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102 Current Pharmacogenomics and Personalized Medicine, 2015, Vol. 13, No. 2 .... in turn may raise the high trans-endothelial electrical resis- tance, which is ...

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Current Pharmacogenomics and Personalized Medicine, 2015, 13, 99-116 ISSN:1875-6921 eISSN: 1875-6913

Pharmacological Benefits of Active Components of Natural Products Against Traumatic Brain Injury - A Review BENTHAM SCIENCE

Selvaraju Subash1,2, Musthafa M. Essa1,2,3*, Samir Al-Adawi2,4, Mushtaq A. Memon5, Thamilarasan Manivasagam6, Arokiasamy J. Thenmozhi6, Mohammed Akbar7, Byoung-Joon Song7 and Gilles J. Guillemin8

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Department of Food Science and Nutrition, College of Agricultural and Marine Sciences, Sultan Qaboos University, Oman; 2Ageing and Dementia Research Group, Sultan Qaboos University, Oman; 3 Food and Brain Research Foundation, India; 4College of Medicine and Health Sciences, Sultan Qaboos University, Oman; 5College of Veterinary Medicine, Washington State University, Pullman, Washington, USA; 6Department of Biochemistry and Biotechnology, Annamalai University, Tamilnadu, India; 7Section of Molecular Pharmacology and Toxicology, LMBB, NIAAA, National Institutes of Health, Rockville, Maryland, USA; 8Neuroinflammation Group, Department of Biomedical Research, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia

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Abstract: Background: Since the last decade, the therapeutic potentials of natural phenolic antioxidants in human diseases associated with oxidative damage have received great attention. Within the last few years, a rapidly growing number of natural compounds with neuro-protective effects have been described. Many efforts have been made to explore the mechanisms for the neuro-protective properties of natural compounds. This review focuses on the beneficial effects of natural products in treating traumatic brain injury (TBI). Numerous epidemiological studies have shown consistent health benefits through the consumption of fruits, vegetables and nuts. In this review, we have summarized the protective effects of natural compounds [apocynin, (-)-epigallocatechin Gallate (EGCG), baicalein, caffeic acid, caffeic acid phenethyl ester, hydroxysaffloryellow A, osthole, oxy-resveratrol, pycnogenol, resveratrol, salvianolicacid B, triptolide and wogonin], and omega-3 fatty acid, particularly docosahexaenoic acid and its metabolites, may be used as personalized medicine against TBI and we have also discussed some of the barricades in translating these biofunctional compounds into relevant therapeutics for TBI.

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Conclusion: The benefits of natural products for traumatic brain injury show high inter-individual variability in their therapeutic effects and thus, this article addresses the intersection between novel therapeutics for traumatic brain injury and personalized medicine that will allow a broader range of interventions including the evidence-based natural products.

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Received: October 15, 2015

INTRODUCTION

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Keywords: EGCG, natural products, oxidative stress, phytochemicals, resveratrol, traumatic brain injury. Revised: November 27, 2015

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Current Pharmacogenomics and Personalized Medicine

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Traumatic brain injury (TBI) is a leading cause of disability and death in healthy populations of all ages living in the industrialized world [1]. TBI has long been called a “silent epidemic” and it affects up to 10 million people globally [2, 3]. Estimates suggest that between 2.5 million and 6.5 million individuals in the U.S.A. are living with the consequences of TBI, much of which were caused by motor vehicle accidents [4, 5]. It is estimated that more than 300,000 U.S. veterans of the wars in Iraq and Afghanistan (20% of the 1.6 million) have experienced a sustained TBI [6]. Data aggregated from Europe and the U.K. suggest that 235 per 100,000 people suffer from TBI severe enough to warrant hospitalization each year, although no truly efficacious and approved specific therapies are currently available [7]. Approximately one percent population of the developed countries experience TBI each year [8]. The World Health *Address correspondence to this author at the Department of Food Science & Nutrition, P.O. 34, CAMS, Sultan Qaboos University, Al-Khoud, Muscat, P.C. 123, Sultanate of Oman; Tel: +968 2414 3604; Fax: +968 2441 3418; E-mail: [email protected]; [email protected] 1875-6913/15 $58.00+.00

Accepted: November 27, 2015

Organization, in its 2004 World Report on Road Traffic Injury Prevention, predicted that by 2020, road traffic accidents would be within the top three leading causes of the global burden of disease, ahead of HIV and tuberculosis [9]. According to the aforementioned facts, TBI is one of the most serious and prevalent public health problems worldwide [10]. The pathophysiology of TBI is complex and heterogeneous. TBI can manifest clinically from concussion to coma and death, depending on the extent of brain damage. Two major pathophysiological processes contribute to brain injury after trauma: primary injury, where damage is caused as a direct result of the mechanical impact; and secondary injury, which is initiated immediately after trauma, activates multiple pathways due to further cellular damage from the effects of primary injuries. The secondary injury can continue to develop over a period of minutes, hours, days, or weeks later following the initial traumatic assault [4, 11, 12] (Fig. 1). Neuronal damage in TBI is caused by direct mechanical forces to the brain as well as by consequent vascular, cellular and molecular alterations that result in acute and delayed neuronal death or injury [13-15]. © 2015 Bentham Science Publishers

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activation of a cascade of events that include activation of calcium-dependent enzymes, destruction of the cellular architectures, and ultimately the demise of various cell types in the brain [24, 25]. This cellular demise occurs via the activation of both necrotic and apoptotic cell death pathways [23].

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The primary injury can represent any combination of skull fractures, intracranial hematomas, lacerations, contusions, and/or penetrating wounds. The primary injury results in the compression of neuronal, glial, astrocytic, and vascular tissue [16] and is associated with disruption of the cell membrane and disturbance of ionic homeostasis due to membrane leakiness [16, 17]. The initial impact to the brain was shown to stimulate multiple death pathways that include activation of cellular proteases such as calpains (papain-like calcium-dependent protease) and caspases [17, 18]. The primary injury is usually irreversible since neural cell death occurs at the moment of injury. On the contrary, the secondary injury is likely a reversible process because delayed neural cell death is a protracted event that can be regulated at many points in the death pathway. Therefore, intervention in the program of delayed neural cell death has become a therapeutic target for the successful treatment of TBI.

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Fig. (1). Schematic diagram of Traumatic Brain Injury (TBI) and the time frame resulting in primary and secondary brain damage. Use of personalized medicine and natural compounds may alleviate the insults induced by primary and secondary brain damage.

