Introduction

Over the past decades, a large number of polyphenolic compounds with neuroprotective effects have been described. One of the main sources of these molecules is green tea, the most widely consumed beverage next to water. The chemical composition of green tea contains a number of bioactive components, mainly including polyphenols, caffeine, and amino acids ( ). Green tea polyphenols, generally known as catechins which make up 30% of the dry weight of green tea leaves, are the main bioactive constituents of green tea with a wide variety of beneficial health effects ( ). The main catechins in green tea include (+)-catechin, (−)-epicatechin, (+)-gallocatechin, (−)-epigallocatechin, (+)-catechin gallate, (−)-epicatechin gallate, (+)-gallocatechin gallate, and (−)-epigallocatechin-3-gallate (EGCG) ( ). EGCG, chemically (2 R ,3 R )-5,7-dihydroxy-2-(3,4,5trihydroxyphenyl)chroman-3-yl 3,4,5-trihydroxybenzoate ( Fig. 1 ), is the most abundant composition of the tea catechins, account for 65% of the total catechin content and is thought to be responsible for the majority of biological activity of green tea extracts ( ). In terms of bioavailability, EGCG is predominantly absorbed in the intestine and presented more than 77% in a free form in plasma as well as its metabolites excreted in urine after oral administration ( ; ; ). The half-life of EGCG in a purified form is around 3 h ( ). Meanwhile, it is well documented that EGCG is able to cross the blood-brain barrier (BBB) and can reach to nervous tissue even at a very low concentration, the first requirement of a dietary compound to apply neuroprotective effects ( ; ). Several experimental studies have shown that EGCG can afford neuroprotection against brain ( ) and spinal cord ( ) injuries, neurodegenerative diseases ( ), and peripheral nerve injuries ( ). These beneficial effects have been mainly attributed to free radical scavenging or anti-oxidant, anti-inflammatory, and anti-apoptotic properties of EGCG ( ; ; ). In this regard, it is well known that green tea catechins due to the hydroxyl groups on the B- and D-rings of the galloylated catechins can bind to the free radicals and neutralized those ( ). On the other hand, scavenging effects of EGCG lead to attenuation of nuclear factor kappa B (NF-κB) activity ( ), which regulates genes involved in inflammatory processes such as tumor necrosis factor alpha (TNFα), cyclooxygenase-2 (COX-2), and interleukin-1 beta (IL-1β), beside modulation of nitric oxide synthase isoforms ( ). Also, catechins have proven to modulate apoptosis at various points in the sequence and messengers, and so regulate the mitochondrial membrane permeabilization ( ; ).

Chemical structure of epigallocatechin-3-gallate. Chemical structure of epigallocatechin-3-gallate with the molar mass of 458.372 g/mol obtained from Sigma-Aldrich website. The hydroxyl groups on the B- and D-rings can bind to the free radicals and neutralized those.

In this chapter, we have reviewed the neuroprotective effects of EGCG and its molecular mechanisms responsible for the neuroprotection following spinal cord injury (SCI). Meanwhile, we also compared the neuroprotective effects of EGCG in SCI to other neurological disorders.

