The mechanism of neuroprotective action of natural compounds

Accepted Manuscript Title: The mechanism of neuroprotective action of natural compounds Author: Agnieszka W˛asik Lucyna Antkiewicz-Michaluk PII: DOI: Reference:

S1734-1140(16)30471-6 http://dx.doi.org/doi:10.1016/j.pharep.2017.03.018 PHAREP 689

To appear in: Received date: Revised date: Accepted date:

22-12-2016 24-3-2017 29-3-2017

Please cite this article as: W˛asik A, Antkiewicz-Michaluk L, The mechanism of neuroprotective action of natural compounds, Pharmacological Reports (2017), http://dx.doi.org/10.1016/j.pharep.2017.03.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Highlights: 1. Natural compounds with neuroprotective potential. 2. Oxidative stress as the main factor causes the neurodegenerative disordes.

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3. Antioxidant activity and ability to reduce ROS generation as a main neuroprotective mechanism of action.

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The mechanism of neuroprotective action of natural compounds

Agnieszka Wąsik and Lucyna Antkiewicz-Michaluk

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31-343 Kraków, Smętna Street 12, Poland

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Institute of Pharmacology, Polish Academy of Sciences, Department of Neurochemistry,

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e-mail: [email protected]

Acknowledgments

This study was financially supported through a grant from the National Science Centre Grant No. DEC-2012/07/B/NZ7/01149, and statutory funds from the Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.

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The mechanism of neuroprotective action of natural compounds

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Abstract Disturbance of cerebral redox homeostasis is the primary cause of human neurodegenerative disorders, such as Parkinson’s disease or Alzheimer’s disease. Well known experimental

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research demonstrates that oxidative stress is a main cause of cell death. A high concentration of reactive oxygen and nitrogen species leads to damage of a lot of proteins, lipids and also

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DNA. Synthetic compounds used for the treatment in the neurodegenerative diseases failed to meet the hopes they had raised and often exhibit a number of side effects. Therefore, in recent

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years interest in natural compounds derived from plants appears to be on the rise. This review describes a few natural compounds (1MeTIQ, resveratrol, curcumin, vitamin C and Gingko biloba) which revealed neuroprotective potential both in experimental studies and clinical

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trials. 1MeTIQ has a privileged position because, as opposed to the remaining compounds, it is an endogenous amine synthesized in human and animal brain. Based on evidence from

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research, it seems that a common protective mechanism for all the above-mentioned natural

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compounds relies on their ability to inhibit or even scavenge the excess of free radicals generated in oxidative and neurotoxin-induced processes in nerve cells of the brain. However, it was demonstrated that further different molecular processes connected with neurotoxicity (e.g. the inhibition of mitochondrial complex I, activation of caspase-3, apoptosis) follow later and are initiated by the reactive oxygen species. What is more, these natural compounds are able to inhibit further stages of apoptosis triggered by neurotoxins in the brain.

Keywords: oxidative stress; 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ); resveratrol; curcumin; vitamin C (L-ascorbic acid); Gingko biloba (Egb 761)

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Introduction

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Abbreviations: AD, Alzheimer’s disease; Akt, protein kinase B; AMPK, AMP-activated kinase; ATP, adenosine triphosphate; BDNF, brain-derived neurotrophic factor; 1BnTIQ, 1benzyl-1,2,3,4-tetrahydroisoquinoline; Cat, catalase; COMT, catechol-O-methyltransferase; COX-1 and COX-2, cyclooxygenase-1 and 2; DAT, dopamine transporter; DOPAC, 3,4dihydroxyphenylacetic acid; GSH/GSSG, glutathione/oxidized glutathione; HO-1, heme oxygenase 1; IL-1β, interleukin 1β; JNK, c-Jun N-terminal kinases; LPS, lipopolysaccharides; MAO, monoamine oxidase; MDA, malodialdehyde; 1MeTIQ, 1-methyl-1,2,3,4tetrahydroisoquinoline; MMP-9, matrix metallopeptidase 9; MPTP, 1-methyl-2-phenyl1,2,3,6-tetrahydropyridine; 3-MT, 3-methoxytyramine; NFκB, nuclear factor kappa-lightchain-enhancer of activated B cells; NGF, nerve growth factor; Nrf2, transcription factor erythroid 2; 6-OHDA, 6-hydroxydopamine; PD, Parkinson’s disease; PEA – phenylethylamine; skPI3K, phoshoinositide 3-Kinase; PGC-1α, peroxisome proliferatoractivated receptor gamma coactivator 1-alpha; PTEN, phosphatase and tensin homolog; RNS, reactive nitrogen species; ROS, reactive oxygen species; SIRT1, sirtuin 1; SOD, superoxide dismutase; SOA, superoxide anion; TNF- α, tumor necrosis factor-alpha;

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Disturbance of cerebral redox homeostasis is the primary cause of human neurodegenerative

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disorders. Imbalance between internal antioxidant system and toxic reactive oxygen species (ROS) is defined as oxidative stress. This phenomenon plays the main role in the pathology and progression of neurodegenerative disorders, such as Parkinson’s disease (PD) [1] or Alzheimer’s disease (AD) [2]. Moreover, the phenomenon of oxidative stress is considered to be an essential factor in ageing process [3]. Oxidative stress is a universal mechanism causing cell death [4]. In PD oxidative stress is induced via different mechanisms, like modification of iron accumulation in the substantia nigra, changes in α-synuclein aggregation and proteolysis, changes in calcium channel activity, and protein mutations [5]. Furthermore, an increase in malondialdehyde, hydroperoxides and protein oxidation has been reported in the substantia nigra of PD patients [6]. In addition, the accumulation of lipid peroxidation products was observed in cerebral spinal fluid of PD patients [7]. Overproduction of ROS and reactive nitrogen species (RNS) leads to disruption of natural cellular homeostasis and is the cause of oxidative and nitrosative stress. A high concentration of ROS and RNS leads to damage of a lot of proteins, lipids and also DNA, while, low concentration of ROS and RNS during normal cellular metabolism acts as signaling molecules [8]. Dopaminergic neurons show the greatest sensitivity to oxidative stress because they contain neuromelanin [9]. Neuromelanin

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is a black pigment which contains ferrous ions (Fe2+). The presence of Fe2+ promotes the Fenton reaction. Beyond natural factors causing the oxidative stress, such as environmental toxins (heavy metals, herbicides, pesticides), UV radiation, heat shock, also the dopamine itself plays a considerable role in this adverse phenomenon. Namely, ROS are formed during dopamine catabolism. Dopamine at low concentrations can block mitochondrial respiration mainly by MAO-dependent oxidation pathway in which H2O2 is formed [10]. Dopamine can

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be nonenzymatically oxidized or enzymatically deaminated by monoamine oxidase (MAO). Both processes: autoxidation and MAO-mediated catabolism of dopamine lead to H2O2

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formation. The mitochondrial complexes I, II, and III are highly sensitive to the inhibitory effect of ROS [11, 12]. A deficiency in the mitochondrial complex-1 of the electron transport

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chain, which leads to elevation of O2 - production and adenosine triphosphate (ATP) reduction, was reported to be one of the main factors of the etiopathology of PD [13]. The

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reduced level of ATP causes a fall in the ratio of the reduced glutathione/ glutathionedisulfide (GSH/GSSG) which is a measure of redox state of cells [14]. The redox couple

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GSH/GSSG acts in concert with enzymes: glutathione peroxidase/reductase, glutaredoxin and thioredoxin to maintain protein thiol redox homeostasis [15, 16]. The production of free radicals during dopamine biosynthesis and catabolism causes the loss of a lot of dopaminergic

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neurons [17]. Moreover, these phenomena are boosted by the presence of neuromelanin in

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dopaminergic neurons [18]. Thus, neuromelanin promotes the Fenton reaction. Dopamine is catabolized via two metabolic pathways: about 80% of dopamine is intraneuronally Noxidized by MAOB to the intermediate metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), while 20 % of dopamine is extraneuronally O-methylated by catechol-O-methyltransferase (COMT) to the intermediate metabolite 3-methoxytyramine

(3-MT). Large amounts of

dopamine released into the synaptic cleft are easily taken up by dopamine transporter (DAT) and catabolized by MAOB which is located on mitochondrial membranes. In addition, dopamine is able to oxidize to ortho-quinones in the absence of metal-ion catalysts. This reaction of dopamine oxidation catalyzed by oxygen will produce dopamine o-semiquinone radical and superoxide. Next, dopamine o-semiquinone radical is converted into dopamine oquinone, which cyclizes and autoxidizes to form aminochrome [19]. As it demonstrated by Zecca et al. [20], both dopamine o-quinone and aminochrome induces mitochondria dysfunction. α-Synuclein is the major component of Lewy bodies and mutations at gene encoding this protein are the main genetic risk factor for PD [21]. Moreover, α-synuclein can activate microglia and elevate the expression of ROS, RNS, tumor necrosis factor-alpha

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(TNF- α), matrix metallopeptidase 9 (MMP-9) and interleukin 1β (IL-1β) [21]. Therefore, αsynuclein induces pro-inflammatory changes in the dopaminergic neurons and in consequence, causes a progressive loss of these cells [22]. Various antioxidants, such as GSH, melatonin, coenzyme Q10 and neuromelanin act as scavengers of free radicals and simultaneously rejuvenate mitochondrial complex-1 oxidoreductase, which is an enzyme involved in ATP synthesis [22]. It is interesting, that neuromelanin has shown both toxic and

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protective role in dopaminergic neurons. In physiological condition it can protects neurons from harmful effects of dopamine and its metabolites. Furthermore, neuromelanin can induces

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chelating redox/toxic metals such as iron, copper or manganese to form stable complexes. On the other hand, when the iron is overload, neuromelanin induces exacerbation of oxidative

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stress [19].