The primary injury is followed by a series of secondary processes that continue to cause axonal and neuronal damage on a cellular level. Such mechanisms include amino acid excitotoxicity, lipid peroxidation, free radical damage, calcium mediated complication, neuroinflammation, hypoxia and ischemia [19-21]. The secondary injuries can proceed within minutes or days after the initial head injury and culminate in widespread cell death [18, 22]. TBI-induced cell death is accompanied by release of the excitatory amino acids, increased production of reactive oxygen species (ROS)/reactive nitrogen species (RNS), disruption of mitochondrial bioenergetics, disturbances in calcium homeostasis, and neuroinflammatory responses such as reactive gliosis [17, 23-24]. These disturbances are then accompanied by the

Neurodegeneration can continue for months after TBI, both in humans and in experimental models [14]. Importantly, the mechanisms for post-traumatic cell death can differ from those of apoptotic programmed cell death, depending on the time delay from the primary TBI. There is also evidence that genetic background, gender, age, type and severity of the insult, metabolic state of the brain and other conditions (e.g. other pre-existing diseases, medication) associated with TBI can affect the severity and/or mechanisms of neurodegeneration [26]. Morphologically, neuronal death can be divided into two major types: necrosis and apoptosis. The two categories provide some clues about the underlying mechanisms of neuronal death, even though the usefulness of morphological criteria as a starting point for understanding biochemical cascades has been recently challenged [27]. Electron microscopic morphology of necrosis consists of inflated cellular appearance with swollen mitochondria, vacuolated cytoplasm, dilated endoplasmic reticulum (ER), pycnotic nuclei and plasma membrane rupture. Necrosis can be initiated by mechanical damage that leads to neuronal membrane failure, Ca2+ influx and disruption of ionic homeostasis which triggers the release of cytotoxic glutamate [28]. Disruptions of membrane potential can also be caused by TBI-associated ischemia or hypoglycemia, leading to membrane depolarization, glutamate release and overstimulation of postsynaptic N-methyl-D-aspartate (NMDA)

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preventative agents against TBI. Natural antioxidants, that can scavenge free radicals and prevent oxidative cell damage, have been evaluated for their potential neuro-protective properties [46]. Through numerous preclinical and clinical studies for potential neuro-protection, several natural compounds showed promising effects when evaluated with in vitro and in vivo models [47]. In this review, we have summarized the protective effects of a few natural compounds such as apocynin, (-)epigallocatechin gallate (EGCG), caffeic acid, resveratrol, etc., against TBI. We have also discussed some of the barricades in translating these biofunctional compounds into relevant therapeutics against TBI. APOCYNIN Apocynin (4-hydroxy-3-methoxyacetophenone) (Fig. 2) is a naturally occurring methoxy-substituted catechol, experimentally used as an inhibitor of Nicotinamide Adenine

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and -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (vide infra). These events result in high intracellular Ca2+, increased oxidative stress, mitochondrial failure with depleted ATP, and activation of Ca2+-dependent proteases (e.g., Calpains), that cause cytoskeletal destruction of postsynaptic neurons [29]. In addition, the spillover of lysosomal cathepsins contributes to necrotic death. An inflammatory response caused by the extracellular release of cytoplasmic components and/or breakdown of the bloodbrain barrier (BBB) is another factor that exposes adjacent neurons to death signals and secondary damage (e.g., activation of caspase 1). Necrotic appearance is most common for cells dying within minutes or a few days after TBI. Neurotransmitter release, calcium over-load, free radical-mediated damage, proapoptotic gene activation, mitochondrial dysfunction, and inflammatory responses are the major pathological mechanisms of the secondary injury [30-32]. All these mechanisms can be induced via synaptic transmission and subsequent activation of postsynaptic receptors. Several proteins on the postsynaptic membrane are believed to form a special postsynaptic structure known as the postsynaptic density that serves as a multi-protein complex with a molecular network among neural cells after injury.

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Pharmacological Benefits of Active Components of Natural Products

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Fig. (2). Chemical structure of apocynin.

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Dinucleotide Phosphate oxidase (NADPH-oxidase). In 1971, apocynin was isolated from Apocynum cannabinum (Canadian hemp) and Picrorhiza kurroa (Scrophulariaceae) roots [48, 49]. Extracts of apocynin, a well-known traditional Indian medicine, were used to counter dropsy and heart problems [50]. The main mechanism of action of apocynin is to prevent the translocation of the cytosolic subunit, p47phox, to the NADPH-oxidase catalytic membrane domain [51]. In several different models of middle cerebral artery occlusion (MCAO), administration of apocynin has been shown to reduce infarct size in rats [52-54]. However, most of these studies used only a single dose of apocynin and those using more than a single dose noted that neuro-protection occurred within a narrow dose range when measured 24 h postMCAO [55, 56]. In addition, different outcomes of infarct size were observed with apocynin, depending on the timing of apocynin treatment, the method of MCAO, the length of reperfusion (ranging from 22 h to 3 days post-MCAO). The efficacy of apocynin in attenuating NADPH-oxidase mediated oxidative stress has been evaluated in different animal models, and it has been extensively used as an effective antioxidant and anti-inflammatory agent in oriental medicine [57].

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Secondary injury results from the activation of multiple pathways, leading to altered ionic balance, BBB permeability, edema, increased intracranial pressure, oxidative stress, neuronal cell death, and eventual neurologic impairment [33]. Mitochondrial dysfunction is increased in the aged TBI brain, with enhanced oxidative damage of synaptic mitochondria, contributing to significant impairments in bioenergetics function [34]. After TBI, aged animals show increased evidence of oxidative stress (e.g., elevated levels of 4hydroxynonenal and acrolein) and reduced antioxidant capacity (e.g., ascorbate), when compared with those in younger counterparts [35-37]. At the time of BBB disruption, a neuroinflammatory response is activated and this event can persist for several weeks following TBI [38, 39]. This disruption results from mechanical shearing of blood vessels at the time of injury and/or chemically mediated signaling cascades [38-40]. Infiltrating peripheral immune cells (i.e. leukocytes) activate resident astrocytes and microglia to stimulate the pro-inflammatory signaling pathways, contributing to further BBB break-down and brain edema. These events cause structural damage and functional deficits due to both primary and secondary injuries [38, 40-42]. However, it has been clearly shown that beneficial outcomes can be achieved, if neuroinflammation is properly controlled in a regulated manner and at the defined time periods [43]. Posttraumatic neuroinflammation is also significantly impacted by aging, with more pronounced and prolonged glial cell activation in the hippocampus [44] through the altered expression of CCAAT/enhancer binding protein (C/EBP) transcription factors [45]. The pathogenesis of TBI is not completely understood, because of the lack of understanding of the pathological mechanisms for the development of secondary damage. Considering the limits of existing preventive methods, intervention strategies using antioxidants and/or flavonoid-rich natural products, such as fruits, vegetables and nuts, are of paramount importance. The therapeutic potential of herbs and marine natural products can also become important as the

ROS generation and oxidative stress through NADPHoxidase have been implicated in promoting neuronal cell death and functional impairments following TBI, and neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) [58-62]. A single intraperitoneal administration of apocynin (100 mg/kg) significantly

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[85]. Remarkably, EGCG treatment significantly decreased malondialdehyde (MDA) levels in the rat model. EGCG absorbs TBI-mediated free radicals, thereby preventing apoptotic cell death in neurons and neural stem cell (NSC) populations. Consistently, other studies also showed that EGCG treatment increased the number of nestin-positive cells and NSCs around the damaged area after TBI [85-87].