In vivo studies

SCI is a complex multifactorial process caused first by ischemia or mechanical trauma and then by various mechanisms of secondary injury ( ). The neurological outcome of SCI depends on the extent of secondary cellular, molecular, and biochemical cascades such as oxygen free radical-induced lipid peroxidation, inflammatory reaction, and apoptosis ( ; ; ). In recent years, much attention has been paid to secondary injuries, as they appear to be prone to therapeutic interventions that may include the use of natural anti-oxidants, anti-inflammatory, and anti-apoptotic agents ( ) such as EGCG ( Table 1 ). In this regard, our previous studies have shown that intraperitoneal injection of EGCG (50 mg/kg, i.p., immediately and 1 h after SCI) can protect spinal cord tissue and improve behavioral function after traumatic and ischemia-reperfusion injury (IRI) in rats ( ; ; ). In regard to mechanisms of neuroprotective effects of EGCG, our results revealed that malodialdehyde (MDA) levels as an index of tissue lipid peroxidation, an important pathologic event in post-traumatic neuronal degeneration, were significantly decreased in traumatized spinal cord tissue after EGCG treatment ( ). It is well documented that EGCG due to hydroxyl groups can bind to the free radicals and neutralize those, while can indirectly increase the body’s endogenous antioxidants ( ). We detected immunohistochemically anti-apoptotic properties of EGCG with decreasing pro-apoptotic protein Bax and increasing anti-apoptotic protein Bcl-2 staining in EGCG-treated rats, which was correlated with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining method ( ). Also, our other study showed that EGCG treatment (50 mg/kg, i.p., immediately and 1 h after SCI) attenuated pro-inflammatory cytokines such as TNFα and IL-1β in traumatized spinal cord tissue ( ). In line with the anti-inflammatory properties of EGCG, documented that EGCG treatment (100 mg/kg, between 24 and 72 h after SCI) decreased spinal tissue edema through down-regulation of astrocyte expressing aquaporin-4 (AQP4), which plays a critical role in the transport of water from blood/CSF to spinal cord parenchyma, and through down-regulation of glial fibrillary acidic protein (GFAP) as a specific marker of astrocytes. Also, another study found that attenuated NF-κB pathway is a pivotal anti-inflammatory affect of EGCG (intra-spinal injection of 50 mg/kg EGCG immediately and then weekly for up to 28 days) after SCI ( ). Meanwhile, this study showed a significant increase in the gene expression of fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor (VEGF) after SCI. documented that EGCG (100 mg/kg, i.p., immediately after SCI) can protect secondary SCI by potential mechanism of regulating p38MAPK\NF -κB\AQP4 signaling pathway and thus reduce edema after SCI in rats. Also, another study documented that intrathecal administration of EGCG (10 or 20 mg/kg immediately after SCI) can significantly improve locomotors recovery, which may be related to the inhibition of Bcl-2-associated X protein (Bax) and to the up-regulation of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) ( ). Studies have shown that EGCG has beneficial effects not only on the tissue destruction but also on behavioral and functional outcome, so that intravenous infusion of EGCG (20 mg/kg/hour for continuous 36 h) in acutely (initiated within 4 h post-trauma 0 time) and chronically (initiated after 12 months of SCI onset) spinal cord injured rats improved significantly motor and sensory functions measured using Basso-Beattie-Bresnehan behavioral score test, Louisville forced swim test, and pain behavior assessment tests ( ). One of the common complications of SCI is neuropathic pain. About the effect of EGCG on neuropathic pain, documented that short time EGCG treatment (30 mg/kg i.p., 30 min after and daily during the first week post-SCI) reduced thermal hyperalgesia and gliosis via ras homologue gene family member A (RhoA) and fatty acid synthase (FASN) pathway. In this regard, it is mentioned that some biological properties of EGCG are attributed to its inhibitory action on FASN ( ). In another study, the synergistic effects of curcumin and EGCG in an animal model of acute SCI were investigated ( ). Results of this study revealed that combination of curcumin and EGCG reduced glial scar formation, increased axonal sprouting, and changed the amount of macrophage inflammatory protein 1-alpha (MIP-1α), IL-1β, interleukin-4 (IL-4), and interleukin-6 (IL-6). Recently, our laboratory assessed the neuroprotective effects of EGCG on spinal cord IRI in rats ( ). The level of MDA was significantly reduced in EGCG-treated rats. Attenuated caspase-3 ( Fig. 2 ), TNFα ( Fig. 3 ), and inducible nitric oxide synthase (iNOS) expression could be significantly detected in the EGCG-treated rats. Also, EGCG reduced the extent of degeneration of the spinal cord neurons, in addition to a significant reduction of motor deficit index (MDI). Overall, the behavioral, biochemical, and histopathological evidences demonstrated that pre- (50 mg/kg, i.p., before IRI) and post-ischemic (50 mg/kg, i.p., after IRI) treatment with EGCG had protective effects against spinal cord IRI in rats.

Immunohistochemical staining of casepase-3. Light photomicrographs show immunohistochemical expression of caspase-3 as an index of apoptosis in control and epigallocatechin-3-gallate treatment groups after spinal cord injury (magnification, × 200). The positive staining of caspase-3 is presented by a brown color of cytoplasm (arrows). This figure prepared in our laboratory.

Immunohistochemical staining of tumor necrosis factor alpha. Light photomicrographs show immunohistochemical expression of tumor necrosis factor alpha (TNFα) as an index of inflammation in control and epigallocatechin-3-gallate treatment groups after spinal cord injury (magnification, × 200). The positive staining of TNFα is presented by a brown color of cytoplasm (arrows). This figure prepared in our laboratory.

In vitro studies

A number of in vitro studies regarding EGCG’s neuroprotection and its underlying molecular mechanisms in neural cells are starting to accumulate which summarized in Table 2 .