In recent years, an increasing number of researchers have attempted to search for efficient

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drugs for neurodegenerative diseases using natural substances of plant origin. These compounds are often well known and have been used for centuries in traditional medicine and

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now are rediscovered by scientists and studied in detail in order to understand its molecular mechanism of action. In this review we would like to present a few interesting natural

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compounds with neuroprotective potential.

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Natural compounds as a neuroprotectants The origin and synthesis of 1MeTIQ

1-Methyl-1,2,3,4-tetrahydroisoquinoline

(1MeTIQ)

is

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derivative

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tetrahydroisoquinoline group. This compound was detected in the plants as well as in the mammalian brains, e.g. in rodents, monkeys and humans [23, 24, 25, 26]. Two enantiomers (S)- and (R ) of 1-MeTIQ were identified in the brain (Fig. 1) [27]. Worth of the emphasis is the fact that both stereoisomers have shown similar biological action [28, 29]. What is especially worth emphases highest concentrations of 1MeTIQ was detected in dopaminergic structures mainly in the extrapyramidal system (substantia nigra and striatum) [26]. In the rat brain the concentration of 1MeTIQ was measured as 3.5 ng/g tissue [30]. 1MeTIQ as an endogenous substance can be synthesized enzymatically in the brain from biogenic amines (phenylethylamine [PEA] and pyruvate) [31]. The enzyme which is involved in this process was localized in the mitochondrial-synaptosomal fraction and is called 1MeTIQase [31, 32]. Interestingly, PEA, which is a substrate for 1MeTIQ generation in the brain, is catabolized by MAO. Therefore, the intracellular concentration of 1MeTIQ can be elevated by MAO

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inhibition. On the other side the synthesis of 1MeTIQ can be inhibited by agents that induce experimental parkinsonism, e.g. 1-methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or βcarbolines [26]. Moreover, 1MeTIQ can be supplemented to the brain in the diet [25, 27] like bananas, cheese or red wine and as it was demonstrated easily crosses the blood-brain barrier [33, 34]. Ayala et al. [35] showed that the concentration of 1MeTIQ in the substantia nigra

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was reduced in parkinsonian patients and in aged rats by approximately 50%. The neuroprotective mechanism of action of 1MeTIQ:

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1MeTIQ shows a very wide and modulating action in the brain. It exhibited neuroprotective, antiaddictive and antidepressant-like properties [36, 37, 38, 39, 40, 41]. It has

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been reported that 1MeTIQ induces production of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) [33]. It should be underline its

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main and distinct effect on monoamines metabolism strongly connected with 1MeTIQproduced neuroprotection in CNS. Both these processes protect especially dopamine cells before the attack of free radicals, and additionally 1MeTIQ as the structure possesses the

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ability to scavenge of free radicals [42]. 1MeTIQ is a reversible MAOA and MAOB inhibitor and strongly blocks the MAO-dependent oxidative pathway. Additionally, 1MeTIQ increases

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the COMT-dependent O-methylation pathway [42]. Therefore, this compound possesses

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antioxidant potential. 1MeTIQ blocks free radicals formation and reduces H2O2 generation from dopamine by the Fenton reaction [37, 43, 44]. As it was previously reported, no tolerance to its neuroprotective properties after chronic administration was observed (the strength of the effects is the same as after a single dose of 1MeTIQ) [41, 42]. Some data indicated that different MAO inhibitors, such as selegiline and rasagiline prevented MPTP toxicity by blocking MAOB activity [45], although both drugs have shown antioxidant and antiglutamatergic properties, and neurotrophic effect [46, 47]. Clinical studies revealed that early treatment with MAO inhibitors had a stronger positive effect compared to delayed introduction of therapy [48, 49]. Our previous results demonstrated that 1MeTIQ displaced [3H]apomorphine, which is a dopamine receptor agonist, from dopamine D2 receptors [50]. These data suggest that agonist radioligand binds preferentially to the high-affinity state. So, 1MeTIQ is an antagonist of agonistic form of the dopamine D2 receptors [50]. This mechanism of action is reflected by the inhibition of dopaminergic stimulation without affecting the basal locomotor activity. In vivo microdialysis studies indicated that both enantiomers of 1MeTIQ in not large degree increased the release of dopamine in the rat striatum [29].

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In vitro studies have pointed on another very essential from the view of its neuroprotective activity molecular mechanism of action of 1MeTIQ. The studies demonstrated that 1MeTIQ inhibited glutamate-induced neurotoxicity (caspase-3 activity and concentration of lactate dehydrogenase) in primary cell cultures [37]. Moreover, 1MeTIQ in a dose-dependent manner, blocked

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Ca2+ influx and prevented glutamate-induced cell death. The above data

suggest that 1MeTIQ has shown antagonistic properties to the glutamatergic system, can

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inhibit excitotoxicity, however its affinity to NMDA receptor was in µmolar concentrations about 1000 weaker from MK-801 [37]. In fact, how it was previously demonstrated 1MeTIQ

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exhibits neuroprotective activity in different animal models of PD, e.g. rotenone, 1-benzyl1,2,3,4-tetrahydroisoquinoline (1BnTIQ), 6-hydroxydopamine (6-OHDA), MPTP and β-

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carbolines models [26, 36, 40, 41].

Summarize, 1MeTIQ possesses the ability in braking of many processes connected with

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neurotoxicity in this: inhibits MAO; scavenges free radicals, inhibits glutamate-induce

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The origin and properties of resveratrol

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excitotoxicity.

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Resveratrol (3,5,4-trihydroxy-trans-stibene) is a natural compound from polyphenol group (Fig. 2) and is present in seeds of different plants, such as peanuts, berries, grains and grapes. Moreover, it is the main component in the red wine [51]. Bioavailability of resveratrol after oral administration is rather weak [52] however after intraperitoneal (ip) administration it cross blood-brain barrier and has shown neuroprotective properties [53]. Therefore, resveratrol has been investigated by numerous researchers in different animal models of neurodegeneration [54, 55]. This compound has shown multiple biological activities, e.g. antiapoptotic effects, cardioprotective properties, anti-tumor, anti-aging, anti-diabetes, antioxidant, anti-inflammatory and neuroprotective effects [56, 57, 58, 59, 60]. As it demonstrated by epidemiological studies, resveratrol in combination with other components of red wine, such as polyphenols, may have a positive impact on human health [53, 61]. The neuroprotective mechanism of action of resveratrol: The antioxidant properties of resveratrol are connected with its ability to upregulate antioxidant enzymes, e.g. glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) [62]. In the ischemia model, resveratrol enhanced the expression of the transcription factor

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erythroid 2 (Nrf2) and in this way modulated genes linked to redox pathways [63]. Some data indicated that resveratrol could act as a scavenger of free radicals and was cytoprotective in the neuroblastoma cells exposed to Abeta and Abeta-metal complexes [64]. In vitro study demonstrated that resveratrol revealed protective properties to mitochondrial respiration process [65]. It strongly influenced mitochondrial biogenesis and ROS production, via activating sirtuin 1 (SIRT1) [66, 67]. SIRT 1 stimulation lead to activation of 5’ AMP-

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activated protein kinase (AMPK). Next, AMPK elevates the expression and function of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the master

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regulator of mitochondrial biogenesis [68]. Furthermore, resveratrol modulates respiratory chain complexes, namely in low concentrations activates the enzyme ATP synthase while in

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high concentration blocks its activity [69, 70]. Treatment with resveratrol significantly inhibited MPTP-induced toxicity in mice. Additionally, it protected striatal neurons against

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hydroxyl radical overproduction and prevented reduction of dopamine in the mouse brain [71]. In the 6-OHDA model of PD, resveratrol induced an increase in activity of antioxidant enzymes and revised cellular redox status in the dopaminergic neurons [72]. Oral

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administration of grape seeds extract (containing resveratrol) normalized lipid peroxidation and diminished the accumulation of oxidative DNA damage in aged rats [73]. In vitro studies

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indicated that resveratrol could protect cells against oxidative stress induced by H2O2 [74, 75].

