Extract of Ginkgo biloba leaf (GBE) has been generally used as a nutritional supplement for preventing memory loss and age-related dementias (Mutsunobu YOSHIOKA et al.,2006) it has been employed in dealing with cognitive deficits associated with normal and pathological brain conditions such as dementia, Alzheimer’s disease (Rosemarie Martin et al.,2011). GBE has also been reported to employed anti-inflammatory and neuroprotective effects (Liang T et al. 2018). The leaves of ginkgo biloba have long been used as medicinal point. GBE can decrease the neuronal loss and improves memory performance in different stress conditions. As stated above chronic hypoxia leads to memory impairment and neurodegeneration. Ginkgo biloba is known to improve cognitive functions. There is a protective effect of Ginkgo biloba on oxidative stress as well as memory impairments induced by transient cerebral ischemia (Vaghef L et al., 2017). Similarly our results has showed that GBE significantly decreases path length and latency to reach the platform in the memory testing of Morris water maze and increases the number of entries and platform crossing in the probe trial.
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A couple of studies have shown that standardized GBE has significant influences on memory and cognitive dysfunctions associated with ageing and senility (Kamilla Blecharz-Klin et al., 2009) Exposure to simulated HA affects CNS and results in several pathological changes including cerebral palsy, mental retardation, learning disability and memory impairment and neurodegeneration. A variety of studies have established the efficacy of ginkgo biloba in improving the cognitive impairment of patients with Alzheimer’s disease (Zhou X et al., 2016). Ginkgo biloba has been reported to have role in behavioral and mental symptoms of dementia. (Egemen Savaskan et al., 2018) Ginkgo biloba has an antioxidative properties and are neuroprotective in a variety of conditions such as ischemia (Chandrasekaran et al., 2001), hypoxia induced oxidative stress (Oyama et al., 1996) and toxicity induced by β-amyloid- (Bastianetto et al., 2000)., Effects of Ginkgo extracts have been tested Clinically also in a series of neurological disorders, like Alzheimer’s disease, Parkinson’s in which Ginkgo biloba may diminish aggregated α-Syn-induced cell apoptosis (Hua J et al., 2017) and dementia (Dongen et al., 2003, M.-S. Kim et al., 2004). Ginkgetin (a natural biflavonoid isolated from leaves of Ginkgo biloba L) considerably repressed cell apoptosis induced through the caspase-3 and Bcl2/Bax pathway (Wang YQ et al., 2015) and prevents neuronal damage in ischemia induced stress (Zhou X et al, 2017).
In our case GBE significantly ameliorated the HH induced neuronal damage as evident from decreased number of fluorojade B positive neurons and caspase-3 positive neurons which were otherwise increased in 14 days of HH exposure. HH exposure also damages the neuronal morphology of the neurons in the cresyl violet staining however GBE recovers the neuronal morphology. A variety of studies have established the efficacy of ginkgo biloba in improving the cognitive impairment of patients with Alzheimer’s disease. A large number of stressors like hypoxia, ischemia, and aging can leads to oxidative stress including ROS production, lipid peroxidation, protein oxidation, and DNA damage. Oxidative stress may leads to the pathogenesis of neurodegenerative disorders as arteriosclerosis, (Xiaomei Zhou et al, 2017., Belviranlı M et al., 2015) amyotrophic lateral sclerosis, Parkinson’s disease and Alzheimer’s disease. GBE is among the most widely used traditional herbal medicines, and has been used to treat various diseases including atherosclerosis, diabetes, poor circulation, fatigue, vertigo, tinnitus, and cognitive disorder ( Zhou X et al., 2016) anxiety and depression.
Hypoxia could cause increased cellular oxidative damage with consequent damage to lipids, proteins, and DNA that further induced decrease inmemory (Maiti et al., 2006, K. Jayalakshmi,et al., 2007, Hota el al, 2008). Antioxidant activity of ginkgo biloba has been attributed to its neuroprotective effects of on brain disorders and it is considered to be natural antioxidant. GBE significantly recovers rat brain from oxidative damage and protects against stress induced oxidative stress in variuos regions of rat brain. (Wang A et al., 2018, Yallapragada PR and Velaga MK., 2015). There is a decrease in ROS production, lipid peroxidation and LDH release which were found to be increased in HH. Additionally due to its antioxidant property level of reduced glutathione (GSH) increases and oxidized form GSSG decrease significantly. Total antioxidant capacity of GBE treated samples was also increased significantly as compared to HH group. Ginsenosides (GS) are a group of natural product steroid glycosides and triterpene saponins isolated from various parts of the plant specifically by roots. Study has been shown to inhibit Ca2+ channels in ventricular myocytes of Wistar rats.( Zhang WJ et al., 1994)
Hyperpolarization leads to rise and/or stabilization of Ca2+ entry in the cell membrane.( Himmel HM et al., 1993, Luckhoff A, Busse R.., 1990) K+ channels play a essential role in the physiological response of vascular endothelial cells to a huge range of physical and hormonal stimuli.( Colden-Stanfield M, et al., 1990, Sauve R et al., 1990) Indeed, K+ channels are found to be important feedback regulators of the Ca2+ influx process. Hyperpolarization is caused by K+ efflux by the activation of K+ channels. Though, the deficiencies of voltage-sensitive L-type Ca2+ channels in endothelial cells boost up the dynamic force for Ca2+ influx. Secretion of nitric oxide (NO) increases via non-selective cationic channels when Ca2+ enters into the endothelial cells (Waldron GJ et al., 1996, Geary GG, et al., 1998, Quignard JF et al., 1999). Study indicates that GBE and GS increase NOS activity by means of SK channels in cultured porcine endothelial cells. GBE increased SK channel activity in endothelial cells (zy li et al., 2001, Seiichiro Nishida et al., 2009).
