PHYTOTHERAPY RESEARCH Phytother. Res. 29: 978–985 (2015) Published online 17 April 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ptr.5353

REVIEW

The Potential for Plant Derivatives against Acrylamide Neurotoxicity O. O. Adewale,1,2,4† J. M. Brimson,4† O. A. Odunola,1 M. A. Gbadegesin,1 S. E. Owumi,1 C. Isidoro3* and T. Tencomnao4* 1

Cancer Research and Molecular Biology Unit, Department of Biochemistry, College of Medicine, University of Ibadan, Ibadan, Nigeria Department of Chemical Sciences, Faculty of Basic and Applied Sciences, Osun State University, Osogbo, Nigeria 3 Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale ‘A. Avogadro’, Novara, Italy 4 Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand 2

Certain industrial chemicals and food contaminants have been demonstrated to possess neurotoxic activity and have been suspected to cause brain-related disorders in humans. Acrylamide (ACR), a confirmed neurotoxicant, can be found in trace amount in commonly consumed human aliments as a result of food processing or cooking. This discovery aroused a great concern in the public, and increasing efforts are continuously geared towards the resolution of this serious threat. The broad chemical diversity of plants may offer the resources for novel antidotes against neurotoxicants. With the goal of attenuating neurotoxicity of ACR, several plants extracts or derivatives have been employed. This review presents the plants and their derivatives that have been shown most active against ACR-induced neurotoxicity, with a focus on their origin, pharmacological activity, and antidote effects. Copyright © 2015 John Wiley & Sons, Ltd. Keywords: medicinal plants; neuroprotection; oxidative stress; plant products; reactive oxygen species. Abbreviations: ACR, acrylamide; DSS, dark soy sauce; GSK-3β, glycogen synthase kinase 3 beta; GSH, reduced glutathione; ROS, reactive oxygen species; SOD, superoxide dismutase

INTRODUCTION Acrylamide (ACR), a water soluble vinyl monomer, finds its main application in the production of polymers that are used in various chemical industries such as cosmetics, water and wastewater management, road construction, and pulp and papermaking industries (Dearfield et al., 1988). ACR also has an important application in laboratory research, used in gel electrophoretic separation of molecules. Because of its wide application, people experience high levels of exposure. Neurotoxicity is a major consequence of exposure to ACR, and considerable attention has been drawn to this area of investigation over the past 40 years. Increased incidence of neurotoxicity among occupationally exposed population has been ascertained by various epidemiology studies (He et al., 1989; Deng et al., 1993). Among the neurotoxicity symptoms of ACR are characteristic ataxia, skeletal muscle weakness, weight loss (LoPachin, 2005), distal swelling, and degeneration of axons in the central nervous system and peripheral nervous system (El-Tantawi, 2007). Neurotoxicity of ACR has been shown in animal studies and is characterized by sensory, autonomic, and * Correspondence to: Ciro Isidoro, Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale ‘A. Avogadro’, Novara, Italy; Tewin Tencomnao, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand. E-mail: [email protected]; [email protected] † These two authors equally contributed to the work.

Copyright © 2015 John Wiley & Sons, Ltd.

motor deficits resulting from nerve terminal dysfunction in the thalamus, basal ganglia, and other brain regions (Mehri et al., 2014a, 2014b; Lehning et al., 2003; LoPachin, 2004, 2005). These effects are brought about by ACR through the alteration of synthesis, storage, uptake, and release of neurotransmitters (Goldstein and Lowndes, 1981). Furthermore, ACR causes structural changes in neurofilament distribution, (Endo et al., 1994; Lehning et al., 1998), apoptosis of neurons and astrocytes (Kim et al., 2009), and demyelinization of neurons (El-Tantawi, 2007). In hamsters, cronic ACR treatment resulted in reduction in body weight, decreased red blood cell counts and hemoglobin levels, and axonal/myelin degeneration, along with gate and movement problems (Imai and Kitahashi, 2014). In animal models, ACR was shown to interfere with nitric oxide signaling in the presynaptic region (Seale et al., 2012) and to reduce cytosolic calcium in response to glutamate stimulation (Sisnaiske et al., 2014). Furthermore, ACR has been shown to disrupt the blood–brain barrier and the blood–cerebral spinal fluid barrier (Yao et al., 2014). In humans, ACR has been reported to cause ataxia, skeletal weakness, and numbness in the hands and feet (LoPachin and Gavin, 2012). Several studies have addressed the critical question as to whether the quantity of ACR present in food is indeed toxic or not. Although the majority of these studies actually concluded that there was no association between dietary ACR and risks of human diseases (Lujan-Barroso et al., 2014; Raju et al., 2013), the concern about the possibility of its accumulation and Received 08 December 2014 Revised 12 March 2015 Accepted 18 March 2015

