Abstract
Hypobaric hypoxia (HH) is a stressful condition, which is more common at high altitudes and can impair cognitive functions. Ginkgo biloba L. leaf extract (GBE) is widely used as herbal medicine against different disorders. Its ability to improve cognitive functions, reduce oxidative stress, and promote cell survival makes it a putative therapeutic candidate against HH. The present study has been designed to explore the effect of GBE on HH-induced neurodegeneration and memory impairment as well as possible signaling mechanisms involved. 220–250 gm (approximately 6- to 8-week-old) Sprague Dawley rats were randomly divided into different groups. GBE was orally administered to respective groups at a dose of 100 mg/kg/day throughout the HH exposure, i.e., 14 days. Memory testing was performed followed by hippocampus isolation for further processing of different molecular and morphological parameters related to cognition. The results indicated that GBE ameliorates HH-induced memory impairment and oxidative damage and reduces apoptosis. Moreover, GBE modulates the activity of the small conductance calcium-activated potassium channels, which further reduces glutamate excitotoxicity and apoptosis. The exploration of the downstream signaling pathway demonstrated that GBE administration prevents HH-induced small conductance calcium-activated potassium channel activation, and that initiates pro-survival machinery by activating extracellular signal–regulated kinase (ERK)/calmodulin-dependent protein kinase II (CaMKII) and the cAMP response element–binding protein (CREB) signaling pathway. In summary, the current study demonstrates the beneficial effect of GBE on conditions like HH and provides various therapeutic targets involved in the mechanism of action of GBE-mediated neuroprotection.
Highlights
Hypobaric hypoxia (HH) at high altitude (HA) has been known to reduce the availability of oxygen to tissue by reducing its partial pressure
We have studied the expression of calmodulin-dependent protein kinase II (CaMKII), and it was found that Ginkgo biloba L. leaf extract (GBE) treatment reduces the activity of CaMKII, which indicates that calcium homeostasis is maintained, promoting neuroprotection (Figure 8D)
Since extracellular signal–regulated kinase (ERK) further activates its downstream transcription factor, i.e., cAMP response element–binding protein (CREB), which plays an important role in cell survival, we studied the phosphorylation of CREB after GBE treatment and speculated that administering GBE during HH exposure can restore the phosphorylation level of CREB that was only reduced during HH, so that the basal level of CREB in different groups remains the same (Figures 8E, 9)
Summary
Hypobaric hypoxia (HH) at high altitude (HA) has been known to reduce the availability of oxygen to tissue by reducing its partial pressure. HH causes electrophysiological changes and memory disability in the central nervous system It is associated with deleterious effects on cognitive functions, neurodegeneration, and state of anxiety and depression (Hale et al, 1996; Basnyat B and Murdoch DR., 2003; Jain et al, 2012, 2013; Kushwah et al, 2016). Neuropsychological functions such as learning and memory, focusing, and processing thoughts are provocatively influenced, which may be, at least partly, because of the episode of neuronal loss in different brain regions. Brain hypoxia along with different medical conditions results in apoptosis via caspase-3 activation in the hippocampus and other brain regions (Maiti et al, 2008; Kushwah et al, 2018)
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