However, activity of the BK channels also modulated by GBE (Jung Jun Kim et al., 2011) As it is clear that GBE modulate SK channels activity hence in our case GBE inhibit the SK channels activity significantly at dose of 100 mg/kg/body wt. this inhibition of SK channels by GBE provides neuroprotection in HH induced apoptosis and glutamate excitotoxicity. The intracellular calcium concentration is prominent in neurons that are susceptible to cell death induced by glutamate-excitotoxicity in neurological disorders. Study examined the molecular mechanisms of ginkgo biloba treatment in falling cell death caused by excitotoxicity. Glutamate-induced apoptosis inhibited by the EGb 761 in the SH-SY5Y cells through the inhibition of excessive calcium influx and consequent inhibition of excitotoxicity and cell death confirmed by the decreased expression of caspase 3 (Huang DS et al., 2016). Pretreatment with EGb761 strongly reduces neurodegeneration under conditions of ischemia. The mechanism of action appears to be associated with reduction of excitotoxicity, because ischemia-induced release of glutamate was strongly suppressed by the ginkgo. Ginkgo extracts such as EGb761 may be significant to avert ischemia-induced cell damage in stroke-prone patients as well (Alexander Mdzinarishvili et al., 2012).
Although few of neurodegenerative diseases are due to cell death induced by glutamate excitotoxicity and oxidative stress, ginkgo biloba may be very important for preventing and/or treating such diseases (Aimi KANADA et al., 2005). Correspondingly in our study GBE prevents HH induced glutamate excitotoxicity significantly that further reduced by SK channels inhibition. EGb 761 may provide protection against Intermittent hypoxia-induced memory impairment, neuronal DNA damage and oxidative stress, most likely via multiple mechanisms that involves its potential antioxidant effect (Basel A. Abdel-Wahaba,∗, Samy M. Abd El-Azizb et al., 2012,). In our study we have shown two groups GBE pretreatment with SK channels activator and inhibitor. The activator of SK channels groupalong with GBE not showing significant results however SK channels inhibition reduced glutamate excitotoxicity significantly. Further apoptosis was also checked which shown reduction in the caspase-3 expression in GBE treated group that further reduced its expression in SK2 inhibited group. GBE provides neuroprotection in opposition to ischemia-induced neuronal cell death in vivo and glutamate-induced excitotoxicity in vitro by collaborative mechanisms involving anti-excitotoxicity or antioxidant properties, inhibition of free radical generation, and regulation of mitochondrial gene expression that further leads to reduced apoptosis (Chandrasekaran K et al., 2003). Ginkgo biloba may modulate the synaptic plasticity and survival by activating cAMP response element-binding protein (CREB). Components of GBE had differential influences on phosphorylated CREB that further activates upstream kinase pathways. Continued pCREB expression was observed in 24 h and beyond the treatment of ginkgo biloba. These clarifications may be relevant to the finding that CaM kinase mediates rapid, activity-dependent CREB phosphorylation, and that mitogen-activated protein kinases (MAP) ⁄ extracellular signal-regulated kinases (ERK) ⁄ ribosomal S6 kinase (RSK) exclusively promotes a slow phase of Constant CREB phosphorylation (Wu et al., 2001). GBE increases the levels of pCREB and brain-derived neurotrophic factor (BDNF) (Yanan Xu et al., 2007) Data showed that pCREB induced by GBE might be dependent on ERK signaling. A schematic diagram has been shown which results increase in P-CREB, P-ERK and elevated BDNF expression in ginkgo biloba treated groups when compared with HH group. However expression of P-CaMKII decreased after GBE treatment which higher during HH exposure due to calcium overload which causes excitotoxicity. GBE augmented the level of growth factors like BDNF. Hence GBE provides neuroprotection via SK2 inhibition followed by ERK- CaMKII-CREB signaling.