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Moreover, resveratrol induced an increase in phosphatase and phosphatase and tensin homolog (PTEN) [76, 77]. Ingles et al. [78] reported that resveratrol elevates PTEN levels, which in turn blocks phosphoinositide 3-kinase (PI3K) function, leading to a decrease in protein kinase B (Akt) level. And then, this action of PTEN induces upregulation of antioxidant genes (manganese superoxide dismutase [MnSOD] and catalase [Cat]) expression. Finally, elevation of MnSOD and Cat mRNA levels caused reduction of H2O2 levels [78]. The above results suggest that resveratrol has a protective potential and can prevent cell death induced by oxidative stress. Another investigation indicated that treatment with resveratrol significantly diminished anxiety, learning and cognitive deficits provoked by an intermittent hypoxia. This effect could be attributed to reducing the increase in the level of hippocampal glutamate, which is an important factor in the mechanism of oxidative stress [79]. Some evidence demonstrated that resveratrol could modulate the concentration of serotonin and noradrenaline in the CNS by an impact on MAOA activity and upregulation of brain-derived neurotrophic factor (BDNF) [80, 81, 82]. As shown by Virgili and Contestabile [83], resveratrol diminished kainite-induced excitotoxicity. Another in vitro study revealed that resveratrol administration protected against glutamate exposure and that the antioxidant

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enzyme heme oxygenase 1 (HO-1) was responsible for this effect [84]. The neuroprotective mechanism of action of resveratrol is very complex [85]. It activates a lot of cellular factors, such as SIRT1 [86], AMP-activated kinase (AMPK) [87] and nuclear factor erythroid derived 2 (Nrf2) [88, 89]. The chemical structure of resveratrol allows it to directly scavenge free radicals [90]. Furthermore, in different rodent models, treatment with resveratrol induced reduction of lipid peroxidation by enhancing GSH levels and decreasing nitric oxide (NO)

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concentrations [91, 92]. Numerous studies demonstrated that resveratrol administration inhibited the release of pro-inflammatory cytokines and diminished inflammation by

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decreasing microgial activation in in vitro [93] and in vivo experiments [94, 95]. In addition, resveratrol can block cyclooxygenase-1 and 2 (COX-1 and COX-2) and in this way also

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diminishes inflammation [95, 96]. Song et al. [93] indicated that treatment with resveratrol elevated levels of anti-inflammatory cytokines, e.g. interleukin-10 (IL-10) and BDNF, which

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led to an increase in cell viability. The neuroprotective action of resveratrol is mediated synergistically by numerous pathways that reduce oxidative stress, apoptosis and

The origin and applying of curcumin

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inflammation and normalize mitochondrial function.

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Curcumin (1,7-bis[4-hydroxy, 3-methoxy phenyl]-1,6-heptadiene-3,5-dione) is a nonflavonoid polyphenol (Fig. 3) which is a yellow pigment obtained from the root of the

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Curcuma longa. It is the main active ingredient of the curry spice. This natural compound demonstrated numerous biological activities, such as anti-inflammatory, antioxidant, antidiabetic, anticancer and chemopreventive properties [97, 98, 99]. Furthermore, it was reported that curry consumption improved cognitive functions in the elderly [100]. For centuries curcumin has been used as herbal medicine, cosmetic and foodstuff especially in South and Southeast Asia. It is a very popular spice in the diet of Asian population. Epidemiological studies indicated that prevalence of Alzheimer’s disease is 4.4 fold lower in India in comparison to the United States population [101]. The neuroprotective mechanism of action of curcumin: Curcumin is a highly lipophilic substance that easily crosses the blood-brain barrier. However, the bioavailability of this substance is rather poor. Interestingly, this molecule binds to plaques thus inhibiting the amyloid-β peptide aggregation [102]. Also Kim and coworkers [103] observed a protective role of curcumin against aggregation of amyloid-β peptide in in vitro experiments. It is well known that oxidative stress induced by amyloid-β is one of the

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factors causing AD [104]. Some authors indicated that strong antioxidant properties of curcumin caused reduction of amyloid-β, diminished the increase of tau hyperphosphorylation and lowered the intracellular calcium levels [105]. Simultaneously, treatment with curcumin induced elevation in the antioxidant enzyme concentrations in PC12 cells culture [105]. Moreover, another in vitro study demonstrated that curcumin increased cell viability by reduction of ROS production and blocking pro-apoptotic signals [106]. An in vivo study

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showed that in the rat model of cerebral artery occlusion curcumin protected the rat brain against cerebral ischemia [107]. Furthermore, in the homocysteine model of neurotoxicity,

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curcumin significantly blocked lipid peroxidation and reduced malondialdehyde (MDA) and superoxide anion (SOA) concentrations in the hippocampus [108]. As demonstrated by

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Rajeswari [109], curcumin has shown neuroprotective properties in the MPTP model via prevention of lipid peroxidation and GSH depletion induced by this toxin. In vivo and in vitro

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studies demonstrated that treatment with curcumin changed the activity of numerous signaling pathways, for instance by decreasing the NFκB and increasing Nrf2 activity [110]. Antiinflammatory properties of curcumin are linked not only with the inhibition of NFκB (which

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is responsible for transcription of inflammatory cytokines), but also with blockade of cyclooxygenase 2 (COX-2) and NOS [111, 112]. Some authors indicated that curcumin

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inhibited a number of steps in the inflammatory cascade, such as activation of iNOS, protein-

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1 transcription and JNK [113, 114]. Moreover, curcumin showed antioxidant potential via NO-related radical production: It inhibited the expression of the NOS gene [111]. The antioxidant properties of curcumin were proven several times in different animal models of brain trauma, AD and cerebral ischemia [115, 116, 117]. In addition, this compound inhibited IL-1β in both acute inflammation and chronic AD model [115]. As shown by Weber and coworkers [114], curcumin strongly blocked LPS-induced increase in iNOS protein and mRNA by restricting the activity of transcription factors. Reduction of plaque pathogenesis by inhibiting the fibril and oligomer formation is another very important effect of curcumin [103, 115]. In addition, curcumin suppressed the activity of β-secretase and ROS production induced by amyloid-β [118]. The origin and properties of vitamin C Vitamin C (L-ascorbic acid) is a water-soluble vitamin which has shown many functions in mammals (Fig. 4). This vitamin acts as a scavenger of free radicals, such as hydroxyl radical, superoxide anion and aqueous peroxyl. This compound can neutralize ROS in the extracellular space by contributing an electron to reduce free radicals prior to its reaction with

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biological molecules [119, 120]. Moreover, vitamin C acts as a co-factor in several enzymatic reactions, such as synthesis of cholesterol, carnitine, catecholamines, amino acids and peptide hormones [121]. Some mammals can synthesize vitamin C in the liver, but higher primates (including humans), fruit bats and guinea pigs need supplementation of this vitamin in the diet [122]. Vitamin C is contained mainly in the fruits and vegetables. Interestingly, lack of dietary vitamin C by approximately 1 week leads to reduction in its concentration in most tissues to

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near zero in vitamin C–deficient mice [123]. High level of vitamin C in the lung fluid was reported to prevent the generation of free radicals by toxic substances in the air, e.g. cigarette

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smoke, metal fumes or ozone [119, 124].

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The neuroprotective mechanism of action of Vitamin C:

Vitamin C plays an essential role in myelination via the synthesis of basement membrane

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components and collagen crosslinking [125, 126]. As reported in numerous papers, vitamin C has shown antioxidant properties in different animal models by preventing oxidative stress and reducing lipid peroxidation [127, 128]. Because ROS are the key factor involved in

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neuroinflammation and neurodegeneration, treatment with vitamin C may block these processes via inhibition of ROS generation. Moreover, vitamin C can also regenerate other

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antioxidants, e.g. GSH, β-carotene and α-tocopherol (vitamin E) [119, 120, 129]. Some data

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indicated that vitamin C could prevent neurodegeneration induced by ethanol or glutamate in a rat model [130, 131]. Furthermore, this compound has shown a protective activity against paraquat toxicity when it was given prior to paraquat. In contrast to this, treatment with vitamin C after tissue damage induced by paraquat caused elevation of the oxidative stress [132]. The mechanism responsible for this effect is connected with the ability of vitamin C to increase redox cycling of metal ions, such as Fe+3/Fe+2 [119, 120]. Sil and coworkers [133] indicated a neuroprotecive role of vitamin C in colchicine-induced neurotoxicity and memory impairments mediated by the inhibition of several neuroinflammatory factors. In those experiments, treatment with vitamin C (200 and 400 mg/kg) reduced the neuroinflammatory markers (such as cytokine, ROS and RNS) in the rat hippocampus [133]. However, in the higher dose (600 mg/kg) vitamin C caused an increase in the levels of neuroinflammatory markers in comparison with colchicine-induced AD rats. These opposite effects of vitamin C seem to be dependent on the redox state of cells and concentration gradients [134]. Furthermore, an in vitro study indicated that vitamin C could inhibit cell damage induced by glutamate via prevention of NMDA receptor activation [135, 136]. In addition, ischemia causes the release of large amounts of vitamin C from neurons with simultaneous uptake of

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glutamate by neurons and glia which is intended to limit neuronal damage [137, 138]. Both human and animal studies indicated a correlation between the aging process and decreasing concentrations of vitamin C in tissue [139]. Numerous mechanisms may be responsible for the age-related reduction of vitamin C, e.g. reduced absorption, accelerated turnover, elevated usage and decreased cellular uptake [140]. Schaus [141] reported that in people at the age of 80 and older the concentration of vitamin C in the cerebral cortex is significantly decreased

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compared to younger individuals. The concentration of vitamin C plays also a role in neurodegenerative diseases, such as PD or AD. Ide and coworkers [142] revealed that in PD

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patients, the lymphocyte vitamin C levels were significantly diminished compared to the control group. This compound, administered to elderly PD patients, increased bioavailability

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of lewodopa, [143]. Also in animal models of PD, vitamin C has shown neuroprotecive activity, by inhibiting the oxidative stress induced by MPP+ [144]. In addition, some authors

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demonstrated that maintaining healthy levels of vitamin C has shown a protective potential against AD [145].