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its harmful on long term was raised. A recent study supported that low and high levels of ACR can elicit toxic effects, depending on the duration of exposure (Erkekoglu and Baydar, 2014). This suggests that exposure to low doses of ACR might be followed by a symptom-silent period. In this period, the deleterious effects of the chemical are not clinically apparent, but nevertheless, morphological and/or biochemical alterations may be present (Costa et al., 2004). The concern over ACR general toxicity was heightened following the discovery of its presence in some commonly consumed human food items (Tareke et al., 2002). A study in Poland revealed that food stuffs commonly eaten by both adults and children contain ACR, with potato chips, French fries, and bread containing 904 ± 793, 313 ± 168, and 69 ± 24 μg/kg (mean ± standard deviation), respectively (Mojska et al., 2010). Possibly even more alarming is the presence of ACR in a number of baby foods, such as jarred baby foods (55 ± 36 μg/kg), follow-on formula (73 ± 78 μg/kg), and infant biscuits (219 ± 139 μg/kg) (Mojska et al., 2012). Furthermore, the problem of ACR content in foods is not isolated to Europe and the West; Chinese studies have found similar levels of ACR in common snack foods from China, for example, roasted rice cakes (68 ± 65 μg/kg), fried flour snacks (131 ± 122 μg/kg), and fried prawn strips (341 ± 122 μg/kg) (Chen et al., 2012). The intake of ACR from such foods has been assessed in the polish study, with children (1–6 years old) being exposed to 13 ± 24 μg/kg/day, children/adolescent (7–18 years old) being exposed to 27 ± 43 μg/kg/day, and adults being exposed to 23 ± 25 μg/kg/day (Mojska et al., 2010). An average daily ACR intake was calculated to be 34.03 μg/person/day, which is equivalent to 0.57 μg/kg body weight/day (body weight 60 kg) (Tawfik and ElZiney, 2008). Although this quantity may appear objectively low, based on the report that humans have lifetime exposure to dietary ACR (Rodríguez-Ramiro et al., 2011), the possibility that toxic side effects arise in the long term should be considered (Costa et al., 2004). Thus, it is recommended to pursue researches aimed at finding appropriate therapeutics to alleviate ACR toxicity and to prevent potential irreversible neuronal damages. In this regard, bioactive products from a variety of plants have been tested and proved to reverse the neurotoxic effect of ACR with encouraging results in in vitro and in vivo models, as illustrated in the following sections. Panax ginseng Generally, ginsengs are herbal remedies derived from the roots of several plants, yet one of the most popularly used is Panax ginseng, also called Asian or Korean ginseng (Kiefer and Pantuso, 2003). P. ginseng is from the Araliaceae family and can be found throughout East Asia and Russia (Chong and Oberholzer, 1988). It is generally cultivated in Korea, China, and Japan for export and use as a medicinal herb. There are two distinct forms of P. ginseng: red and white ginseng. The difference is in the pigment compositions, as it results from the method of processing. White ginseng is produced by direct drying under the sun of the harvested root, while red ginseng is steamed soon after harvest and Copyright © 2015 John Wiley & Sons, Ltd.