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Fig. (3). Chemical structure of EGCG.

BAICALEIN

Baicalein (5, 6, 7-trihydroxyflavone) (Fig. 4) is a major flavonoid extracted from the root of Scutellaria baicalensis Georgie (also called Huang Gui), an important medicinal plant widely used in China against allergic and inflammatory diseases such as hepatitis and asthma [88]. This flavonoid has been shown to exert potent anti-inflammatory effects in vitro as well as in vivo [89]. It has been shown to attenuate the focal cerebral ischemia/reperfusion injury and offer neuro-protective effects in PD while it can also inhibit amyloid-- and -synuclein-induced neuronal cell death [90-95].

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reduced the oxidative injury in the hippocampus mediated by ischemia and hypoglycemia in rats [63]. Apocynin is a highly selective, cell-permeable inhibitor of NADPHoxidase [64] with a half-life of about 1-h [65]. The process of neuronal death occurs within 1-h after TBI. Thus, if delivered within 1-h, a single concentrated dose of apocynin can prevent TBI-induced NADPH oxidase activation. In fact, apocynin acted as a neuroprotective agent, when administered during the critical time immediately after TBI [63]. The cellular mechanisms underlying TBI-induced neuronal injury might be more complex than simple mechanical injury and involves several factors downstream of the initial injury. These factors include sustained activation of the glutamate receptors [66], poly ADP-Ribose polymerase (PARP) activation [67] and zinc translocation [68, 69]. In addition, administration of apocynin strongly attenuated the elevation of superoxide anion (O2-.), which can be converted to highly toxic free radicals such as hydroxyl ion and peroxynitrite, which can cause nitroxidative damage to neurons and other cells [70], possibly through post-translational protein modifications including nitration, as reviewed for the peripheral tissues [71, 72]. Apocynin (i.p., at 4 mg/kg) treated 20 min preTBI or 2-h post-TBI significantly reduced oxidative damage in the cortex and hippocampus in mice.

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(-)-EPIGALLOCATECHIN GALLATE (EGCG)

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Green tea is a widely consumed beverage which contains many biologically important polyphenols. EGCG (trans-3, 4, 3’, 5’-tetrahydroxystilbene) (Fig. 3) is the major constituent, accounting for more than 10% of the extract in dry weight [74]. It exhibits a variety of biological functions and health benefits, including anti-obesity, anti-inflammatory, antiatherogenic and neuro-protective properties [75-78]. The proposed mechanisms for these beneficial effects include: inhibition of proteasome activity, inhibition of oncogene gene expression, and protection from DNA damage in normal cells [79-81]. Numerous in vitro and in vivo studies during the last decade have shown that EGCG can prevent and/or reduce the deleterious effects of oxygen-derived free radicals, which are associated with several human diseases [82]. The structural characteristics of green tea polyphenols for scavenging the superoxide anion radical have been reported [83]. In addition to ROS scavenging, green tea catechins are also able to trap reactive carbonyl species (RCS) such as glyoxal (GO), methylglyoxal (MG), and 3deoxyglucosone (3-DG) [84]. The importance of EGCG in enhancing cell resistance to oxidative stress goes beyond its simple ROS-scavenging and iron-chelating activities, and its effects are most profound in many pathological conditions where oxidative stress and iron accumulation are involved.

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The results described above strongly indicate oxidative damage, BBB disruption and subsequent microglial activation as a key mechanism of neuronal death after TBI. Intraperitoneal administration of apocynin significantly decreased the levels of ROS production, oxidative stress markers of lipid peroxidation, BBB disruption, DNA oxidative damage and microglia activation and thus showed profound neuroprotective properties against TBI [63, 73].

EGCG [0.1% (w/v)] in drinking water inhibits neuronal cell death caused by TBI-related free radicals in Wistar rats

Fig. (4). Chemical structure of baicalein.

Rats, subjected to controlled cortical impact (CCI) injury, were treated with a single or 4 consecutive daily doses of baicalein (30 mg/kg/dose) or vehicle immediately after injury [96]. Post-injury administration of baicalein significantly protected the rats from long-term neurological deficits and brain damage following the CCI injury. The functional and histological improvements were accompanied with decreased levels of TNF-, IL- and IL-6 mRNA transcripts and proteins in the brain. Thus, the protective effects of baicalein are mediated, in part, through modulation of the TBIinduced proinflammatory cascades. The advantages of baicalein treatment include: 1) chronic dosing is not required; 2) baicalein has relatively low levels of toxicity; and 3) it is easy to administer in emergency situations. Thus, baicalein offers a great promise as a potential treatment for TBI. CAFFEIC ACID Caffeic acid (3,4-dihydroxycinnamic acid) (Fig. 5) is a natural phenolic compound widely distributed in medicinal plants, vegetables, honeybee propolis and beverages such as wine, coffee, tea and apple juice [97, 98]. It is known for its

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anti-depressive, anti-tumor, anti-viral and anti-diabetic activities [99-102]. Furthermore, it possesses anti-oxidant properties as it scavenges a number of reactive species, including 1, 1-diphenyl-2-picryl-hydrazyl free radical (DPPH), peroxyl and hydroxyl radicals, superoxide anion and peroxynitrite [103-105]. It also inhibits 5-lipoxygenase (5-LOX) activity, protein kinase C (PKC), PKA and nuclear factor-B (NF-B) activation induced by ceramides in U937 cells [106-108].

Fig. (5). Chemical structure of caffeic acid.

Recently Kerman et al. have shown that a single dose of CAPE (10 mol/kg, i.p), given 15 min after trauma, can restore the suppressed activities of antioxidant enzymes (e.g., SOD, CAT and GPx) and thus ameliorate neuronal damage in experimental TBI model in Sprague–Dawley rats [119]. Additionally, CAPE administration inhibits lipid peroxidation in spinal cord and kidney after ischemia–reperfusion [120]. CAPE exhibits these protective effects through its high anti-oxidant capacity, but the exact mechanism of action of CAPE remains to be elucidated. Treatment with CAPE markedly reduced the immunereactivity of degenerating neurons after trauma. CAPE treatment has also been shown to inhibit apoptotic cell death by down-regulating caspase 3 in rat brain following transient focal cerebral ischemia [121], which caused shrunken cytoplasma, extensive dark pyknotic nuclei and vacuolization. These results indicate that the tissue edema were observed in the TBI neurons. However, the dark stained nuclei and the distorted nerve cells were mainly absent in the CAPE-treated traumatized rats in comparsion to the TBI animals [119].