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The origin and applying of Ginkgo biloba

Ginkgo biloba (Ginkgoaceae) is an ancient Chinese tree. For centuries the seeds and leaves of

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this plant have been used in traditional Chinese medicine [146]. At present, extracts of the

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Gingko biloba leaves are widely used both in Europe and in the United States as a phytomedicine and as a dietary supplement [147]. Compounds contained in the extract (flavonoids [Fig.5A], bilobalide [Fig.5B] and gingkolides [Fig.5C]) can cross the blood-brain barrier and cause pharmacological effects in the CNS [148]. The neuroprotective mechanism of action of Gingko biloba Clinical and preclinical studies indicated that patented extract of Gingko biloba leaves (EGb761) has shown protective properties against vascular and neuronal damage [149, 150]. Numerous clinical studies demonstrated therapeutic activity of ginkgo extracts in a variety of disorders, such as poor cerebral and ocular blood flow, age-related dementias, failing memory, and AD [147]. In addition, gingko is administered in the treatment of cerebrovascular dysfunctions and peripheral vascular disorders thanks to its ability to increase peripheral and cerebral circulation. There are evidences that EGb-761 extract diminishes apoptosis induced by different factors, such as staurosporine, serum deprivation, olfactory nerve sectioning or hydroxyl radicals [151, 152]. Moreover, EGb 761 produces an increase of the catecholamine release from its intracellular stores [153]. Chronic treatment with EGb 761

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elevates the release of noradrenaline with simultaneous decreases in the density of cerebral βadrenoceptors in the rat brain [154]. The extract of Gingko biloba has shown neuroprotective properties against MPTP-induced toxicity. It blocks the degeneration of dopaminergic neurons in the mouse striatum [155, 156]. The mechanism responsible for this neuroprotective effects of EGb 761 is based on its ability to inhibit both MAOA and MAOB activity and to block the conversion of MPTP to MPP+ ion [157, 158]. Moreover, treatment with EGb 761

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prevented the loss of tyrosine hydroxylase content induced by MPTP [158]. Some authors indicated antioxidant activity of EGb 761 [159]. This extract inhibits the production of free

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radicals in cultured neurons by blocking oxidative stress induced by iron sulfate and hydrogen peroxide [160, 161]. The results indicated that EGb 761 could stabilize the cellular redox

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homeostasis by up-regulating the protein level and activity of antioxidant enzymes, such as GSH reductase and SOD [162, 163]. Results from in vitro studies indicated that EGb 761

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significantly diminished oxidative damage of cerebellar granule cells induced by H2O2/FeSO4 [164]. Moreover, the extract of Gingko biloba blocked mitochondrial oxidative stress. An in vitro study indicated that EGb 761 elevated the viability of neuronal cells treated with

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hydrogen peroxide [160]. Jansens and coworkers [165] demonstrated that EGb 761 reversed ischemia-induced reduction in the mitochondrial complex I and IV activity and led to

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improvement of mitochondrial respiratory activity. Furthermore, in the rat mitochondria this

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extract was able to reverse aging-induced decrease in GSH/GSSG ratio [166]. Egb 761 could also prevent mitochondrial dysfunction induced by amyloid β peptide (Aβ) via reduction of ROS production [167]. The same authors demonstrated that EGb 761 extract significantly blocked the decrease in mitochondrial ATP and GSH amount as well as cytochrome c oxidase (COX) activity in two in vivo mouse models [168]. Some authors investigated the ability of EGb 761 to scavenge ROS, and the results confirmed the scavenging activity of EGb 761 in different experimental models [169, 170]. In addition, EGb 761 has shown anti-apoptotic properties. It can act upon different intracellular signaling pathways leading to apoptosis [171]. The mechanisms responsible for its anti-apoptotic activity are connected with the inhibition of apoptotic caspase cascade and apoptosome with simultaneous elevation of antiapoptotic Bcl-2 protein level [167, 171].

Conclusion:

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A common feature of all discussed compounds is their antioxidant activity and ability to reduce ROS generation. Another essential feature of natural compounds is their very wide mechanism of action, namely they have significant impact on different metabolic pathways and activity of numerous enzymes or genes (Table 1). Synthetic bioactive substances which are used to reduce oxidative stress very often are toxic. In contrast, natural compounds, such as plant extracts act as antioxidants and can repair the central nervous system (CNS) and

containing

bioactive

compounds

has

a

stronger

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prevent neurodegeneration by decreasing oxidative stress [172, 173]. A diet rich in plants neuroprotective

effect

against

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neurodegenerative disorders [174, 175, 176, 177]. It is advisable to use natural substances offered by the surrounding nature since these compounds have a broad spectrum of actions

an

us

without side effects.

References:

M

1. Jenner P. Oxidative stress in Parkinson’s disease. Ann Neurol, 2003; 53(3):26-36.

d

2. Nunomura A, Perry G, Pappolla MA, Wade R, Hirai K, Chiba S, et al. RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer’s disease. J Neurosci, 1999; 19(6):1959-64.

Ac ce pt e

3. Harman D. The free radical theory of aging. Antioxid Redox Signal 2003; 5(5):55761. 4. Dykens JA. Free radicals and mitochondria dysfunction in excitotoxicity and neurodegenerative disease. In: Koliatos, V. E., Ratan, R. R., (eds) Death and diseases of the nervous system. 1999; Humana Press, Totowa. 5. Schapira AH, Jenner P. Etiology and pathogenesis of Parkinson’s disease. Mov Disord, 2011;26:1049-55. 6. Dexter DT, Wells FR, Lees AJ, Agid F, Agid Y, Jenner P, Marsden CD. Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson’s disease. J Neurochem, 1989;52:1830-6. 7. Faucheux BA, Martin ME, Beaumont C, Hauw JJ, Agid Y, Hirsch EC. Neuromelanin associated redox-active iron is increased in the substantia nigra of patients with Parkinson’s disease. J Neurochem, 2003;86:1142-8. 8. Irani K, Xia JL, Zweier et al. Mitogenic signaling mediated by oxidants in Rastransformed fibroblasts. Science 1997;275:1649-52.

Page 15 of 38

9. Graham DG. Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones. Mol Pharmacol, 1987;14(4):633-43. 10. Gluck M, Ehrhart J, Jayatilleke E, Zeevalk GD. Inhibition of brain mitochondrial respiration by dopamine: involvement of H(2)O(2) and hydroxyl radicals but not glutathione-protein-mixed disulfides. J Neurochem, 2002;82(1): 66-74.

ip t

11. Bulteau AL, Ikeda-Saito M, Szweda LI. Redox-dependent modulation of aconitase activity in intact mitochondria. Biochemistry 2003;42(50):14846-55. 12. Bunik VI. 2-Oxo acid dehydrogenase complexes in redox regulation. Eur J Biochem, 2003;270(6):1036-42.

cr

13. Papa S, De Rasmo D. Complex I deficiencies in neurological disorders. Trends Mol Med, 2013;19(1):61-9.

an

us

14. Perry TL, Yong VW. Idopathic Parkinson’s disease, progressive supranuclear palsy and glutathione metabolism in the substantia nigra of patients. Neurosci Lett, 1986;67(3): 269-74.

M

15. Rojo AI, McBean G, Cindric M, Egea J, López MG, Rada P, et al. Redox control of microglial function: molecular mechanisms and functional significance. Antioxid Redox Signal, 2014;21(12):1766-1801.

d

16. McBean GJ, Aslan M, Griffiths HR, Torrão RC. Thiol redox homeostasis in neurodegenerative disease. Redox Biol, 2015;5:186-94.

Ac ce pt e

17. Fornstedt B, Pileblad E, Carlsson A. In vivo autoxidation of dopamine in guinea pig striatum increases with age. J Neurochem, 1990; 55(2):655-9. 18. Enoch WS, Sarna T, Zecca L, Riley PA, et al. The roles of neuromelanin, Winding of metal ions, and the oxidative cytotoxicity In the pathogenesis of Parkinson’s disease: a hypothesis. J Neural Transm, 1994;7: 83-100. 19. Segura-Aquilar J, Paris I, Munoz P, Ferrari E, Zecca L, Zucca FA. Protective and toxic roles of dopamine in Parkinson’s disease. J Neurochem, 2014; 129:898-915. 20. Zecca L, Fariello R, Riederer P, Sulzer D, Gatti A, Tampellini D. The absolute concentration of nigral neuromelanin, assayed by a new sensitive method, increases throught the life and is dramatically decreased in Parkinson’s disease. FEBS Lett, 2002;510:216-20. 21. Devine MJ, Gwinn K, Singleton A, Hardy J. Parkinson’s disease and αSyn expression. Mov Disord, 2011;26: 2160-8. 22. Sharma S, Moon CS, Hogali A, Haidou A, Chabenne A, Ojo C, et al. Biomarkers in Parkinson’s disease (recent update). Neurochem Int, 2013; 63:201-29.

Page 16 of 38

23. Abe K, Saitoh T, Horiguchi Y, Utsunomiya I, Taguchi K. Synthesis and neurotoxicity of tetrahydroisoquinoline derivatives for studying Parkinnson’s disease. Biol Pharm Bull, 2005;28:1355-62.

ip t

24. Yamakawa T, Kotake Y, Fujitani M, Shintani H, Makino Y, Ohta S. Regional distribution of parkinsonizm-preventing endogenous tetrahydroisoquinoline derivatives and an endogenous parkinsonizm-preventing substance-synthesizing enzyme in monkey brain. Neurosci Lett, 1999;276: 68-70.

cr

25. Yamakawa T, Ohta S. Isolation of 1-methyl-1,2,3,4-tetrahydroisoquinolinesynthesizing enzyme from rat brain: a possible Parkinson’s disease-preventing enzyme. Biochem Biophys Res Commun, 1997;236:676-81.

us

26. Yamakawa T, Ohta S. Biosynthesis of a parkinsonism-preventing substance, 1-methyl1,2,3,4-tetrahydroisoquinoline, is inhibited by parkinsonism-inducing compounds in rat brain mitochondrial fraction. Neurosci Lett, 1999;259:157-60.

