed to determine antioxidant mechanism and activity. Org Lett 2000;2(18):2841
3. 46. Priyadarsini KI. Photophysics photochemistry and photobiology of curcumin. Studies from organic solutions bio-mimetics and living cells. J Photochem Photobiol C 2009;10:81
95. 47. Lee W-H, Loo C-Y, Bebawy M, Luk F, Mason R, Rohanizadeh R. Curcumin and its derivatives: their application in neuropharmacology and neuroscience in the 21st century. Curr Neuropharmacol 2013;11(4):338
78.

CURCUMIN FOR NEUROLOGICAL AND PSYCHIATRIC DISORDERS

REFERENCES

41

48. Wang YJ, Pan MH, Cheng AL, Lin LI, Ho YS, Hsieh CY, et al. Stability of curcumin in buffer solutions and characterization of its degradation products. J Pharm Biomed Anal 1997;15(12):1867
76. 49. Nasri H, Sahinfard N, Rafieian M, Rafieian S, Shirzad M, Rafieian-kopaei M. Turmeric: a spice with multifunctional medicinal properties. J Herbmed Pharmacol 2014;3(1):5
8. 50. Jurenka JS. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Altern Med Rev 2009;14(2):141
53. 51. Tonnesen HH, Karlsen J, Vanhenegouwen GB. Studies on curcumin and curcuminoids. 8. Photochemical stability of curcumin. Z Lebensm Unters For 1986;183:116
22. 52. Tonnesen HH, Greenhill JV. Curcumin as a reducing agent and as a radical scavenger. Int J Pharm 1992;87:79
87. 53. Sundaryono A, Nourmamode A, Gardrat C, Grelier S, Bravic G, Chasseau D, et al. Studies on the photochemistry of 1,7-diphenyl-1,6-heptadiene-3,5-dione, a nonphenolic curcuminoid model. Photochem Photobiol Sci 2003;2:914
20. 54. Lestari ML, Indrayanto G. Curcumin. Profiles Drug Subst Excip Relat Methodol 2014;39:113
204. 55. Ravindranath V, Chandrasekhara N. In vitro studies on the intestinal absorption of curcumin in rats. Toxicology 1981;20:251
7. 56. Hoehle SI, Pfeiffer E, So´lyom AM, Metzler M. Metabolism of curcuminoids in tissue slices and subcellular fractions from rat liver. J Agric Food Chem 2006;54:756
64. 57. Pan MH, Huang TM, Lin JK. Biotransformation of curcumin through reduction and glucuronidation in mice. Drug Metab Dispos 1999;27:486
94. 58. Ireson C, et al. Characterization of metabolites of the chemopreventive agent curcumin in human and rat hepatocytes and in the rat in vivo, and evaluation of their ability to inhibit phorbol ester-induced prostaglandin E2 production. Cancer Res 2001;61:1058
64. 59. Ireson CR, et al. Metabolism of the cancer chemopreventive agent curcumin in human and rat intestine. Cancer Epidemiol Biomarkers Prev 2002;11:105
11. 60. Wahlstro¨m B, Blennow G. A study on the fate of curcumin in the rat. Acta Pharmacol Toxicol (Copenh) 1978;43(2):86
92. 61. Hoehle SI, Pfeiffer E, Metzler M. Glucuronidation of curcuminoids by human microsomal and recombinant UDP-glucuronosyltransferases. Mol Nutr Food Res 2007;51 (8):932
8. 62. Asai A, Miyazawa T. Occurrence of orally administered curcuminoid as glucuronide and glucuronide/sulfate conjugates in rat plasma. Life Sci 2000;67:2785
93. 63. Holder GM, Plummer JL, Ryan AJ. The metabolism and excretion of curcumin (1,7bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) in the rat. Xenobiotica 1978;8:761
8. 64. Dutta B. Study of secondary metabolite constituents and curcumin contents of six different species of genus Curcuma. JMPS 2015;3(5):116
19. 65. Prakash P, Misra A, Surin WR, Jain M, Bhatta RS, Pal R, et al. Anti-platelet effects of Curcuma oil in experimental models of myocardial ischemia-reperfusion and thrombosis. Thromb Res 2011;127(2):111
18. 66. Negi PS, Jayaprakasha GK, Jagan Mohan Rao L, Sakariah KK. Antibacterial activity of turmeric oil: a byproduct from curcumin manufacture. J Agric Food Chem 1999;47:4297
300. 67. Nishiyama T, Mae T, Kishida H, Tsukagawa M, Mimaki Y, Kuroda M, et al. Curcuminoids and sesquiterpenoids in turmeric (Curcuma longa L.) suppress an increase in blood glucose level in type 2 diabetic KK-Ay mice. J Agric Food Chem 2005;53:959
63. 68. Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin as “curecumin”: from kitchen to clinic. Biochem Pharmacol 2008;75(4):787
809.