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Caffeic acid inhibited astrocyte proliferation (astrogliosis) and glial scar formation in the late phase of cryoinjury in rats and mice [109-111]. This could be at least associated with its anti-oxidant ability. These findings suggest that caffeic acid may represent a new prototype compound of potential neuroprotective agents in the treatment of early and late TBIs [109].

provement might be resulted from increased levels of the tight junction protein claudin-5 in brain micro-vessels. This in turn may raise the high trans-endothelial electrical resistance, which is critical for maintaining proper BBB permeability for brain homeostasis.

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Pharmacological Benefits of Active Components of Natural Products

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HYDROXYSAFFLOR YELLOW A

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The flower of the safflower plant (Carthamus tinctorius L.) is extensively used in the traditional Chinese medicine for the treatment of cardiovascular and cerebrovascular diseases and used as a natural dye. Hydroxysafflor yellow A (HSYA) (Fig. 7) is one of the most important active ingredients of the safflower plant. Chinese State Food and Drug

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Caffeic acid phenethyl ester (CAPE) [3-(3, 4Dihydroxyphenyl)-2-propenoic acid 2-phenylethyl ester] (Fig. 6) is one of the most interesting bioactive compounds extracted from honeybee propolis. CAPE shows the potential therapeutic effects on many diseases and has been used for many years as a folk medicine. CAPE has been reported to decrease the inflammatory processes and brain lipid peroxidation with neuroprotective and antioxidant properties [110114]. CAPE can also modulate the Ca2+-induced release of cytochrome c in isolated brain and liver mitochondria [115, 116]. Gocer and Gulcin [117] studied the antioxidant and anti-radical activities of CAPE compared with standard antioxidant compounds. In addition, CAPE can be used as an easily accessible natural antioxidant and possibly as a food supplement. It can be also used to stabilize the food against oxidative deterioration.

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CAFFEIC ACID PHENETHYL ESTER

Fig. (6). Chemical structure of CAPE.

Zhao et al. [118] reported that post-injury administration of CAPE effectively reduces BBB permeability in both Sprague-Dawley rat and C57BL/6 mouse models of TBI. The beneficial effects of CAPE seem to be mediated through preserving claudin-5 levels. These results are associated with that activation of endogenous antioxidant proteins restores claudin-5 levels and markedly protects against TBI-induced enhanced permeability. Furthermore CAPE could be able to reduce cortical tissue loss, which is consistent with these studies [118]. However, the molecular mechanisms by which CAPE reduces BBB permeability are not known. This im-

Fig. (7). Chemical structure of HSYA.

Administration has approved HSYA (2,5-Cyclohexadien-1one,2,4-di--D-glucopyranosyl-3,4,5-trihydroxy-6-[(2E)-3(4-hydroxyphenyl)-1-oxo-2-propen-1-yl]) in March 2005 as a neuroprotective agent for the treatment of acute cerebral contusion (state drug permit document: Z20050146) [122]. Earlier data demonstrated that HSYA could provide neuroprotective effects via increasing the activity of SOD and decreasing the level of lipid peroxidation [123, 124]. It was also shown to prevent cerebral ischemia injury through its antioxidant action [125, 126]. Another study demonstrated

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Fig. (8). Chemical structure of osthole.

It has been reported that osthole can reduce cerebral water content (edema), improve neurological recovery, delay neuronal death and reduce hippocampal neuron loss at 24 h after TBI in Sprague–Dawley rats. Pretreatment with osthole (40 mg/kg, i.p.) significantly decreased the levels of MDA including ROS, while it increased GSH levels and SOD activity against the progression of secondary brain injuries. In addition, osthole increased the expression of Bcl-2 and decreased the expression of Bax, thus ameliorating the decreased Bcl-2/Bax ratio induced by TBI in the cerebral cortex [141]. Wu et al. reported that osthole may reduce calcium influx through the inhibition of L-type calcium channels in neuronal cells [140]. Furthermore, the number of TUNEL-positive cells was significantly reduced by osthole pretreatment at the same sites in the brain at 24 h after TBI. Caspase-3, a key executor in apoptosis, can stimulate a DNA fragmentation factor, which activates endonucleases to cleave nucleic acids and finally leads to cell death. These results suggest that the protective effect of osthole may be attributable to the reduction in apoptotic activity of brain tissue after TBI [142].

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Matrix metalloproteinases (MMPs) represent a family of calcium-requiring, zinc-containing proteolytic enzymes, which degrade the proteins of the extracellular matrix. Among MMP isozymes, gelatinase A (MMP-2) and gelatinase B (MMP-9) are able to digest the components of the basement membrane. The increased MMPs are implicated in the pathogenesis of several central nervous system diseases, such as cerebral ischemia [130, 131]. When treated with HSYA at 30 min before and 6 h after the onset of TBI, the percent of MMP-9 positive cells decreased, suggesting that HYSA has beneficial effects on cerebral ischemia [124, 130, 131]. All these studies suggest that HSYA may exert potential therapeutic properties to improve the outcome following the TBI. These results may be, at least in part, resulted from improved mitochondrial activity, antioxidant capacity, and antithrombotic with fibrinolytic effects.

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Tissue plasminogen activator (t-PA) is the major physiological plasminogen activator and is inhibited by Plasminogen activator inhibitor-1 (PAI-1). t-PA can cause thrombus fibrinolysis, whereas PAI-1 can lead to thrombus formation by inhibiting t-PA activity [129]. HSYA, administered at 30 min before and 6 h after the onset of TBI, could down regulate t-PA activity and upregulate PAI-1 activity in the TBI. These additional antithrombotic and fibrinolytic effects of HSYA may provide important benefits to the effective management of TBI [124].

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HYSA, injected via tail-vein at 4 mg/kg, significantly reduced the contusion volume in male Sprague–Dawley rats 24 h after the TBI. Morphological evidence of cell death, caused by the irreversibly impaired oxidative respiratory enzymes Ca2+-ATPase and Mg2+-ATPase after the TBI, is commonly detected by 2, 3, 5-triphenyl-tetrazolium chloride (TTC) staining, a sensitive histochemical indicator of mitochondrial respiratory enzyme function [124]. Its inhibition would result in a decline of Na+ and K + electrochemical gradients and ultimately lead to cell death as a result of osmotic damage and the accumulation of intracellular Ca2+ secondary to the decreased active Ca2+ influx by the Na+/Ca2+ exchange system [128]. When treated with HSYA at 30 min before and 6 h after the onset of TBI, the activities of Na+, K+-ATPase, Ca2+-ATPase, and Mg2+-ATPase were significantly elevated, especially at 24 and 48 h, compared with the TBI-control groups, suggesting the improvement in mitochondrial activity with reduced the contusion volume. In addition, HYSA treatment increased the SOD activity compared to that in the TBI-group after 48 h [124].

apoptotic properties in brain ischemia models and immunesuppressive actions in both in vivo and in vitro experiments were reported [135-139]. Osthole is a potent antioxidant which can eliminate oxygen free radicals, inhibit lipid peroxidation and potentially block the calcium channel in NG108-15 neuronal cells [140].

