Abstract
Janus activated kinase/signal transducers and activators of transcription (JAK/STATs) pathway are associated with various neuronal functions including cell survival and inflammation. In the present study, it is hypothesized that protective action of aqueous extract of Hippophae rhamnoides in hippocampal neurons against hypoxia is mediated via JAK/STATs. Neuronal cells exposed to hypoxia (0.5% O2) display higher reactive oxygen species with compromised antioxidant status compared to unexposed control cells. Further, these cells had elevated levels of pro-inflammatory cytokines; tumor necrosis factor α and interleukin 6 and nuclear factor κappa B. Moreover, the expression of JAK1 was found to be highly expressed with phosphorylation of STAT3 and STAT5. Cells treated with JAK1, STAT3 and STAT5 specific inhibitors resulted in more cell death compared to hypoxic cells. Treatment of cells with extract prevented oxidative stress and inflammatory response associated with hypoxia. The extract treated cells had more cell survival than hypoxic cells with induction of JAK1 and STAT5b. Cells treated with extract having suppressed JAK1 or STAT3 or STAT5 expression showed reduced cell viability than the cell treated with extract alone. Overall, the findings from these studies indicate that the aqueous extract of Hippophae rhamnoides treatment inhibited hypoxia induced oxidative stress by altering cellular JAK1, STAT3 and STAT5 levels thereby enhancing cellular survival response to hypoxia and provide a basis for possible use of aqueous extract of Hippophae rhamnoides in facilitating tolerance to hypoxia.
Highlights
High altitude illnesses is a term that indicates various symptoms of acute mountain sickness comprising headache, nausea, pulmonary edema and cerebral edema occurring during rapid ascent to high altitude by an un-acclimatized sojourn [1,2]
Treatment of cells with extract prevented activation of caspase 3 and lactate dehydrogenase leakage induced by the hypoxia and the effects were dose dependent
The findings suggest that extract augment JAK1 expression probably by decreasing STAT3 under hypoxia
Summary
High altitude illnesses is a term that indicates various symptoms of acute mountain sickness comprising headache, nausea, pulmonary edema and cerebral edema occurring during rapid ascent to high altitude by an un-acclimatized sojourn [1,2]. Impairment of cognitive functions, memory loss, anxiety and depression are some of the nervous system related ill effects of hypoxia [3]. Acclimatization to high altitude environment helps alleviate related disorders and finding an agent of herbal origin that promotes acclimatization at a faster rate will be promising to tackle the problems during rapid ascent to high altitude. Hippocampus neurons are the first ones to lose their electrical activity during hypoxia [6]. Cellular responses including proliferation and survival to many external signaling molecules are executed via Janus kinase-signal transducers and activators of transcription (JAK/STAT) signalling pathway [7]. Signal transducers and activators of transcription (STATs) include seven structurally and functionally related proteins namely, STAT1, 2, 3, 4, 5a, 5b and 6. Cytokine binding with its corresponding receptor initiates the signalling cascade of JAK/STAT pathway [8]
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