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before drying (Blumenthal, 2003). P. ginseng contains main active components commonly referred to as ginsenosides (such as triterpene glycosides or saponins). In addition, many other active compounds can be found in all parts of the plant, including amino acids, alkaloids, phenols, proteins, polypeptides, and vitamins B1and B2 (Blumenthal, 2003; Kiefer and Pantuso, 2003). P. ginseng is often referred to as an adaptogen because of its reported ‘nonspecific’ resistance to biochemical and physical stressors, which results in improvement of general well-being and enhanced mental capacity (Blumenthal, 2003; Kiefer and Pantuso, 2003). Ginsenosides have been demonstrated to possess a variety of beneficial medical effects, which include antiinflammatory, antioxidant, and Anticancer effects (Kiefer and Pantuso, 2003). Relevant to the present context, several studies support the neuroprotective effect of P. ginseng active components in various cell cultures and in animals (Li et al., 2007; Choi et al., 2007). Most of its known pharmacological effects on the central nervous system have been attributed to the major ginsenosides. López et al. (2007) evaluated the antioxidant activity of some isolated ginsenosides and found that pre-treatment with protopanaxadiols Rb(1), Rb(2), Rc, and Rd and protopanaxatriols Re and Rg (1) could counteract the production of reactive oxygen species (ROS) and loss of cell viability in primary astrocytes exposed to hydrogen peroxide (H2O2) through activation of antioxidant enzymes. Sakanaka (2007) reported that intravenous infusion of ginsenoside Rb1, one of the major components of red ginseng root, and dihydroginsenoside Rb1, a stable chemical derivative of ginsenoside Rb1, prevented compressive spinal cord injury and ischemic brain damage through upregulation of vascular endothelial growth factor and B-cell lymphoma extra large. In addition, the ginsenosides compound K and Rh(2) could inhibit the induction of the nuclear factor-kappa light chain B and c-Jun-N-terminal kinase pathways in human astroglial cells by TNF-α (Choi et al., 2007). Ameliorative effect of Panax ginseng against acrylamideinduced neurotoxicity. Acrylamide is very highly soluble in water, and, as a result, it is rapidly absorbed and distributed throughout the body organs. ROS are certainly produced during ACR metabolism in the body. ACR significantly increased the levels of oxidative stress and lipid peroxidation (Mannaa et al., 2006), along with a significant decrease of the activity of antioxidant superoxide dismutase (SOD) in the brain of ACR-treated rats, and the administration of P. ginseng could reverse these effects to the level found in controls (Mannaa et al., 2006). The ability of ginseng to inhibit lipid peroxidation in the brain of ACR-treated rats is likely attributable to its well-known free radical scavenging activity (Abdel-Wahhab and Ahmed, 2004). In addition, an increase in lactic acid dehydrogenase activity in the brain and increase in creatinine kinase activity and decrease in serotonin and adrenaline levels in the serum were also reported in ACR-intoxicated rats, which indicates that ACR could also induce cell membrane damage in neurons and muscle cells (Pennisi et al., 2013). Ginseng could prevent these alterations by direct free radical scavenging, thereby inhibiting membrane lipid peroxidation (Mei et al., 1993), or by enhancement of the activity of glutathione peroxidase Phytother. Res. 29: 978–985 (2015)

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Figure 2. The structure of linalool, molecular weight: 610.52 g/mol.

Figure 1. The three main tautomers of curcumin. (A) Enol form, (B) enol–keto form, and (C) keto–keto form.

and SOD (Xie et al., 1993; Abdel-Wahhab and Ahmed, 2004). Increases in creatinine kinase and lactic acid dehydrogenase have been linked to oxidative stress (Lim et al., 2013). Thus, the enhancement of glutathione peroxidase and SOD by P. ginseng is indicative of its ability to suppress oxidative stress, hence reducing ACR neurotoxicity.

Acorus calamus Acorus calamus belongs to the family Aracae, and it is known under different names, which include sweet flag, sweet sedge, and myrtle flag (Kumar, 2013). A. calamus (Fig. 1) contains many active components, which include terpinen-4-ol, α-terpineol and α-calacorene, acorone, acorenone, acoragermacrone, asarone, elemicin, cisisoelemicine, cis-isoeugenol and trans-isoeugenol and their methyl ethers, β-cadinene, camphor, 2-deca4,7dienol, shyobunones, camphene, P-cymene, β-gurjunene, linalool, pre-isocalamendiol, α-selinene, isohyobunones, and calamusenone. A. calamus has been used in traditional Chinese medicine since long time, and it is now recognized to possess several medicinal properties such as antiulcer, analgesic (Mukherjee, 2007), anticonvulsant (Achliya et al., 2005), and antiinflammatory (Mehrotra et al., 2003), besides neuroprotective properties (Shukla et al., 2006; Manikandan et al., 2005). Alleviation of acrylamide-induced neurotoxicity by Acorus calamus. Acorus calamus was shown to have neuroprotective effect against stroke and chemically induced neurodegeneration in rats (Shukla et al., 2006) and to provide beneficial effects on memory disorder and learning performance (Manikandan et al., 2005). The latter were attributed to the ability of A. calamus to decrease the content of brain lipid peroxide (Manikandan et al., 2005). Rats treated with ACR showed reduced movement, including reduced distance traveled, ambulatory time, stereotypic time, and basal stereotypic movements, and also present signs of hind limb paralysis (Shukla et al., 2002). In addition, compared with controls, they had reduced glutathione (GSH) content and glutathione-S-transferase activity in the corpus striatum and presented an increase in striatal dopamine receptors (Shukla et al., 2002). These findings are consistent with results from other studies (Dixit et al., 1981; Spencer et al., 2000). The ability of ACR to decrease antioxidant level could be related, directly or indirectly, to its free radical producing ability, thus leading to oxidative stress. Upon treatment of these Copyright © 2015 John Wiley & Sons, Ltd.