M

an

27. Makino Y, Tasaki Y, Ohta S, Hirobe M. Confirmation of the enantiomers of 1-methyl1,2,3,4-tetrahydroisoquinoline in the mouse brain and foods applying gas chromatography/mass spectrometry with negative ion chemical ionization. Biomed Environ Mass Spectrom, 1990;19: 415-19.

d

28. Abe K, Taguchi K, Wasai T, Ren J, Utsunomiya I, Shinohara T, et al. Stereoselective effect of (R)- and (S)-1-methyl-1,2,3,4-tetrahydroisoquinolines on a mouse model of Parkinson’s disease. Brain Res Bull, 2001;56:55-60.

Ac ce pt e

29. Wąsik A, Romańska I, Michaluk J, Antkiewicz-Michaluk L. Comparative behavioral and neurochemical studiem of R- and S-1 methyl-1,2,3,4-tetrahydroisoquinoline stereoisomers in the rat. Pharmacol Rep, 2012;64:857-69. 30. Inoue H, Matsubara D, Tsuruta Y. Simultaneous analysis of 1,2,3,4tetrahydroisoquinolines by high-performance liquid chromatography using 4-(5,6dimethoxy-2-phthalimidinyl)-2-methoxyphenylsulfonyl chloride as a fluorescent labeling reagent. J Chromatogr B Anal Technol Biomed Life Sci, 2008;867:32-6. 31. Niwa T, Yoshizumi H, Tatematsu A, Matsuura S, Yoshida M, Kawachi M, et al. Endogenous synthesis of N- methyl-1,2,3,4-tetrahydroisoquinoline, a precursor of Nmethylisoquinolinium ion, in the brains of primates with parkinsonism after systemic administration of 1,2,3,4-tetrahydroisoquinoline. J Chromatogr, 1990;533:145-51. 32. Tasaki Y, Makino Y, Ohta S, Hirobe M. Biosynthesis of 1-methyl-1,2,3,4tetrahydroisoquinoline (MeTIQ), a possible antiparkinsonism agent. Adv Neurol, 1993; 60:231-3. 33. Kikuchi K, Nagatsu Y, Makino Y, Mashino T, Ohta S, Hirobe M. Metabolism and penetration through blood-brain barrier of parkinsonism-related compounds 1,2,3,4-

Page 17 of 38

tetrahydroisoquinoline and 1-methyl-1,2,3,4-tetrahydroisoquinoline. Drug Metab Dispos, 1991;19: 257-62. 34. Makino Y, Ohta S, Tachikawa O, Hirobe M. Presence of tetrahydroisoquinoline and 1-methyl-1,2,3,4-tetrahydroisoquinoline in foods: compounds related to Parkinson’s disease. Life Sci. 1988; 43:373-8.

ip t

35. Ayala A, Parrado J, Cano J, Machado A. Reduction of 1-methyl-1,2,3,4tetrahydroisoquinoline level in substantia nigra of the aged rat. Brain Res, 1994;638: 334-6.

us

cr

36. Antkiewicz-Michaluk L, Wardas J, Michaluk J, Romanska I, Bojarski A, Vetulani J. Protective effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline against dopaminergic neurodegeneration in the extrapyramidal structures produced by intracerebral injection of rotenone. Int J Neuropsychpharmacol, 2004;7:155-63.

an

37. Antkiewicz-Michaluk L, Łazarewicz JW, Patsenka A, Kajta M, Zieminska E, Salinska E, et al. The mechanizm of 1,2,3,4-tetrahydroisoquinolines neuroprotection: the importance of free radicals scavenging properties and inhibition of glutamate-induced excitotoxicity. J Neurochem, 2006;97: 846-856.

d

M

38. Wąsik A, Romanska I, Antkiewicz-Michaluk L. The effect o fan endogenous compound 1-methyl-1,2,3,4-tetrahydroisoquinoline on morphine-induced analgesia, dependence and neurochemical changes in dopamine metabolism in rat brain structures. J Physiol Pharmacol, 2007;58:235-52.

Ac ce pt e

39. Wąsik A, Romańska I, Michaluk J, Kajta M, Antkiewicz-Michaluk L. 1-Benzyl1,2,3,4-tetrahydroisoquinoline, an endogenous neurotoxic compound, disturbs the behavioral and biochemical effects of 1-DOPA: in vivo and ex vivo studies in the rat. Neurotox Res, 2014;26(3):240-54. 40. Wąsik A, Romańska I, Antkiewicz-Michaluk L. Comparison of the effects of acute and chronic administration of tetrahydroisoquinoline amines on the in vivo dopamine release: a microdialysis study in the rat striatum. Neurotox Res, 2016a; 30(4): 648-57. 41. Wąsik A, Romańska I, Michaluk J, Zelek-Molik A, Nalepa I, Antkiewicz-Michaluk L. Neuroprotective effect of endogenous amine 1MeTIQ in animals model of Parkinson’s disease. Neurotox Res, 2016b;29:351-63. 42. Antkiewicz-Michaluk L, Michaluk J, Mokrosz M, Romanska I, Lorenc-Koci E, Ohta S, et al. Different action on dopamine catabolic pathways of two endogenous 1,2,3,4tetrahydroisoquinolines with similar antidopaminergc properties. J Neurochem, 2001;78:100-8. 43. Patsenka A, Antkiewicz-Michaluk L. Inhibition of rodent brain monoamine oxidase and tyrosine hydroxylase by endogenous compounds-1,2,3,4-tetrahydroisoquinoline alkaloids. Pol J Pharmacol, 2004;56:727-34.

Page 18 of 38

44. Singer TP, Ramsay RR. Flavoprotein structure and mechanism2. Monoamine oxidases: old friends hold many suprises. FASEB J, 1995;9: 605-10. 45. Jenner P. Preclinical evidence for neuroprotection with monoamine oxidase-B inhibitors in Parkinson’s disease. Neurology, 2004;63:13-22. 46. Jenner P, Langston JW. Explaining ADAGIO: a critical review of the biological basis fot the clinical effects of rasagiline. Mov Disord, 2011;26:2316-23.

ip t

47. Mandel S, Weinreb O, Amit T, Youdim MB. Mechanism of neuroprotective action of the anti-Parkinson drug rasagiline and its derivatives. Brain Res Rev, 2005;48:379-87.

us

cr

48. Olanow CW, Hauser RA, Jankovic J, Langston W, Poewe W, Tolosa E, et al. A randomized, double-blind, placebo-controlled, delayed stsrt study to assess rasagiline as a disease modifying therapy in Parkinson’s disease (the ADAGIO study): rationale, design, and baseline characteristics. Mov Disord, 2008;23:2194-201.

an

49. Parkinson Study Group A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study Arch Neurol, 2002;59:1937-43.

M

50. Vetulani J, Antkiewicz-Michaluk L, Michaluk J. Modification of morphine analgesia, tolerance and abstinence by 1,2,3,4-tetrahydroisoquinoline. Eur Neuropsychopharmacol, 2003;113:29-30.

d

51. Sun AY, Wang Q, Simonyi A, Sun GY. Botanical phenolics and brain health. Neuromol Med, 2008;10: 259-74.

Ac ce pt e

52. Juan ME, Maijo M, Planas JM. Quantification of trans-resveratrol and its metabolites in rat plasma and tissues by HPLC. J Pharm Biomd Anal, 2010;51: 391-8. 53. Bastianetto S, Menard C, Quirion R. Neuroprotective action of resveratrol. Biochim Biophys Acta, 2015; 1852:1195-1201 54. Baur JA, Sinclair DA. Therapeutic potential of resveratrol: The in vivo evidence. Nat Rev Drug Discov, 2006;5:493-506. 55. Walle T. Bioavailability of resveratrol. Ann N Y Acad Sci, 2011;1215: 9-15. 56. Mahal H, Mukherjee T. Scavenging of reactive oxygen radicals by resveratrol: antioxidant effect. Res Chem Intermed, 2006;32:59-71. 57. Athar M, Back JH, Kopelovich L, Bickers DR, Kim AL. Multiple molecular targets of resveratrol: anti-carcinogenic mechanisms. Arch Biochem Biophys, 2009;486:95-102. 58. Szkudelska K, Szkudelski T. Resveratrol, obesity and diabetes. Eur J Pharmacol, 2010;635:1-8.

Page 19 of 38

59. Kasiotis KM, Pratsinis H, Kletsas D, Haroutounian SA. Resveratrol and related stilbenes: their anti-aging and anti-angiogenic properties. Food Chem Toxicol, 2013;61:112-20. 60. Jing YH, Chen KH, Kuo PC, Pao CC, Chen JK. Neurodegeneration in streptozotocininduced diabetic rats is attenuated by treatment with resveratrol. Neuroendocrinology, 2013;98(2):116-27.

ip t

61. Caruana M, Cauchi R, Vassallo N. Putative role of red wine polyphenols against brain pathology in Alzheimer’s and Parkinson,s disease. Front Nutr, 2016; 3:31.

cr

62. Liu GS, Zhang ZS, Yang B, He W. Resveratrol attenuates oxidative damage and ameliorates cognitive impairment in the brain of senescence-accelerated mice. Life Sci, 2012;91:872-7.

an

us

63. Ren J, Fan C, Chen N, Huang J, Yang Q. Resveratro pretreatment attenuates cerebral ischemic injury by upregulating expression of transcription factor Nrf2 and HO-1 in rats. Neurochem Res, 2011;36:2352-62.