In regard to anti-apoptotic effects of EGCG, some studies indicated that EGCG led to significant inhibition of apoptosis in PC12 cells by scavenging reactive oxygen species (ROS), modulating cytochrome c and caspases, activation of phosphoinositide 3-kinase (PI3K), activation of survival-promoting pathways, and inhibition of glycogen synthase kinase-3 (GSK-3) ( ; ; ; ; ; ; ; ). Also, studies showed that EGCG has a protective effect on cell death in SH-SY5Y (or SHSY-5Y) cell line through inhibiting ROS production and caspase activity along with activation of protein kinase C (PKC) ( ; ; ; ). EGCG protects N18D3 neural cells from quinolinic acid-induced apoptosis by regulation of phosphatidyl inositol 3-kinase (PI3K) and modulation of pro- and anti-apoptotic genes due to decreased intra-cellular calcium levels and nitric oxide (NO) production ( ). Results of a study showed that EGCG protects the neuronal cells against human prion protein-induced damage through inhibiting Bax and cytochrome c translocation and autophagic pathways in primary neuron cells ( ). Recently, it was documented that EGCG reduced amyloid beta-induced neurotoxicity via inhibiting endoplasmic reticulum stress-mediated apoptosis in SH-SY5Y cells in a dose-dependent manner which is contributed to the down-regulation of cleaved-caspase-3 and -12 ( ).

In regard to microglial activation, a study indicated that EGCG exerts significant protection against microglial activation-induced neuronal injury through the down-regulation of iNOS and TNFα expression ( ).

In regard to antioxidant properties of EGCG, in vitro study revealed that EGCG treatment decreased MDA level, up-regulated superoxide dismutase (SOD) and catalase (CAT) levels against advanced glycation end products (AGEs)-induced injury in neuronal cell culture ( ). Also, it was documented that EGCG decreased markedly ROS production via the SIRT1/PGC-1α signaling pathway in 1methyl4-phenyl-pyridine (MMP +)-induced PC12 cells damage ( ). Evaluation of EGCG’s effects on acrylamide-induced cytotoxicity in PC12 cells showed that EGCG inhibited the cytotoxicity of acrylamide and increased the cell viability ( ).

In regard to anti-inflammatory properties of EGCG, in vitro studies also revealed that EGCG treatment potently inhibited lipopolysaccharide (LPS)-activated microglial secretion of TNFα and significantly exerted anti-inflammatory effects partly as a suppressor of TNFα signaling via the NF-κB pathway in SH-SY5Y ( ) and RPE cells ( ).

It is well known that anti-oxidants can also affect the stem cells differentiation and potency. In this regard, using the PC12 cell model showed for the first time that low concentration of EGCG and unfractionated green tea polyphenols potentiate nerve growth factor (NGF)-induced and BDNF-induced neuritogenesis likely through induction sub-lethal levels of ROS or dependent on 67 kDa laminin receptor (67LR) and H ₂ O ₂ ( ; ).

Applications to other areas of neuroscience

It is well known that EGCG has neuroprotective effects in another neurological disorder such as brain injury, nerve injury, and neurodegenerative diseases ( Table 3 ).

Table 3

Neuroprotective effects of epigallocatechin-3-gallate against other neurological disorders.