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that HSYA reduced apoptosis of vascular endothelial cells under hypoxia through up-regulation of the HIF-1-VEGF pathway and the ratio of Bcl-2/Bax [127]. However, the exact mechanism is still unclear.

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OSTHOLE Osthole (7-methoxy-8-isopentenoxycoumarin) (Fig. 8), a natural coumarin derivative, is a component extracted from the medicinal plants Cnidium monnieri (L), Cusson and Peucedanum ostruthium, whose dried fruits have been used as a traditional folk medicine for many years. Previous studies have shown that osthole has a broad spectrum of pharmacological properties [132-134]. In addition, neuro-protective effects such as anti-inflammatory, anti-oxidative, and anti-

OXYRESVERATROL Oxyresveratrol (2, 4, 3’, 5’-tetrahydroxystilbene) (Fig. 9), isolated from mulberry wood (Morus alba L.), is a potent antioxidant and free-radical scavenger [143, 144]. Its pharmacological properties include a wide range of biological activities. However the neuroprotective effects of oxyresveratrol have been demonstrated in experimental models of ischemia/ reperfusion injury and other neurological pathologies [144146]. It also protects cultured rat cortical neurons from amyloid- and NMDA-induced neurotoxicities by reducing the number of apoptotic cells in transient cerebral ischemia and inhibiting the -secretase (BACE1) activity [147-149]. The protective effect of oxyresveratrol after middle cerebral arterial occlusion was reported to be mediated through significant reduction of the infarct volume [148]. Neuroblastoma cells exposed to 6-hydroxydopamine, used as a model of PD, were also protected by oxyresveratrol treatment [150]. In experimental models of exposures to both NMDA and 6hydroxydopamine, oxyresveratrol was more potent than resveratrol in providing neuroprotection. Oxyresveratrol differs from resveratrol due to the presence of an extra hydroxyl group, which enhances its antioxidant activity.

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Fig. (9). Chemical structure of oxyresveratrol.

RESVERATROL Resveratrol (trans-3,4,5-trihydroxystilbene) (Fig. 11) is a naturally occurring non-toxic polyphenol mainly present in some plants (cranberries, grapes and peanuts) and constitutes one of the components in red wine, which shows beneficial effects on the age-related metabolic diseases, such as type-2 diabetes and obesity [161, 162]. In addition, other studies have reported that resveratrol exerts a variety of desirable biological activities, including anti-inammatory properties, cardio-protective, hypoglycemic, hypolipidemic, anti-aging, anti-cancer and neuro-protective properties [163-167]. The neuroprotective effects of this compound have been investigated in various models of neurodegenerative diseases, such as epilepsy, stroke, AD, PD, Huntington’s diseases (HD), cerebral ischemia, amyotrophic lateral sclerosis (ALS) and nerve injury [168-176]. The cellular mechanisms for resveratrol-induced neuro-protection must be better elucidated. Moreover, evidences show that resveratrol-mediated neuroprotective effects against ischemia injury are mediated by influencing the levels of certain neurotransmitters and neuromodulators released during ischemia/reperfusion. Furthermore, resveratrol has been shown to ameliorate apoptotic cell death and retinal structural damage in light-exposed mice [177]. These results showed that the neuroprotective effects of resveratrol are attributed to its antioxidant and NOscavenging properties with inhibition of excitatory synaptic transmission [178-180].

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Pycnogenol® (PYC) (Fig. 10) is a patented combination of bioflavonoids extracted from the bark of the French maritime pine, Pinus maritima. Major constituents of PYC are polyphenols, specifically mono- and oligomeric units of caffeic acid, ferulic acid, catechin, epicatechin, taxifolin, and caffeic acid [107, 152]. PYC has been reported to possess a strong antioxidant property to prevent neurotoxicity and apoptotic cell death caused by various stressors such as lipid peroxides, pro-oxidants and peroxynitrite [105, 153]. Protective effect of PYC, as a potent antioxidant, on the acroleininduced cytotoxicity has been demonstrated in human neuroblastoma (SH-SY5Y) cells [154]. The cellular antioxidant network and the expression of those genes that are regulated by cell redox status have been studied in various in vitro and in vivo models [155-159].

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Weber et al [151] analyzed the neuroprotective potential of oxyresveratrol in an in vitro model of stretch-induced trauma by using co-cultures of cortical neurons and glia. Oxyresveratrol (100 M) protected cortical neurons in the co-cultured cells, but not the glia as demonstrated by elevated S-100B protein release and a high proportion of cells with condensed nuclei. These results show that neuronal cells in high traumatic conditions and high glutamate treatment are differentially protected by oxyresveratrol in comparison to glia. Studies involving oxyreserveratrol in trauma models are necessary, as selective toxicity to glia could be beneficial by inhibiting reactive gliosis, which often occurs after trauma. The exact mechanisms of the observed effects are still unknown.

PYC (100 mg/kg/dose, three i.p. injections at 15 min, 3 h, and 6 h following a cortical contusion injury for 48 h), significantly reduced the levels of oxidative stress markers [e.g., TBARS, 4-hydroxynonenal (4-HNE), 3-nitrotyrosine (3-NT)] in Sprague-Dawley rats [160]. In addition, increased antioxidant levels (GSH, SOD, and catalase) and reduced levels of neuroinflammation markers (TNF- and IL-6) were observed. After 96 h, the reduction of key synaptic proteins (postsynaptic density protein 95, PSD-95) was also recognized in the cerebral cortex and hippocampus. These results support the idea that a combinational bioflavonoid can offer significant neuroprotection against acute brain trauma. However, the mechanism of action of PYC appears to be more complex than that of a single antioxidant [160].

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Pharmacological Benefits of Active Components of Natural Products

Fig. (11). Chemical structure of resveratrol.

Fig. (10). Chemical structure of pycnogenol.

A single dose of resveratrol, when administered intraperitoneally at 100 mg/kg immediately after TBI, significantly reduced the levels of MDA, xanthine oxidase (XO), nitric oxide (NO), and oxidative stress in Wistar albino male rats [181]. It also increased the GSH level and decreased the area of tissue lesion in traumatic rats. These results indicated that resveratrol, treated immediately after TBI, can effectively reduce oxidative stress and the lesion volume.

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TRIPTOLIDE Triptolide, a diterpene triepoxide (Fig. 13), was first isolated from the medicinal plant Tripterygium wilfordii Hook F (TWHF), which had been used for centuries in traditional Chinese medicine. Clinical and experimental studies have demonstrated that triptolide has anti-inflammatory and immunosuppressive properties. Triptolide has been reported as a strong inhibitor of NF-B, a critically important transcription factor in regulating inflammation, while it can protect donor hearts from ischemia/reperfusion-induced injury in heart transplantation [192-194].

Fig. (13). Chemical structure of triptolide.