CURCUMIN FOR NEUROLOGICAL AND PSYCHIATRIC DISORDERS

42

2. HISTORICAL BACKGROUND, CHEMISTRY, PHARMACOLOGICAL ACTION

69. Edwards RL, Luis PB, Varuzza PV, Joseph AI, Presley SH, Chaturvedi R, et al. The anti-inflammatory activity of curcumin is mediated by its oxidative metabolites. J Biol Chem 2017;292(52):21243
52. 70. Zhou H, Beevers CS, Huang S. The targets of curcumin. Curr Drug Targets 2011;12 (3):332
47. 71. Aggarwal BB, Sung B. Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets. Trends Pharmacol Sci 2009;30 (2):85
94. 72. Mishra S, Palanivelu K. The effect of curcumin (turmeric) on Alzheimer’s disease: an overview. Ann Indian Acad Neurol 2008;11(1):13
19. 73. Zeng C, Zhong P, Zhao Y, Kanchana K, Zhang Y, Khan ZA, et al. Curcumin protects hearts from FFA-induced injury by activating Nrf2 and inactivating NF-κB both in vitro and in vivo. J Mol Cell Cardiol 2015;79:1
12. 74. Aoyagi S, Yamazaki M, Miyasaka T, et al. Clarification of enhanced hydroxyl radical production in Fenton reaction with ATP/ADP based on luminol chemiluminescence. J Chem Eng Jpn 2001;34:956
9. 75. Prousek J. Fenton chemistry in biology and medicine. Pure Appl Chem 2007;79:2325
38. 76. Liochev SI, Fridovich I. The Haber
Weiss cycle-70 years later: an alternative view. Redox Rep 2002;7:55
7. 77. Udenfriend S, Clark CT, Axelrod J, Brodie BB. Ascorbic acid in aromatic hydroxylation. I. A model system for aromatic hydroxylation. J Biol Chem 1954;208(2):731
9. 78. Sreejayan N, Rao MNA, Priyadarsini KI, Devasagayam TP. Inhibition of radiation induced lipid peroxidation by curcumin. Int J Pharm 1997;151:127
30. 79. Priyadarsini KI. The chemistry of curcumin: from extraction to therapeutic agent. Molecules 2014;19:20091
112. 80. Akram M, Uddin S, Ahmed A, Usmanghani K, Hannan A, Mohiuddin E, et al. Curcuma longa and curcumin: a review article. Rom J Biol Plant Biol 2010;55 (2):65
70. 81. Toda S, Miyase T, Arichi H, Tanizawa H, Takino Y. Natural antioxidants. III. Antioxidative components isolated from rhizome of Curcuma longa L. Chem Pharm Bull (Tokyo) 1985;33(4):1725
8. 82. Motterlini R, Foresti R, Bassi R, Green CJ. Curcumin, an antioxidant and antiinflammatory agent, induces heme oxygenase-1 and protects endothelial cells against oxidative stress. Free Radic Biol Med 2000;28(8):1303
12. 83. Nathan C. Points of control in inflammation. Nature 2002;420(6917):846
52. 84. Gupta SC, Sung B, Kim JH, Prasad S, Li SY, Aggarwal BB. Multitargeting by turmeric, the golden spice: from kitchen to clinic. Mol Nutr Food Res 2013;57:1510
28. 85. Zhao F, Gong Y, Hu Y, Lu M, Wang J, Dong J, et al. Curcumin and its major metabolites inhibit the inflammatory response induced by lipopolysaccharide: translocation of nuclear factor-κB as potential target. Mol Med Rep 2015;3079:3087
93. 86. Kim YS, Ahn Y, Hong MH, Joo SY, Kim KH, Sohn IS, et al. Curcumin attenuates inflammatory responses of TNF-alpha-stimulated human endothelial cells. J Cardiovasc Pharmacol 2007;50(1):41
9. 87. Mukhopadhyay A, Basu N, Ghatak N, Gujral PK. Anti-inflammatory and irritant activities of curcumin analogues in rats. Agents Actions 1982;12(4):508
15. 88. Begum AN, Jones MR, Lim GP, Morihara T, Kim P, Heath DD, et al. Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer’s disease. J Pharmacol Exp Ther 2008;326(1):196
208. 89. Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, et al. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 2005;280(7):5892
901.