rats with water–ethanol extract of A. calamus, the aforementioned symptoms in ACR-intoxicated rats were significantly reversed (Shukla et al., 2002). Because linalool is reported to be a constituent of A. calamus (Satyal et al., 2013) and has shown a neuroprotective effect against ACR toxicity (Mehri et al., 2014b), there may be a relationship between linalool and A. calamus neuroprotective effect on ACR toxicity (see the following contexts). Linalool Linalool (Fig. 2) is believed to be a major volatile monoterpene component of the essential oils in several aromatic plants (Mehri et al., 2014b). Linalool has been reported to possess many medicinal effects, among which are anxiolytic (Kotilinek et al., 2008), hypnotic, and anticonvulsant (Elisabetsky et al., 1995). Alleviation of acrylamide-induced neurotoxicity by linalool. Initial studies of Peana et al. (2002, 2003) revealed the antinociceptive effects of linalool in different models in which pain was induced by using acetic acid (Peana et al., 2003) or carrageenan (Peana et al., 2002). These studies proved that linalool could cause impedance in the muscarinic, opioid, and dopaminergic transmission (Peana et al., 2003, 2004). In rats, linalool was also reported to antagonize the impaired memory acquisition caused by N-methyl-D-aspartate receptors (Coelho et al., 2011). Acrylamide intoxication induced progressive gait abnormalities in rats, which were significantly decreased when ACR was co-administered with a low dose (12.5 mg/kg) of linalool (p < 0.05 versus ACR-treated group) (Mehri et al., 2014b). A similar protective effect was observed when linalool was supplemented before but not after ACR administration (Mehri et al., 2014b). In this same experimental model, the level of lipid peroxidation, as mirrored by malondialdehyde, was significantly increased after exposure to ACR, and this could be prevented by pre-treatment or co-treatment with low dose of linalool (Mehri et al., 2014b). Finally, a significant decrease in GSH content in cerebral cortex was observed following ACR exposure, while the pretreatment or co-treatment with linalool resulted in significant increase in GSH level in the brain tissue (Mehri et al., 2014b). The antioxidant effect of linalool against ROS production has been reported in several other studies (Deepa and Anuradha, 2011). Taken together, the effects of this substance on the nervous system could possibly explain the significant decrease in gait abnormalities caused by ACR administration in this study. Yet, the fact that linalool could elicit neuroprotection only if it was pre-administered or coadministered with the neurotoxin indicates that this herb cannot reverse the early tissue damage caused by ACR. Phytother. Res. 29: 978–985 (2015)