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Furthermore, in vitro results showed that triptolide defends dopaminergic neurons from inflammation-mediated damage [195] and protects neural cells through the inhibition of chemokine (C-X-C motif) receptor 2 (CXCR2) activities [196]. It is also capable of promoting nerve regeneration and functional recovery after spinal cord and brain injuries [197, 198]. All these studies support the potential use of triptolide in treating peripheral and central nerve injury.

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Danshen, the dried root of Salvia miltiorrhiza Bunge (labiatae), is a traditional Chinese medicine containing salvianolic acid B (Fig. 12), which is bioactive and most abundantly present [187, 188]. In animal model studies, salvianolic acid B has been shown to exhibit many beneficial properties of the danshen herb. For instance, it inhibits hydrogen peroxide-induced endothelial cell apoptosis through regulating the PI3K/Akt signaling pathway, while it protects against skin injury, heart and brain caused by ischemia-reperfusion [189-191].

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A single intraperitoneal injection of resveratrol at 100 mg/kg immediately after the trauma reduced the neuronal loss in all ipsi- and the contralateral hippocampal brain regions of Wistar Albino rats. Additionally, treatment with resveratrol significantly modified the cognitive and behavioral performances of TBI-inflicted immature rats, indicating that resveratrol has a neuroprotective effect on cognitive impairment of hippocampal neurons [186]. Improvement in cerebral function reflects neuroprotective effect of resveratrol on the hippocampal regions.

tion and microglia activation, thus preventing the cellular neuroinflammation after TBI. For instance, salvianolic acid B markedly suppressed the expression of pro-inflammatory cytokines TNF- and IL-1, while it elevated the expression of anti-inflammatory cytokines IL-10 and TGF-1 in the brain at 24 h after TBI.

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Post-injury administration of resveratrol (100 mg/kg, i.p.) in the model of Sprague-Dawley rats significantly reduced the severity of cognitive and motor deficits associated with increased contusion volumes, while it preserved CA1 and CA3 hippocampal neurons with protection from overt hippocampal loss [182]. Although the underlying mechanisms by which resveratrol mediates its neuroprotection are still unclear, the study added to the growing literature of identifying resveratrol as a potential therapy for human brain injury. The two prominent brain regions affected in head trauma are the cortex and the hippocampus that play a crucial role in the processing and execution of spatial memory and learning [183, 184]. Ozdemir et al. showed that neuronal loss is not limited to ipsilateral hippocampal regions, but also in contralateral hippocampal areas at 24 h after trauma and in immature rat brains [185].

Subash et al.

Fig. (12). Chemical structure of salvianolicacid B.

Salvianolic acid B (25 mg/kg by injection), treated within 2 h after TBI in male C57BL/6J mice, significantly alleviated brain edema, reduced lesion volume, suppressed inflammatory responses, reduced motor functional deficits, and improved spatial learning and memory. Nevertheless, the molecular mechanisms for the neuroprotective properties of salvianolic acid B remain to be investigated. Reports have shown that salvianolic acid B suppressed neutrophil infiltra-

Triptolide (1 mg/kg, i.p.) treated soon after the induction of TBI showed anti-inflammatory and neuroprotective effects on the brain injury by inhibiting the levels of proinflammatory cytokines TNF-, IL-1, and IL-6, thus preventing apoptotic cell death and loss of cerebral neurons in Sprague-Dawley rats. In addition, triptolide inhibited the pro-inflammatory prostanoids (PGI2 and PGE2), that contribute to the formation of brain edema and excess cerebral cell apoptosis in several forms of brain injury. In another study, rats treated with a single dose of triptolide, displayed improvement in neurobehavioral outcomes measured. These findings suggest that triptolide confers neuroprotection against TBI and that this protection is mediated through an attenuation of neuroinflammation in the brain [199]. WOGONIN Wogonin (5, 7-dihydroxy-8-methoxyflavone) (Fig. 14), is a flavonoid found in the root of the Chinese herb Scutellaria baicalensis Georgi (also called Huang-Qin), which has been shown to exert potent anti-inflammatory effects in both in vitro and in vivo studies. Additionally, increasing evidence

Pharmacological Benefits of Active Components of Natural Products

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suggests that wogonin may have neuroprotective effects on the injured brain. Wogonin also reduced early ischemic brain injury and improved acute behavioral dysfunctions caused by focal cerebral ischemia [200, 201]. Furthermore, it attenuated excitotoxic and oxidative stress-induced neuronal damage in primary cultured rat cortical cells [202] while it reduced neuronal damage caused by exposure to oxygen and glucose deprivation in cultured rat hippocampal slices [203]. In addition, wogonin attenuated the death of hippocampal neurons and inhibited microglia activation in global ischemia and excitotoxic injury models [204].

reduced (4.4-fold) prevalence of AD in India compared to that in the United States [209]. Curcumin is a potent inhibitor of NF-B [210], thus preventing neuroinflammation and neurological injury in experimental models of AD, ischemic stroke, subarachnoid hemorrhage and focal cerebral ischemia [211-215]. In addition, the curcumin treatment can protect hippocampal neurons against excitotoxic and traumatic injury [216].

Fig. (15). Chemical structure of curcumin.

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Wogonin treatment caused a significant reduction in both sensory-motor deficits [assessed by mNSS (modified neurological severity score)] and post-injury motor dysfunction (assessed by rotarod and beam walk tests), indicating that wogonin can be highly effective in providing long-lasting protection from the TBI. The protection afforded by wogonin was associated with a decrease in neuronal damage and apoptotic cell death with a reduced contusion volume in the cortical regions involved in motor and sensory functions [205]. Further investigations are needed to clarify the underlying mechanisms for the neuroprotective effects of wogonin on TBI.

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The powerful antioxidant effects of curcumin were sufficient to reduce the action of oxidative stress on the BDNF system, synaptic plasticity, and cognitive function altered by TBI. However, more mechanistic and interventional studies are warranted to further evaluate the role of curcumin in clinical brain disorders and injuries.

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The post-injury treatment with wogonin (40 mg/kg, i.p.) has been shown to improve long-term functional and histological outcomes, while it reduced brain edema in a clinically relevant model of TBI in C57BL/6 mice. This could suggest that the neuroprotective effects of wogonin following TBI may be mediated, at least in part, through suppressing the TLR4/NF-kB signaling pathway and downstream factors (e.g., IL-1, IL-6, MIP-2, MMP-9 activity and COX2 expression). Thus, wogonin could be a potential therapeutic choice in the treatment of TBI [205].

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Fig. (14). Chemical structure of wogonin.

The silent information regulator 2 (Sir2) has emerged as an important modulator of genomic stability and cellular homeostasis. Dietary supplementation of curcumin (500 ppm for 4 weeks) ameliorated neuronal damage partly through modulation of the expression of proteins such as AMPK, uMtCK, UCP2, COX-II and Sir2 following fluid percussion injury (FPI). These results show the potential benefits of curcumin supplementation to regulate the molecules involved in the deleterious effects on energy homeostasis, cognitive function and neuronal plasticity following TBI, as demonstrated in male Sprague–Dawley rats [217].