M

64. Granzotto A, Zatta P. Resveratrol acts not through anti-aggregative pathways but mainly via its scavenging properties against Abeta and Abeta-metal complexes toxicity. PLoS One, 2011;6:e21565. doi: 10.1371/journal. pone.0021565.

d

65. Fernandez-Moriano C, Gonzalez-Burgos E, Gomez-Serranillos MP. Mitochondriatargeted protective compounds in Parkinson’s and Alzheimer’s diseases. Oxid Med Coll Longev, 2015;408927. doi: 10.1155/2015/408927.

Ac ce pt e

66. Kitada M, Kume S, Imaizumi N, Koya D. Resveratrol improves oxidative stress and protects against diabetic pephropathy through normalization of Mn-DOD dysfunction In AMPK/SIRT1-independent pathway. Diabetes, 2011;60(2):634-43. 67. Basti J, Lopes-Costa A, Djoudi F. Exposure to resveratrol triggers pharmacological correction of fatty acid utilization in human fatty acid oxidation-deficient fibroblasts. Hum Mol Genet, 2011;20(10):2048-57. 68. Um JH, Park SJ, Kang H, et al. AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes, 2010;59:554-63. 69. Gledhill JR, Montgomery MG, Leslie AG, Walker JE. Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols. Proc Natl Acad Sci USA, 2007;104(34):13632-7. 70. Kipp JL, Ramirez VD. Effect of estradiol, diethylstilbestrol, and resveratrol on F0F1ATPase activity from mitochondrial preparations of rat heart, liver, and brain. Endocrine, 2000;15(2):165-75.

Page 20 of 38

71. Blanchet J, Longpre F, Bureau G, Morissette M, Dipaolo T, Bronchti G, et al. Resveratrol, a red wine polyphenol, protects dopaminergic neurons in MPTP-treated mice. Prog Neuropsychopharmacol Biol Psychiatry, 2008;32:1243-50. 72. Khan MM, Ahmad A, Ishrat T, Khan MB, Hoda MN, Khuwaja G, et al. Resveratro attenuates 6-hydroxydopamine-induced oxidative damage and dopamine depletion in rat model of Parkinson’s disease. Brain Res, 2010;1328:139-51.

ip t

73. Balu M, Sangeetha P, Murali G, Panneerselvam C. Modulatory role of grape seed extract on age-related oxidative DNA damage in central nervous system of rats. Brain Res Bull, 2006;68:469-73.

us

cr

74. Jang JH, Surh YJ. Protective effects of resveratrol on hydrogen peroxide-induced apoptosis in rat pheochromocytoma (PC12) cells. Mutation Res, 2001;496(1-2):181190.

an

75. Quincozes-Santos A, Bobermin LD, Latini A, et al. Resveratrol protects C6 astrocyte cell line against hydrogen proxide-induced oxidative stress through heme oxygenase 1. PLoS ONE, 2013;8(5):Article ID e64372.

M

76. Waite KA, Sinden MR, Eng C. Phytoestrogen exposure elevates PTEN levels. Hum Mol Gen, 2005;14(11):1457-63.

d

77. Wang Y, Romigh T, He X, et. al. Resveratrol regulates the PTEN/AKT pathway through androgen receptor-dependent and –independent mechanisms in prostate cancer cell lines. Hum Mol Gen, 2010;19(22):4319-29.

Ac ce pt e

78. Ingles M, Gambini J, Graça MM, Bonet-Costa V, Abdelaziz KM, El Alami M, et al. PTEN mediates the antioxidant effect of resveratrol at nutritionally relevant concentrations. Bio Med Res Int, 2014;Article ID 580852,doi:10.1155/2014/580852. 79. Abdel-Wahab BA, Abdel-Wahab MM. Protective effect of resveratrol against chronic intermittent hypoxia-induced spatial memory deficits, hippocampal oxidative DNA damage and increased p47Phox NADPH oxodase expression In young rats. Behav Brain Res, 2016;305:65-75. 80. Xu Y, Wang Z, You W, Zhang X, Li S, Barish PA, et al. Antidepressant-like effect of trans-resveratrol: involvement of serotonin and noradrenaline system. Eur Neuropsychopharmacol, 2010; 20:405-13. 81. Yu Y, Wang R, Chen C, Du X, Ruan I, Sun J, et al. Antidepressant-like effect of transresveratrol in chronic stress model: Behavioral and neurochemical evidences. J Psychiatric Res, 2013;47: 316-22. 82. Hurley IL, Akinfiresoye L, Kalejaiye O, Tizabi Y. Antidepressant effects of resveratrol in an animal model of depression. Behav Brain Res, 2014;268:1-7.

Page 21 of 38

83. Virgili M, Contestabile A. Partial neuroprotection of in vivo excitotoxic brain damage by chronic administration of the red wine antioxidant agent, trans-resveratrol in rats. Neurosci Lett, 2000;281:123-6. 84. Sakata Y, Zhuang H, Kwansa H, Kohler RC, Doré S. Resveratrol protects against experimental stroke: putative neuroprotective role of heme oxygenase 1. Exp Neurol, 2010;224(1):325-9.

ip t

85. Lopez MS, Dempsey RJ, Vemuganti R. Resveratrol neuroprotection in stroke and traumatic CNS injury. Neurochem Int, 2015;89:75-82.

cr

86. Borra MT, Smith BC, Denu JM. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem, 2005;280:17187-95.

us

87. Dasgupta B, Milbrandt J. Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci U S A, 2007;104:7217-22.

an

88. Chen CY, Jang JH, Li MH, Surh YJ. Resveratrol upregulates heme oxygenase-1 expression via activation of NF-E2 related factor 2 in PC12 cells. Biochem Biophys Res Commun, 2005;331:993-1000.

M

89. Ungvari Z, Bagi Z, Feher A, Recchia FA, Sonntag WE, Pearson K, et al. Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2. Am J Physiol Heart Circ Physiol, 2010;18-24.

Ac ce pt e

d

90. Shang YJ, Qian YP, Liu XD, Dai F, Shang XL, Jia WQ, et al. Radical-scavenging activity and mechanism of resveratrol-oriented analogues: influence of the solvent, radical, and substitution. J Org Chem, 2009;74:5025-31. 91. Ates O, Cayli S, Altinoz E, Gurses I, Yucel N, Sener M, et al. Neuroprotection by resveratrol against traumatic brain injury in rats. Mol Cell Biochem, 2007;294:137-44. 92. Karaoglan A, Akdemir O, Barut S, Kokturk S, Uzun H, Tasyurekli M, et al. The effects of resveratrol on vasospasm after experimental subarach-noidal hemorrhage in rats. Surg Neurol, 2008;70:337-43. 93. Song J, Cheon SY, Jung W, Lee WT, Lee JE. Resveratrol induces the expression of interleukin-10 and brain-derived neurotrophic factor in BV2 microglia under hypoxia. Int J Mol Sci, 2014;15:15512-29. 94. Shin JA, Lee H, Lim YK, Koch Y, Choi JH, Park EM. Therapeutic effects of resveratrol during acute periods following experimental ischemic stroke. J Neuroimmunol, 2010;227:93-100. 95. Simao F, Matte A, Pagnussat AS, Netto CA, Salbego CG. Resveratrol preconditioning modulates inflammatory response in the rat hippocampus following global cerebral ischemia. Neurochem Int, 2012;61:659-65.

Page 22 of 38

96. Mohamed HE, El-Swefy SE, Hasan RA, Hasan AA. Neuroprotective effect of resveretrol in diabetic cerebral ischemic-reperfused rats through regulation of inflammatory and apoptotic events. Diabetol Metab Syndr, 2014; 6:88-101. 97. Agrawal DK, Mishra PK. Curcumin and its analogues: potential anticancer agents. Med Res Rev, 2010;30:818-60.

ip t

98. Soni D, Salh B. A neutraceutical by design: the clinical application of curcumin in colonic inflammation and cancer. Scientifica (Caro), 2012;757890.

cr

99. Ataie A, Shadifar M, Ataee R. Polyphenolic antioxidants and neuronal regeneration. Basic Clin Neurosci, 2016;7(2):81-90.

us

100. Ng TP, Chiam PC, Lee T, Chua HC, Lim L, Kua EH. Curry consumption and cognitive function in the elderly. Am J Epidemiol, 2006;164:898-906.

an

101. Ganguli M, Chandra V, Kamboph MI, Johnston JM, Dodge HH, Thelma BK, et al. ApolipoproteinE polymorphism and Alzheimer’s disease: The Indo-US CrossNational Dementia Study. Arch Neurol, 2000;57(6):824-30.

M

102. Baum L, Ng A. Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer’s disease animal models. J Alzh Dis, 2004;6(4):367-77.