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Zingiber officinale Zingiber officinale is commonly known as ginger and belongs to the family Zingiberaceae. There are numerous bioactive components of ginger, but the major constituents that reportedly possess the highest pharmacological activities are gingerol and its analogues shogoals, paradol, and zingerone (Mishra et al., 2012). Generally, the constituents of Z. officinale vary depending on the place of origin and the physical state of the rhizome (Mishra et al., 2012). Various reported pharmacological effects have been documented for Z. officinale, which include antioxidative (Wang et al., 2003) and antinociceptive (Ma et al., 2004) effects. Neuroprotective effect of Zingiber officinale against acrylamide toxicity. The first study on the potential neuroprotective effect of ginger on ACR toxicity in mice was carried out by El-Tantawi (2007). ACR (at a dose of 200 p.p.m in drinking water, three times a week for 10 weeks) caused demyelination of the nerve fibers present in the white matter of the spinal cord and in cerebellum, along with shrinkage of the neurons and chromatolysis of granule cells of the cerebellum (El-Tantawi, 2007). On administration of 22% ethanol extract of ginger, 1 h prior to ACR exposure, an improvement and preservation of the normal histological and ultrastructural features of the nervous tissues were reported (El-Tantawi, 2007). Various studies have recorded that ginger elicits an antioxidative effect by decreasing lipid peroxidation, increasing GSH concentration and maintaining normal levels of antioxidant enzymes (Ahmed et al., 2000; Fuhrman and Rosenblat, 2000). Oral supplementation of geraniol, which is found in aromatic herbs such as ginger, has been shown to reduce the oxidative stress, and offset ACR induced neuropathic symptoms in rats and flies (Prasad and Muralidhara, 2012, 2014a, 2014b). Because free radical production has earlier been mentioned as one of the mechanisms of ACR toxicity, it is conceivable that the aforementioned neuroprotective effects were related to the free radical scavenging antioxidative activity of ginger.

Curcuma longa Curcumin is one of the main curcuminoids that can be isolated from Curcuma longa, otherwise known as turmeric, which is part of the ginger family. Curcumin, along with the other two main curcuminoids desmethoxycurcumin and bis-desmethoxycurcumin, are natural phenols that give turmeric its yellow color (Manolova et al., 2014). Curcumin exists in three main tautomeric forms (Fig. 1), which may differ in bioavailability, solubility, and activity (Indira Priyadarsini, 2013). Curcumin suffers from poor bioavailability because of its insolubility in water, and various studies have shown that curcumin is poorly absorbed in the gut resulting in low plasma levels of curcumin (Anand et al., 2007). Curcumin bioavailability can be increased by formulating the curcumin as phospholipid compound (Marczylo et al., 2007) and by dissolving it in oils (Chang et al., 2013), whereas heating will reduce its bioavailability (Suresh et al., 2009). Copyright © 2015 John Wiley & Sons, Ltd.

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The bioactivity of curcumin and its protective effect against acrylamide toxicity. Curcumin has many biological and cellular effects, including strong antioxidant effects (Jha et al., 2015). Various studies have shown curcumin to have a protective effect against ACR toxicity. In cultured HepG2 cells, the protective mechanism appeared to be antioxidant in nature (Cao et al., 2008), with curcumin increasing cell viability after ACR treatment as well as reducing free radical production. Similar findings have been reported in Drosophila melanogaster (fruit fly) studies (Prasad and Muralidhara, 2012, 2014a). Glycogen synthase kinase 3 beta (GSK-3β) is activated by ACR treatment, causing a lack of neurogenesis in the hippocampus (Song et al., 2014), and curcumin was shown to inhibit this enzyme (Aggarwal and Sung, 2009; Bustanji et al., 2009). Although no study has looked into both ACR toxicity and GSK-3β inhibition by curcumin, it seems reasonable to assume that this mechanism of action contributes to the protective effect of curcumin, especially when considering that lithium, another GSK-3β inhibitor, also protects against ACR (Song et al., 2014). Rutin Rutin (Fig. 3) is a plant pigment (flavonoid) that occurs in certain fruits and vegetables. The major sources of rutin include many different fruits and vegetables, among which are Fagopyrum sp. (buckwheat), Saussurea involucrata, and Eucalyptus macrorhyncha (Zielinska et al., 2010). It is also referred to as rutoside, quercetin3-O-rutinoside, or sophorin, and it is the glycoside between the flavonol quercetin and the disaccharide rutinose ((α-L- rhamnopy-ranosyl-(1→6))-β-D-glucopyranose) (Lucci and Mazzafera, 2009). Several pharmacological activities have been attributed to rutin, and these include cytoprotective, antioxidant, anticarcinogenic, vasoprotective, and neuroprotective activities. Furthermore, rutin has shown antiaging potency in mice through antioxidative mechanisms (Katsube et al., 2006; Nassiri-Asl et al., 2008; Gupta et al., 2003; Koda et al., 2008). Rutin was found to provide additional benefit over myricetin, quercetagenin, and other flavonoids that act as prooxidant agents catalyzing oxygen radical production in certain conditions (Hodnick et al., 1986). In fact, it is used as a standard for measuring flavoring contents of different plant extracts (Brimson et al., 2012). Different mechanisms of actions have been identified for different preventive and therapeutic effects of rutin. Protection by rutin in acrylamide-induced neurotoxicity. Motamedshariaty et al. (2014) studied the effect of rutin on ACR neurotoxicity in PC-12 cells and in male Wistar rats. In animals, ACR treatment resulted in significantly