CURCUMIN Curcumin [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6heptadiene-3,5-dione] (Fig. 15), a low molecular weight, lipophilic, natural yellow colored polyphenolic compound of Indian spice turmeric derived from the rhizome Curcuma longa. It has been consumed by humans for centuries as an anti-inflammatory and antioxidant in ayurvedic medicine [206]. It also reduces oxidative damage and cognitive deficits associated with aging and other pathological conditions. The curcumin is known to protect not only the brain from free radical-induced damage [207] but also for the cardiovascular, pulmonary, autoimmune and neoplastic diseases [208]. A single epidemiological study suggested that curcumin, as one of the most prevalent nutritional and medicinal compounds used by the Indian people, is responsible for the

DOCOSAHEXAENOIC ACID In addition to natural compounds that are present in various fruits, vegetables, nuts, and seeds, sea foods also contain tremendous amounts of healthy oils and fats that are equally beneficial in overall metabolic, cardiovascular and specifically neurological diseases. Dietary intake of general polyunsaturated fatty acids (PUFAs), including omega-3 fatty acids in particular, is important for the normal development and functioning of the brain. For instance, docosahexaenoic acid (DHA, 22:6, n-3) (Fig. 16), a long-chain n-3 PUFA, is highly enriched in the human central nervous system [218] and required for proper embryonic neurodevelopment. DHA along with other n-3 PUFAs have been reported to exhibit beneficial effects on the prevention and treatment of a variety of human diseases [219]. DHA offers beneficial effects in autoimmune and inflammatory disorders, cardiovascular diseases and retinopathy [220-223]. Inadequate supply of n-3 PUFAs during prenatal and postnatal development decreases the levels of DHA in neuronal tissues, leading to a variety of visual, cognitive, and/or behavioral deficits in animal models [224-226]. In addition, it has been indicated that low levels of DHA in the brain are associated with neurodegenerative diseases, such as generalized peroxisomal disorders and AD [227, 228].

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loss of DHA in the brain, increase in alpha spectrin II and decrease in NeuN positive cells, suggesting the importance of brain DHA status after TBI [230]. The benefit of omega-3 fatty acids including DHA, against TBI was recently reviewed [231]. CONCLUSION AND FUTURE DIRECTIONS

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Resveratrol, Curcumin

Resveratrol, Salvianolicacid B, Wogonin, Docosahexaenoic acid

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EGCG, Baicalein, Caffeic acid, Caffeic acid phenethyl ester, Osthole, Pycnogenol, Resveratrol, Triptolide, Wogonin, Curcumin

Me mo ry an d Be ha vio r

Increased Apoptosis Astrocyte Proliferation and glial scar formation

Excitotoxicity Impaired Energy Metabolism

Inc rea sed Ap opt osi s

Apocynin, EGCG, Baicalein, Caffeic acid, Caffeic acid phenethyl ester, Hydroxysafflor yellow A, Osthole, Oxyresveratrol, Pycnogenol, Resveratrol, Salvianolicacid B, Wogonin, Curcumin, 51 |Triptolide, Page Docosahexaenoic acid

Caffeic acid, Oxyresveratrol

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Apocynin, Baicalein, Caffeic acid phenethyl ester, Hydroxysafflor yellow A, Osthole, Oxyresveratrol, Resveratrol, Salvianolicacid B, Triptolide, Wogonin, Curcumin

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Recent studies have demonstrated that DHA is beneficial in CCI-induced TBI. Mice fed with a DHA-supplemented diet for two months showed significant short- and long-term beneficial effects after induction of TBI. Supplementation of DHA indeed showed protection against hippocampal neurons and prevented loss of myelin basic protein (MBP). In addition, DHA restored the integrity of myelin sheath, resulting in the maintenance of nerve fiber conductivity in CCImodel animals [229]. In another study, in comparison to an adequate diet, the omega-3 deficient diet fed mice showed significant behavioral deficits evaluated by rotarod and beam walk tests after CCI. Mice fed the DHA-deficient diet also showed anxiety-like behavior assessed by the open field test and novel object recognition test. The dietary deficiency regime for three generations resulted in approximately 70%

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Fig. (16). Chemical structure of docosahexaenoic acid.

The potential benefits of natural compounds for the prevention and treatment of TBI have been supported by numerous experimental studies. Evidences suggest that the TBI might be influenced by nutritional factors, i.e., bioactive compounds (Fig. 1 and Table 1). Naturally present bioactive compounds are good for the prevention and cure of various diseases without undesirable side effects. As multiple causative factors exist for the pathology of TBI, diverse mechanisms may be associated with the preventative effects. For instance, dietary changes provide better outcomes for patients with TBI. A ketogenic diet, which produces ketone bodies, was shown to have neuroprotective effects, since metabolism of ketone bodies decreases the amounts of ROS and exerts antioxidant, anti-inflammatory, and anti-apoptotic effects on the brain [232]. Also, magnesium, zinc, and branched-chain amino acids provide neuroprotection and increased cognitive function. Further, supplementation with DHA and other omega-3 fatty acids revealed a reduction in axonal damage and increased cognitive performance of TBIinflicted rats. On the other hand, high fat and high sucrose diets have shown to reduce spatial learning in TBI rats [232]. These results show that correcting the cerebral homeostatic dysfunction through various dietary supplements may allow for better therapeutic outcomes in patients with TBI.

TBI

Hydroxysafflor yellow A, Salvianolicacid B, Curcumin

Mitochondrial dysfunction In cr ea see d O xi da tiv ti e

EGCG, Baicalein, Caffeic acid, Caffeic acid phenethyl ester, Hydroxysafflor yellow A

Apocynin, EGCG, Caffeic acid phenethyl ester

Disruption of Blood brain barrier

Fig. (17). Graphic representation showing the targets for the TBI effects of naturally occurring compounds.

Pharmacological Benefits of Active Components of Natural Products

Shows the published reports on natural compounds against TBI

Natural Compounds

Sources

Class/mechanism/therapeutic mode

Apocynin

Apocynum cannabinum, Picrorhiza kurroa

Inhibitor of NADPH oxidase

EGCG

Green tea Camellia sinensis

Inhibits neuronal cell degeneration and death

Baicalein

Scutellaria baicalensis Georgire

Attenuated expression of TNF-, IL-1  and IL-6 mRNA and protein

Increased the reduced antioxidant enzyme activities (SOD, CAT and GPx) and reduced MDA levels

Propolis

Decreased the MMP-9 expression

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• Neuroprotective effects

• Neuroprotection against brain damage • Antithrombotic and fibrinolytic effects • Reduced pathogenesis brain

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Restore the t-PA and PAI-1 activity

Chen et al., 2008 [96]

Zhang et al., 2007 [109]

Kerman et al., 2012 [119]

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Improve mitochondrial activity and reduce contusion volume

Itoh et al., 2012 [85]

• Reduced neuronal damage

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Carthamus tinctorius

Itoh et al., 2012 [85]

Zhao et al., 2012 [118]

• Reduced neurons distributed

Increasing the activity of SOD and decreasing the level of lipid peroxidation

References

• Reduces BBB permeability

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Altered Caspase-3 activity

Hydroxysafflor yellow A

• Reduce brain oedema and tissue damage

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CAPE

• preventing free radical mediated apoptosis and cell death

• Late astrocyte proliferation and glial scar formation

Inhibition of 5-lipoxygenase (5-LOX) activity

Restores claudin-5 levels

• Reduced free radicals produced by TBI around the damaged brain region

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Propolis, coffee, tea and apple

• Reduced microglial activation in the hippocampus after TBI.