Ac ce pt e

d

103. Kim H, Park BS, Lee KG, Choi CY, Jang SS, Kim YH, et al. Effects of naturally occurring compounds on fibril formation and oxidative stress of vbetaamyloid. J Agric Food Chem, 2005;53:8537-41. 104. Varadarajan S, Yatin S, Aksenova M, Butterfield DA. Review: Alzheimer’s amyloid beta-peptide-associated free radical oxidative stress and neurotoxicity. J Struct Biol, 2000;130:184-208. 105. Park SY, Kim HS, Cho EK, Kwon BY, Phark S, Hwang KW, et al. Curcumin protected PC12 cells against beta-amyloid-induced toxicity through the inhibition of oxidative damage and tau hyperphosphorylation. Food Chem Toxicol, 2008; 46:28817. 106. Dutta K, Ghosh D, Basu A. Curcumin protects neuronal cells from Japanese encephalitis virus-mediated cell death and also inhibits infective viral particle formation by dysregulation of ubiquitin-proteasome system. J Neuroimm Pharm, 2009;4(3):328-37. 107. Yang C, Zhang X, Fan H, Liu Y. Curcumin upregulates transcription factor Nrf2, HO-1 expression and protects rat brains against focal ischemia. Brain Res, 2009;1282:133-41. 108. Ataie A, Sabet-Kasaei M, Haghparast A, Moghaddam AH, Kazemi-Nejad B. Neuroprotective effects of the polyphenolic antioxidant agent, Curcumin, against

Page 23 of 38

homocysteine-induced cognitive impairment and oxidative stress In the rat. Pharmacol Biochem Behav, 2010;96(4):378-85. 109. Rajeswari A. Curcumin protects mouse brain from oxidative stress caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Eur Rev Med Pharmacol Sci, 2006;10(4):157-61.

ip t

110. Shehzad A, Lee YS. Molecular mechanisms of curcumin action: signal transduction. Biofactors, 2013;39:27-36.

cr

111. Chan MM, Huang HI, Fenton MR, Fong D. In vivo inhibition of nitric oxide synthase gene expression by curcumin, a cancer preventive natural product with antinflammatory properties. Biochem Pharmacol, 1998;55:1955-62.

us

112. Zhang F, Altorki NK, Mestre JR, Subbaramaiah K, Dannenberg AJ. Curcumin inhibits cyclooxygenase-2 transcription in bile acid- and phorbol ester-treated human gastrointestinal epithelial cells. Carcinogenesis, 1999;20:445-51.

M

an

113. Pendurthi UR, Williams JT, Rao LV. Inhibition of tissue factor gene activation in cultured endothelial cells by curcumin. Suppression of activation of transcription factors Egr-1, AP-1, and NF-kappa B. Arterioscler Thromb Vasc Biol, 1997;17: 340613.

Ac ce pt e

d

114. Weber WM, Hunsaker LA, Gonzales AM, Heynekamp JJ, Orlando RA, Deck LM, et al. TPA-induced up-regulation of activator protein-1 can be inhibited or enhanced by analogs of the natural product curcumin. Biochem Pharmacol, 2006;72:928-40. 115. Begum AN, Jones MR, Lim GP, Morihara T, Kim P, Heath DD, et al. Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer’s disease. J Pharmacol Exp Ther, 2008;326(1): 196-208. 116. Thiyagarajan M, Sharma SS. Neuroprotective effect of curcumin in middle cerebral artery occlusion induced focal cerebral ischemia in rats. Life Sci, 2004;74: 969-85. 117. Wu A, Ying Z, Gomez-Pinilla F. Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition. Exp Neurol, 2006;197:309-17. 118. Shimmyo Y, Kihara T, Akaike A, Niidome T, Sugimoto H. Epigallocatechin3-gallate and curcumin suppress amyloid beta-induced beta-site APP cleaving enzyme-1 upregulation. Neuroreport, 2008;19:1329-33. 119. Carr A, Frei B. Does vitamin C act as a pro-oxidant under physiological conditions? FASEB J, 1999;13:1007-24.

Page 24 of 38

120. Evans P, Halliwell B. Micronutrients: oxidant/antioxidant status. Br J Nutr, 2001;85: 67-74. 121. Chatterjee IB, Majumder AK, Nandi BK, Subramanian N. Synthesis and some major functions of vitamin C in animals. Ann NY Acad Sci, 1975;258: 24-47. 122. Camarena V, Wang G. The epigenetic role of vitamin C in health and disease. Cell Mol Life Sci, 2016;73:1645-58.

cr

ip t

123. Vissers M., Bozonet SM, Pearson JF, Braithwaite LJ. Dietary ascorbate intake affects steady state tissue concentrations in vitamin C-deficient mice: tissue deficiency after suboptimal intake and superior bioavailability from a food source (kiwifruit). Am J Clin Nutr 2010;93(2): 292-301.

us

124. Menzel DB. The toxicity of air pollution in experimental animals and humans: the role of oxidative stress. Toxicol Lett, 1994;72: 269-77.

an

125. Gould BS, Woessner JF. Biosynthesis of collagen; the influence of ascorbic acid on the proline, hydroxyproline, glycine, and collagen content of regenerating guinea pig skin. J Biol Chem, 1957; 226: 289-300.

M

126. McGarvey ML, Baron-Van Evercooren A, Kleinman HK, Dubois-Dalcq M. Synthesis and effects of basement membrane components in cultured rat Schwann cells. Dev Biol, 1984;105: 18-28.

Ac ce pt e

d

127. Goswami AR, DuttaG, Ghosh T. Effects of vitamin C on the hypobaric hypoxia-induced immune changes in male rats. Int J Biometeorol, 2014;58: 1961-71. 128. Coşkun Ş, Gönül B, Güzel NA, Balabanli B. The effects of vitamin C supplementation on oxidative stress and antioxidant content in the brains of chronically exercised rats. Mol Cell Biochem, 2005; 280: 135-8. 129. Halliwell B. Vitamin C: antioxidant or pro-oxidant in vivo? Free Rad Res, 1996; 25: 439-54. 130. Ahmad A, Shah SA, Badshah H, Kim MJ, Ali T, Yoon GH, et al. Neuroprotection by vitamin C against ethanol-induced neuroinflammation associated neurodegeneration in the developing rat brain. CNS Neurol Disord Drug Targets, 2016;15: 360-70. 131. Shah SA, Yoon GH, Kim HO, Kim MO. Vitamin C neuroprotection against dose-dependent glutamate-induced neurodegeneration in the postnatal brain. Neurochem Res, 2015; 40: 875-84. 132. Kang SA, Jang YJ, Park H. In vivo dual effects of vitamin C on paraquatinduced lung damage: dependence on released metals from the damaged tissue. Free Red Res, 1998;28: 93-107.

Page 25 of 38

133. Sil S, Ghosh T, Gupta P, Ghosh R, Kabir SN, Roy A. Dual role of vitamin C on the neuroinflammation mediated neurodegeneration and memory impairments in colchicine induced rat model of Alzheimer disease. J Mol Neurosci, 2016; DOI 10.1007/s12031-016-0817-5.

ip t

134. Chakraborthy A, Ramani P, Sherlin HJ, Premkumar P, Natesan A. Antioxidant and pro-oxidant activity of vitamin C in oral environment. Indian. J Dent Res, 2014; 25: 499-504.

cr

135. Atlante A, Gagliardi S, Minervini GM, Ciotti MT, Marra E, Calissano P. Glutamate neurotoxicity in rat cerebellar granule cells: a major role for xanthine oxidase in oxygen radical formation. J Neurochem, 1997; 68: 2038-45.

us

136. Ciani E, Groneng L, Voltattorni M, Rolseth V, Conestabile A, Paulsen RE. Inhibition of free radical production or free radical scavenging protects from the excitotoxic cell death mediated by glutamate in cultures of cerebellar granule neurons. Brain Res, 1996; 728: 1-6.

an

137. Rice ME. Ascorbate regulation and its neuroprotective role in the brain. Trends Neurosci, 2000; 23: 209-16.

M

138. Miele M, Boutelle MG, Fillenz M. The physiologically induced release of ascorbate in rat brain is dependent on impulse traffic, calcium influx and glutamate uptake. Neuroscience, 1994;62: 87-91.

Ac ce pt e

d

139. Michels AJ, Hagen TM. Vitamin C status decline with age. In: Asard, H., May, J., Smirnoff, N., (eds) Vitamin C: its function and biochemistry in animals and plants. Garland Science/BIOS Scientific Publishers, Abingdon, 2004 ; 203-28. 140. Attwood EC, Robey E, Kramer JJ, Ovenden N, Snape S, Ross J, et al. A survey of the haematological, nutritional and biochemical state of the rural elderly with particular reference to vitamin C. Age Ageing, 1978; 7: 46-56. 141. Schau R. The ascorbic acid content of human pituitary, cerebral cortex, heart, and skeletal muscle and its relation to age. Am J Nutr, 1957; 5: 39-41. 142. Ide K, Yamada H, Umegaki K, Mizuno K, Kawakami N, Hagiwara Y, et al. Lymphocyte vitamin C levels as potential biomarker for progression of Parkinson’s disease. Nutrition 2015; 31: 406-08. 143. Nagayama H, Hamamoto M, Ueda M, Nito C, Yamaguchi H, Katayama Y. The effect of ascorbic acid on the pharmacokinetics of levodopa In elderly patients with Parkinson disease. Clin Neuropharmacol, 2004; 27: 270-73. 144. Wagner GC, Carelli RM, Jarvis MF. Ascorbic acid reduces the dopamine depletion induced by methamphetamine and the 1-methyl-4-phenyl pyridinium ion. Neuropharmacology 1986; 25: 559-61.