Figure 3. The structure of rutin, molecular weight: 610.52 g/mol. Phytother. Res. 29: 978–985 (2015)

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low neuronal cell viability, high gait score, high lipid peroxidation, and reduced weight. The pre-treatment with rutin significantly inhibited behavioral index changes (namely reduced gait scores) and body weight loss caused by ACR administration in rats (Motamedshariaty et al., 2014). There was also a significant reduction in lipid peroxidation in all animals treated with rutin. Rutin has been established to possess antioxidant activity in several studies (La Casa et al., 2000; Kamalakkannan and Prince, 2006; Anbazhagan et al., 2008; Manivannan et al., 2012; Becker et al., 2007), and scavenging of free radicals and prevention of lipid peroxidation have indeed been reported to be the main effects of rutin (Khan et al., 2009).

Chrysin Chrysin (5,7-dihydroxyflavone) (Fig. 4) is a natural and biologically active flavone (Samarghandian et al., 2011). It can be extracted from passion flowers Passiflora caerulea (Wolfman et al., 1994), Passiflora incarnata (Brown et al., 2007), and Oroxylum indicum. It is also present in chamomile, in the mushroom Pleurotus ostreatus (Anandhi et al., 2013), and in honey. Chrysin (a subclass of flavonoid), together with some other flavones such as apigenin, baicalein, and scutellarein, was identified to play important biological roles in nitrogen fixation and chemical defenses (Zheng et al., 2003). The potential antiinflammatory and antioxidant properties of these flavonoids have been reported (Cook and Samman, 1996). Protective role of chrysin in acrylamide-induced neurotoxicity. Chrysin was able to prevent cell death in pheochromocytoma PC-12 cultures exposed to ACR and also to prevent the gait abnormalities induced by ACR in rats (Mehri et al., 2014a). The protective effects of chrysin were similar to that of vitamin E, indicating that they were due to its antioxidative activity (Pushpavalli et al., 2010) and its inhibition of lipid peroxidation (He et al., 2012). In addition, chrysin is reported to be a potent free radical scavenger, a property probably linked to the hydroxyl groups present in the fifth and seventh positions (Sathiavelu et al., 2009), and this also likely contributes to the neuroprotective effect seen in both PC-12 cells and rats exposed to ACR.

Rosmarinus officinalis Rosmarinus officinalis (Rosemary) is an aromatic plant belonging to the family Lamiaceae (Stefanovits-Bányai et al., 2003). The leaf extracts contain some active components such as caffeic acid derivatives, diterpenes (bitter), flavonoids, triterpenes, and volatile oil (Frankel et al., 1996; Lamaison et al., 1990). R. officinalis has been used in traditional medicine to combat headaches and

Figure 4. The structure of chrysin, molecular weight: 254.24 g/mol. Copyright © 2015 John Wiley & Sons, Ltd.