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Caffeic acid

Cimicifuga heracleifolia, Fruits, vegetables, tea,

Therapeutic effect

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Table 1.

Current Pharmacogenomics and Personalized Medicine, 2015, Vol. 13, No. 2 109

Kerman et al., 2012 [119] Bie et al., 2010 [124] Zhu et al., 2003; 2005 [91, 92] Bie et al., 2010 [124] Bie et al., 2010 [124]

• Reduce cerebral water content, cerebral edema, delayed neuronal death and reduce hippocampal neuron loss

Ameliorating the Bcl-2/Bax ratio and caspase-3 activity

• Reductions in apoptotic activity of brain tissue

Ramulus mori, Morus alba, Artocarpus lakoocha

Elevated S-100B protein release and a high proportion of cells with condensed nuclei

• Inhibiting reactive gliosis

Weber et al., 2012 [151]

Pycnogenol

Pinus maritime, Pinus pinaster

Reduced levels of oxidative stress markers and neuroinflammation markers, increased antioxidants and key synaptic proteins in cortex and hippocampus

• Neuroprotection after acute brain trauma

Scheff et al., 2012 [160]

Reduced MDA, XO and NO levels, increased GSH level

• Attenuated tissue lesion area in trauma

Resveratrol

Cranberries, grapes, peanuts, red wine, mulberries and pomegranate, Veratrum grandiflorum, Polygonum cuspidatum

Oxyresveratrol

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Osthole

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Decreased MDA, increased SOD and GSH level activity and reduce calcium influx

Cnidium monnieri, Peucedanum ostruthium, Angelica pubescens

Reduced contusion volumes, preservation of CA1 and CA3 hippocampal neurons Reduced the neuronal loss in all ipsiand the contralateral hippocampal regions

• Behavioral protection • Behavioral changes

Wu et al., 2002 [140] He et al., 2012 [141] ; Nagata, 1997 [142]

Ates et al., 2007 [181] Singleton et al., 2010 [182]

Sonmez et al., 2007 [186].

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Table (1) contd….

Sources

Class/mechanism/therapeutic mode

Salvianolic acid B

Danshen, Salvia miltiorrhiza

Alleviated brain edema, reduced lesion volume, suppressed inflammatory responses, reduced motor functional deficits, improved spatial learning and memory

• Recovered brain damage and inflammation

Triptolide

Tripterygium wilfordii

Ameliorated inflammatory mediators (TNF-, IL-1 and IL-6)

• Attenuation of neuroinflammation in the brain

Therapeutic effect

Modulation of the TLR4/NF-kB signaling pathway

References

Chen et al., 2011[101]

Lee et al., 2012 [198]

Chen et al., 2012 [198]

Reduction in contusion volume in the cortical regions involved in motor and sensory functions

• Decrease in neuronal damage and apoptotic cell death

Chen et al., 2012 [198]

• Regulate molecules involved in deleterious effects of energy homeostasis and cognitive function

Sharma et al., 2009 [217]

Curcumin

Curcuma longa

Decreased the expression of molecular systems such as AMPK, uMtCK, UCP2, COX-II and Sir2

Docosahexaenoic acid

Fruits, vegetables, nuts, seeds, sea foods, fat fish

Evaluated by rotarod and beam walk

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Wogonin

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• Reduced neuronal damage and behavioral impairment

Scutellaria baicalensis

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TBI often followed by elevated nitroxidative stress conditions. As a consequence, the administration of exogenous antioxidants could be beneficial for the proper handling of cell's oxidative stress status. In fact, epidemiological studies suggested that the regular intake of phenolic-rich vegetables and/or fruits can reduce the risk of oxidative stress-related diseases. In this regard, the important role of certain dietary components in alleviating various disorders is beginning to receive high attention, mainly due to beneficial phytochemicals contained in fruits and vegetables. All these known facts or knowledge should be utilized to find out a novel therapeutic option for the social and medical problems in human TBI survivors. The future research related to the therapeutic potential of natural phenolic antioxidants in human diseases associated with nitroxidative damage will enhance our understanding of these beneficial compounds.

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Over the past several decades, experimental research on TBI models has validated the contribution of free radicalinduced oxidative damage in the multidimensional secondary injury response following the TBI and recent reports confirm that anitoxidants and natural products could offer protection to TBI and other neurodegenerative conditions [233-253]. To date, the development of potent antioxidant compounds remains an attractive and promising strategy for the effective treatment of TBI. In the current review, we briefly described that treatment with naturally occurring compounds such as apocynin, EGCG, baicalein, caffeic acid, caffeic acid phenethyl ester, hydroxysaffloryellow A, osthole, oxyresveratrol, pycnogenol, resveratrol, salvianolicacid B, triptolide, wogonin, curcumin and omega-3 fatty acids (particularly, DHA) with antioxidant properties have been shown to reduce TBI-mediated cognitive deficits and/or functional impairments (Fig. 17 and Table 1). For the therapeutic purposes, it is ideal to focus on the inflammation process or downstream events of neuronal damage, behavioral impairment, apoptotic activity of brain tissue, BBB disruption and lipid peroxidation initiation, because these signaling events associated with the secondary injury may take several days to develop following the primary injury and thus widen the treatment window range. In these cases, the usage of natural components appears to have the significant advantage because of their relatively low toxicity, high availability with low costs and long term retention. So, a "nutritional therapy" emerges as an important strategy for preventing and/or treating TBI, contributing to the welfare of many affected individuals. However, further clinical trials and/or mechanistic studies need to be conducted to establish their efficacies.

Desai et al., 2013 [230]

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Natural Compounds

Endogenous antioxidant defenses available in our body may not be proficient to block or counteract the increased production of ROS/RNS during disease conditions including

CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS This work was supported by a research grant from The Research Council of Oman (Grant # RC/AGR/FOOD/11/01 to MME), which is greatly appreciated. This work was also supported by the Intramural Program Fund of the National Institute of Alcohol Abuse and Alcoholism. The support provided by an internal grant from CAMS, SQU (IG/AGR/FOOD/14/01) is highly acknowldeged. REFERENCES [1]

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