Model of injury	Treatment schedule	Finding	Possible mechanism	Author	Year
Brain injury	50 mg/kg, intraperitoneal, immediately after ischemia	Deoxidizing peroxynitrate/peroxynitrite without affecting blood flow	Attenuation of NO − 3 /NO − 2	Nagai et al.	2002
Brain injury	25 mg and 50 mg/kg, intraperitoneal, immediately after ischemia	Attenuated malodialdehyde level and oxidized/total glutathione ratio	Antioxidant effects	Choi et al.	2004
Brain injury	50 mg/kg, intraperitoneal, immediately after ischemia	Reduced neuronal damage	Reduction of matrix metalloproinase-9 activity	Park et al.	2010
Brain injury	40 mg/kg, intraperitoneal, once daily for three consecutive days prior to surgery	Reduced neuronal damage	Activation of nuclear erythroid 2-related factor 2 /antioxidant response element signaling	Han et al.	2014
Brain injury	50 mg/kg, intraperitoneal, immediately after surgery and once daily till day 7	Promoted angiogenesis	Up-regulation of the nuclear erythroid 2-related factor 2 signaling pathway	Bai et al.	2017
Brain injury	50 mg/kg, intraperitoneal, immediately after ischemia	Modulated inflammatory responses	Amelioration of tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, nuclear factor kappa B /p65, cyclooxygenase-2, inducible nitric oxide synthase	Zhang et al.	2015
Brain injury	50 mg/kg, daily for 1 day and 1 h before ischemia	Reduced nitric oxide synthase and inducible nitric oxide synthase , increased endothelial nitric oxide synthase, preserved complex I–V	Complex signal transduction mechanisms	Sutherland et al.	2005
Brain injury	Consuming 0.1% ( w / v ) epigallocatechin-3-gallate drinking water ad libitum before and after traumatic injury	Increased neural stem cells number around the damaged area	Antioxidant and antiapoptotic activities	Itoh et al.	2011, 2013, 2012
Brain injury	100 mg/kg, intraperitoneal, after traumatic injury	Reduced interleukin-1 beta and tumor necrosis factor alpha mRNA expression, inhibited astrocyte expressing aquaporin-4 and glial fibrillary acidic protein, elevated superoxide dismutase and glutathione peroxidase activities, decreased nicotinamide adenine dinucleotide phosphate oxidase activation	Inhibition of inflammation and oxidative stress	Zhang et al.	2015
Nerve injury	25 mg/kg, injected daily for 5 days and 2 mg/kg orally daily afterwards	Increased density of retinal ganglion cells	Up-regulation of neurofilament triplet L protein expression	Ahadi et al.	Xie 2010
Nerve injury	25 mg/kg, intraperitoneal or orally, daily for 5 days and 2 mg/kg orally daily afterwards	Enhanced motor neuron survival time	Attenuation of nicotinamide adenine dinucleotide phosphate-diaphorase-d/neuronal nitric oxide synthase	Wei et al.	2011
Nerve injury	1 mg/kg, intrathecal, once daily from 1 day before to 3 days after chronic constriction injury	Decreased chronic neuropathic pain	Down-regulation of Toll-like receptor 4, nuclear factor kappa B, high-mobility group box 1 protein, tumor necrosis factor alpha and interleukin-1 beta protein expression	Kuang et al.	2012
Nerve injury	50 mg/kg, intraperitoneal, following rat sciatic nerve crush injury	Enhanced functional recovery and accelerated nerve regeneration	Down-regulation of apoptosis related genes, up-regulation of survivin gene, and up-regulation of glutathione reductase	Renno et al.	2017, 2015
Nerve injury	50 mg/kg, intraperitoneal, starting 1 h after sciatic nerve crush injury	Modulated brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor and neurotrophin-3 and their receptors tropomyosin receptor kinase B, tropomyosin receptor kinase C, and nerve growth factor receptor p75	Up-regulation of neurotrophic factors and their receptors	Renno et al.	2016
Nerve injury	50 mg/kg, intraperitoneal, 1 h after nerve transaction and followed for 3 days	Reduced neural apoptosis	Modulation of malodialdehyde levels, catalase and superoxide dismutase activities, and Caspase3 and cyclooxygenase-2 expression	Kian et al.	2019
Alzheimer’s disease	20 mg/kg, intraperitoneal, daily for 60 days	Effective prophylaxis for Alzheimer’s disease	Modulation of amyloid precursor protein cleavage and cerebral amyloidosis	Rezai-Zadeh et al.	2005
Neurodegenerative disease	2 or 6 mg/day for 4 weeks, intragastrically	Improved degenerative changes of the brain	Modulation of beta-amyloid and amyloid precursor protein	He et al.	2012
Neurodegenerative disease	2 mg/kg/day for 4 weeks, intragastrically	Ameliorated learning and memory deficits	Modulation of TrkA/p75 NTR signaling and apoptosis	Liu et al.	2014
Parkinson’s disease	No available	Alleviated dopaminergic neuronal injury in Parkinson’s disease	Inhibition of nitric oxide and tumor necrosis factor alpha	Li et al.	2004
Parkinson’s disease	25 mg/kg, oral administration for 7 days	Neurorescue effects in Parkinson’s disease	Regulation of the iron-export protein ferroportin and reduction of oxidative stress	Xu et al.	2017
Neurodegenerative disease	300 μg, oral gavage twice daily	Delayed disease onset, induced regeneration of hippocampal axons	Reduction of the inflammatory infiltrates	Herges et al.	2011

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

Traumatic spinal cord injury and outcomes in low-resource settings Osteoporosis-related fractures: What they are and how they occur following spinal cord injury Quality of life tools for spinal cord–injured people Bowel dysfunction in spinal cord injury Curcumin usage for inflammation and spinal cord injury Rehabilitation in spinal cord injury: Exercise and testing for cardiorespiratory endurance and musculoskeletal fitness

Stay updated, free articles. Join our Telegram channel

Join