migraine, states of exhaustion, dizziness, and poor memory (Gruenwald et al., 2000). Protective role of Rosemarinus officinalis against acrylamide-induced neurotoxicity. Waggas and Balawi (2008) studied the neuroprotective effect of R. officinalis in ACR toxicity by evaluating the changes in catecholamine, namely epinephrine, norepinephrine, and dopamine, content in cerebellum, brain stem, striatum, cerebral cortex, hypothalamus, and hippocampus of male albino rats. The treatment with ACR led to a significant decrease of these neurotransmitters in all brain regions. Upon administration of R. officinalis extract, there was a significant improvement in the catecholamine content in most of the tested brain regions. This protective effect of the R. officinalis extract against ACR toxicity has been linked to its 2,2′-diphenyl-1picrylhydrazyl free radical scavenging capability (Bhale et al., 2007). Further, R. officinalis extract is a source of carnosic acid (Waggas and Balawi, 2008), and diterpene carnosic acid has been shown to protect biological membrane from oxidative damage (Haraguchi et al., 1995). Allicin Allicin (Fig. 5), is a volatile organosulfur compound, poorly miscible in aqueous solutions, obtained from garlic, which belongs to the family Alliaceae (Block, 1985). It is produced from enzymatic action of alliinase on alliin, which occurs as garlic is crushed. Protective role of allicin against acrylamide neurotoxicity. The protective efficacy of allicin against ACR toxicity was studied by determining the biochemical parameters in the brain and some other organs of male mice. ACR led to significant increase in thiobarbituric reactive substances and myeloperoxidase levels and significant decrease in SOD and glutathione-S-transferase activities and GSH level. Administration of allicin at concentrations ranging from 5 to 20 mg/kg significantly could reverse these changes (Zhang et al., 2013). Dark soy sauce Dark soy sauce (DSS) is a dark brown salty liquid with a peculiar aroma and a meaty taste (Berk, 1992). It is produced through the fermentation of soybeans by naturally occurring bacteria and fungi. It is generally consumed among Koreans as protein sources and flavoring ingredients (Kim et al., 2009). It is also consumed throughout the world as an ingredient in a whole range of foods and sauces. Apart from its taste and aromatic compounds, DSS contains some bioactive components and possesses antioxidant activity (Long et al., 2000), among others. Alleviation of acrylamide neurotoxicity by dark soy sauce. Co-administration of DSS and ACR resulted in significant increase in the body weight, and relative

Figure 5. The structure of allicin, molecular weight: 162.27 g/mol. Phytother. Res. 29: 978–985 (2015)

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brain weights, and improved the gait abnormalities induced by ACR (Xichun and Min’ai, 2009). DSS significantly counteracted the axonal degeneration and degree of central chromatolysis of the ganglion neurons in peripheral nerves of ACR-treated rats. The mechanism for neuroprotective effect of DSS on ACR toxicity was suggested to be associated with its antioxidative potential (Xichun and Min’ai, 2009).

CONCLUSION The presence of ACR in a range of commonly consumed human foods has stimulated the research into the potential of natural product to prevent the onset of or attenuate its neurological negative effects. This review has enumerated various plants and plant derivatives that have been proved to exert ameliorative effect on ACR neurotoxicity. Antioxidative activity and ability to inhibit lipid peroxidation are among the common neuroprotective mechanisms of these plants and plant derivatives. In addition, some plant products (for example, rutin) exhibited additional properties, such as the abilities to chelate metals and to inhibit the synthesis of eicosanoids and lipoxygenases, thereby promoting antineuroinflammatory effects. However, it should be stressed that the studies here reported have proven a certain efficacy of plant-derived bioactive products only when pre-administered or co-administered with ACR. Besides the obvious consideration that in vitro and in vivo models are far from representing the actual conditions in human beings exposed to ACR, either accidentally or professionally (acutely or chronically), it is conceivable that some organs are so susceptible (because of reduced intrinsic antioxidant capabilities, for instance) that may undergo an irreversible damage soon after ACR exposure, although the clinical manifestations will appear late in the life. In

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such a case, the bioactive natural product may not elicit its beneficial effect. Thus, the goal of the future research is to find appropriate treatments that could halt or retard the progression of the damage in pre-exposed individuals in order to limit the onset of symptoms clinically relevant in the late time. To this end, it is mandatory to improve our knowledge on the mechanism(s) of ACR toxicity at cellular and molecular levels in the various organs. The Food and Agricultural Organization estimates that the world population by the year 2050 will be increased by a third (Alexandratos and Bruinsma, 2012), and one of the recognized challenges that men will have to face is the requirement of more medicines to eradicate human health challenges (Georgiev, 2014). Because many plant species and products obtained from them have provided positive responses towards human health disorders, especially as they have been discussed here, and ACR toxicity is not an issue to be overlooked, further intense and molecular studies on the plants here reported and others should be pursued.

Conflict of Interest The authors declare that there is no conflict of interest in the publication of this review.

Acknowledgements This work was financially supported by the Ratchadaphiseksomphot Endowment Fund of Chulalongkorn University (RES560530255AS), and Omowumi O. Adewale was supported by the Tertiary Education Trust Fund (TETFund) through Osun State University, Osogbo, Nigeria. James M. Brimson and Ciro Isidoro received the visiting fellowship from the Kanjanapisek Chalermprakiat Endowment Fund, Chulalongkorn University.

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