CURCUMIN FOR NEUROLOGICAL AND PSYCHIATRIC DISORDERS

REFERENCES

43

90. Shytle RD, Tan J, Bickford PC, Rezai-Zadeh K, Hou L, Zeng J, et al. Optimized turmeric extract reduces β-amyloid and phosphorylated Tau protein burden in Alzheimer’s transgenic mice. Curr Alzheimer Res 2012;9(4):500
6. 91. Middleton E, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease and cancer. Pharmacol Rev 2000;52:673
751. 92. Jagetia GC, Aggarwal BB. “Spicing up” of the immune system by curcumin. J Clin Immunol 2007;27(1):19
35. 93. Fahey AJ, Adrian Robins R, Constantinescu CS. Curcumin modulation of IFN-beta and IL-12 signalling and cytokine induction in human T cells. J Cell Mol Med 2007;11 (5):1129
37. 94. Deguchi A. Curcumin targets in inflammation and cancer. Endocr Metab Immune Disord Drug Targets 2015;15(2):88
96. 95. Abdollahi E, Momtazi AA, Johnston TP, Sahebkar A. Therapeutic effects of curcumin in inflammatory and immune-mediated diseases: a nature-made jack-of-all-trades? J Cell Physiol 2018;233(2):830
48. 96. Momtazi-Borojeni AA, Haftcheshmeh SM, Esmaeili SA, Johnston TP, Abdollahi E, Sahebkar A. Curcumin: a natural modulator of immune cells in systemic lupus erythematosus. Autoimmun Rev 2018;17(2):125
35. 97. Degterev A, Boyce M, Yuan J. A decade of caspases. Oncogene 2003;22:8543
67. 98. Reuter S, Eifes S, Dicato M, Aggarwal BB, Diederich M. Modulation of anti-apoptotic and survival pathways by curcumin as a strategy to induce apoptosis in cancer cells. Biochem Pharmacol 2008;76(11):1340
51. 99. Zhao J, Yu S, Zheng W, Feng G, Luo G, Wang L, et al. Curcumin improves outcomes and attenuates focal cerebral ischemic injury via antiapoptotic mechanisms in rats. Neurochem Res 2010;35(3):374
9. 100. Mulik RS, Mo¨nkko¨nen J, Juvonen RO, Mahadik KR, Paradkar AR. ApoE3 mediated poly(butyl) cyanoacrylate nanoparticles containing curcumin: study of enhanced activity of curcumin against beta amyloid induced cytotoxicity using in vitro cell culture model. Mol Pharm 2010;7(3):815
25. 101. 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(3):863
70. 102. Jayaraj RL, Elangovan N, Dhanalakshmi C, Manivasagam T, Essa MM. CNB-001, a novel pyrazole derivative mitigates motor impairments associated with neurodegeneration via suppression of neuroinflammatory and apoptotic response in experimental Parkinson’s disease mice. Chem Biol Interact 2014;220:149
57. 103. Farooqui AA, Ong WY, Horrocks LA. Neurochemical aspects of excitotoxicity. New York: Springer; 2008. 104. Lau A, Tymianski M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch 2010;460(2):525
42. 105. Gao M, Zhang WC, Liu QS, Hu JJ, Liu GT, Du GH. Pinocembrin prevents glutamateinduced apoptosis in SH-SY5Y neuronal cells via decrease of bax/bcl-2 ratio. Eur J Pharmacol 2008;591(1
3):73
9. 106. Amano S, Ohashi M, Ishiko T, Hazama F. Humoral factors derived from glial cells protect cultured neuroblastoma cells against glutamate toxicity. Brain Res 1994;645 (1
2):347
50. 107. May JM, Li L, Hayslett K, Qu Z-C. Ascorbate transport and recycling by SH-SY5Y neuroblastoma cells: response to glutamate toxicity. Neurochemical Res 2006;31 (6):785
94.

CURCUMIN FOR NEUROLOGICAL AND PSYCHIATRIC DISORDERS

44

2. HISTORICAL BACKGROUND, CHEMISTRY, PHARMACOLOGICAL ACTION

108. Jiang H, Wang Z, Wang Y, Xie K, Zhang Q, Luan Q, et al. Antidepressant-like effects of curcumin in chronic mild stress of rats: involvement of its anti-inflammatory action. Prog Neuropsychopharmacol Biol Psychiatry 2013;47:33
9. 109. Matteucci A, Cammarota R, Paradisi S, Varano M, Balduzzi M, Leo L, et al. Curcumin protects against NMDA-induced toxicity: a possible role for NR2A subunit. Invest Ophthalmol Vis Sci 2011;52(02):1070
7. 110. Chen K, An Y, Tie L, Pan Y, Li X. Curcumin protects neurons from glutamateinduced excitotoxicity by membrane anchored AKAP79-PKA interaction network. Evid Based Complement Alternat Med 2015;2015:706207. 111. Wang R, Li YB, Li YH, Xu Y, Wu HL, Li XJ. Curcumin protects against glutamate excitotoxicity in rat cerebral cortical neurons by increasing brain-derived neurotrophic factor level and activating TrkB. Brain Res 2008;1210:84
91. 112. Ono K, Hasegawa K, Naiki H, Yamada M. Curcumin has potent anti-amyloidogenic effects for Alzheimer’s beta-amyloid fibrils in vitro. J Neurosci Res 2004;75(6):742
50. 113. Garcia-Alloza M, Borrelli LA, Rozkalne A, Hyman BT, Bacskai BJ. Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model. J Neurochem 2007;102(4):1095
104. 114. Wang Y, Yin H, Wang L, Shuboy A, Lou J, Han B, et al. Curcumin as a potential treatment for Alzheimer’s disease: a study of the effects of curcumin on hippocampal expression of glial fibrillary acidic protein. Am J Chin Med 2013;41(1):59
70.

CURCUMIN FOR NEUROLOGICAL AND PSYCHIATRIC DISORDERS