Page 26 of 38

145. Harrison FE. A critical review of vitamin C for the prevention of age-related cognitive decline and Alzheimer’s disease. J Alzheimer’s Dis, 2012; 29; 711-26. 146. Jacobs BP, Browner WS. Ginkgo biloba: a living fossil. Am J Med, 2000; 108: 341-2. 147. Maclennan KM, Darlington CL, Smith PF. The CNS effects of Ginkgo biloba extracts and ginkolide B. Prog Neurobiol, 2002; 67: 235-57.

ip t

148. DeFeudis FV, Drieu K. Ginkgo biloba extract (EGb 761) and CNS functions: basic studies and clinical applications. Curr Drug Targets, 2000; 1: 25-58.

us

cr

149. Ahlemeyer B, Krieglstein J. Neuroprotective effects of the Ginkgo biloba extract. In: Phytomedicine of Europe: Chemistry and biological activity, ACS Symposium Series, 1998;69:210-20.

an

150. Diamond BJ, Shiflett SC, Feiwel N, Matheis RJ, Noskin O, Richards JA, et al. Ginkgo biloba extract: mechanisms and clinical indications. Arch Phys Med Rehabil, 2000; 81: 668-78.

M

151. Guidetti C, Paracchini S, Lucchini S, Cambieri M, Marzatico F. Prevention of neuronal cell damage induced by oxidative stress in-vitro: effect of different Ginkgo biloba extracts. J Pharm Pharmacol, 2001; 53: 387-92.

Ac ce pt e

d

152. Ahlemeyer B, Möwes A, Krieglstein J. Inhibition of serum deprovation- and staurosporine-induced neuronal apoptosis by Ginkgo biloba extract and some of its constituents. Eur J Pharmacol, 1999; 367: 423-30. 153. Auguet M, Hellegouarch A, Delaflotte S, Baranès J, DeFeudis FV, Clostre F et al. Effects of ginkgo biloba extract on rabbit isolated blood vessels. In: Cerebral Ischemia, 1984;347-54. 154. Brunello N, Racagni G, Clostre F, Drieu K, Braquet P. Effects of an extract of Ginkgo biloba on noradrenergic systems of rat cerebral cortex. Pharmacol Res Commun, 1985; 17: 1063-72. 155. Yang SF, Wu Q, Sun AS, Huang XN, Shi JS. Protective effect and mechanism of Ginkgo biloba leaf extracts for Parkinson disease induced by 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine. Acta Pharmacol Sin, 2001; 22: 1089-93. 156. Rojas P, Serrano-Garcia N, Mares-Sámano JJ, Medina-Campos ON, PedrazaChaverri J, Ogren SO. EGb 761 protects against nigrostriatal dopaminergic neurotoxicity In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonizm in mice. Role of oxidative stress. Eur J Neurosci, 2008; 28: 41-50. 157. Sloley BD, Urichuk LJ, Morley P, Durkin J, Shan JJ, Pang PKT, et al. Identification of kaempferol as a monoamine oxidase inhibitor and potential

Page 27 of 38

neuroprotectant in extract of Ginkgo biloba leaves. J Pharm Pharmacol, 2000; 52: 4519. 158. Rojas P, Rojas C, Ebadi M, Montes S, Monroy-Noyola A, Serrano-Garcia N. EGb 761 pretreatment reduces monoamine oxidase activity in mouse corpus striatum during 1-methyl-4-phenylpyridinium neurotoxicity. Neurochem Res, 2004; 29: 141723.

ip t

159. Ahlemeyer B, Krieglstein J. Neuroprotective effects of Ginkgo biloba extract. Cell Mol Life Sci, 2003; 60: 1779-92.

cr

160. Oyama Y, Chikahisa L, Ueha T, Kanemaru K, Noda K. Ginkgo biloba extract protects brain neurons against oxidative stress induced by hydrogen peroxide. Brain Res, 1996; 712: 349-52.

an

us

161. Song W, Guan HJ, Zhu XZ, Chen ZL, Yin ML, Cheng XF. Protective effect of bilobalide against nitric oxide-induced neurotoxicity in PC12 cells. Acta Pharmacol Sin, 2000; 21: 415-20.

M

162. Bridi R, Crosetti FP, Steffen VM, Henriques AT. The antioxidant activity of standardized extract of Ginkgo biloba (EGb 761) in rats. Phytother Res, 2001; 15: 449-51.

d

163. Sasaki K, Hatta S, Wada K, Ueda N, Yoshimura T, EndoT et al. Effect of extract of Ginkgo biloba leaves and its constituents on carcinogen-metabolizing enzyme activities and glutathione levels in mouse liver. Life Sci, 2002; 70: 1657-67.

Ac ce pt e

164. Wei T, Ni Y, Hou J, Chen C, Zhao B, Xin W. Hydrogen peroxide-induced oxidative damage and apoptosis in cerebellar granule cells: Protection by Ginkgo biloba extract. Pharmacol Res, 2000; 41: 427-33. 165. Janssens D, Remacle J, Drieu K, Michiels C. Protectionof mitochondrial respiration activity by bilobalide. Biochem Pharmacol, 1999; 58: 109-19. 166. Sastre J, Millan A, de la Asuncion JG, Pallardo FV, Droy-Lefaix MT, Vinal J. Prevention of age-associated mitochondrial DNA damage by Ginkgo biloba extract EGb 761. In: Proceedings of the VIII Biennial Meeting of the International Society for Free Radical Research, Prous, J.R. (ed), Barcelona. 1998. 167. Shi C, Fang L, Yew DT, Yao Z, Xu J. Ginkgo biloba extract EGb-761 protects against mitochondrial dysfunction in platelets and hippocampi in ovariectomized rats. Platelets, 2010;21(1):53-9. 168. Shi C, Zhao L, Zhu B, Li Q, Yew DT, Yao Z, et al. Protective effects of Ginkgo biloba extract (EGb761) and its constituents quercetin and ginkgolide B against beta-amyloid peptide-induced toxicity in SH-SY5Y cells. Chem Biol Interact, 2009;181:115-23.

Page 28 of 38

169. Maitra I, Marcocci L, Droy-Lefaix M-T, Packer L. Peroxyl radical scavenging activity of Ginkgo biloba extract EGb-761. Biochem Pharmacol, 1995; 49(11):164955. 170. Marcocci L, Maguire JJ, Droy-Lefaix M.-T, Packer L. The nitric oxidescavenging properties of Ginkgo biloba extract EGb-761. Biochem Biophys Res Commun, 1994b; 201(2):748-55.

ip t

171. Smith JV, Luo Y. Studies on molecular mechanisms of Ginkgo biloba extract. Appl Microbiol Biotechnol, 2004;64:465-72.

cr

172. Blesa J, Przedborski S. Parkinson’s disease: Parkinson’s disease: animal models and dopaminergic cell vulnerability. Front Neuroanat, 2014;8:155.

us

173. Cai ZB, Zeng WJ, Tao K, Gao GD, Yang Q. Myricitrin alleviates MPP+induced mitochondrial dysfunction in a DJ-1-dependent manner in SN 4741 cells. Biochem Biophys Res Commun, 2015; 458(2);227-33.

M

an

174. Kim BW, Koppula S, Park SY, et al. Attenuation of neuroinflammatory responsem and behavioral deficits by Ligusticum officinale (Makino) Kitag In stimulated microglia and MPTP-induced Mouse model of Parkinson’s disease. J Ethnopharmacol, 2015;164:388-97.

d

175. Kumar H, Song SY, More SV, et al. Traditional Korean East Asian medicines and herbal formulations for cognitive impairment. Molecules, 2013;18(12):14670-93.

Ac ce pt e

176. Barbarosa M, Valentao P, Andrade PB. Bioactive compounds from macroalgae in the new millennium: implications for neurodegenerative diseases. Mar Drugs, 2014;12(9):4934-72. 177. Sun AJ, Xu XX, Lin JS, Cui XL, Xu RA. Neuroprotection by saponins. Phytother Res, 2015;29(2):187-200.

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Agent

Mechanism of action Antioxidant; ROS scavenger; MAO-A and MAO-B inhibitor; BDNF and NGF enhancer; NMDA inhibitor Antioxidant; ROS scavenger; GSH and SOD enhancer; SIRT and AMPK and Nrf2 activator; anti-inflammatory activity: COX1 and COX2 inhibitor; enhancer of BDNF and IL-10 Antioxidant; inhibitor of ROS production; inhibitor of amyloid-β peptide and tau hyperphosphorylation; anti-inflammatory activity: inhibitor of COX-2, NOS, NFκB, IL-1β; activator of JNK and Nrf2 Antioxidant; inhibitor of ROS production; GSH, β-carotene and α-tocopherol enhancer; anti-inflammatory activity: inhibitor of NOS and cytokine Antioxidant; ROS scavenger; GSH and SOD enhancer; preserver of mitochondrial function; anti-apoptotic activity: inhibitor of caspase cascade and apoptosome, Bcl-2 enhancer

1MeTIQ

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Resveratrol

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Curcumin

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Vitamin C

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Gingko biloba (EGb 761)

Table 1 The neuroprotective mechanism of action of natural compounds

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Fig. 1 The chemical structure of (R )- and (S)-enantiomer of 1MeTIQ Fig. 2 The chemical structure of resweratrol

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Fig. 3 The chemical structure of curcumin

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Fig. 4 The chemical structure of vitamin C (L-ascorbic acid)

Fig. 5 The chemical structures of compounds included In Gingko biloba extract (EGb 761)

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5A: Flavonoids: Kaempferol: R1 = H, R2 = OH; Quercetin: R1, R2 = OH; Isorhamnetin: R1 = OCH3, R2 = OH 5B: Bilobalide

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5C: Gingkolides: A: R1, R2, R3 = OH; B: R1 = OH, R2, R3 =H; C: R1, R2 = OH, R3 = H

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