Abstract
BackgroundCalcium overload has been implicated as a critical event in glutamate excitotoxicity associated neurodegeneration. Recently, zinc accumulation and its neurotoxic role similar to calcium has been proposed. Earlier, we reported that free chelatable zinc released during hypobaric hypoxia mediates neuronal damage and memory impairment. The molecular mechanism behind hypobaric hypoxia mediated neuronal damage is obscure. The role of free zinc in such neuropathological condition has not been elucidated. In the present study, we investigated the underlying role of free chelatable zinc in hypobaric hypoxia-induced neuronal inflammation and apoptosis resulting in hippocampal damage.MethodsAdult male Balb/c mice were exposed to hypobaric hypoxia and treated with saline or Ca2EDTA (1.25 mM/kg i.p) daily for four days. The effects of Ca2EDTA on apoptosis (caspases activity and DNA fragmentation), pro-inflammatory markers (iNOS, TNF-α and COX-2), NADPH oxidase activity, poly(ADP ribose) polymerase (PARP) activity and expressions of Bax, Bcl-2, HIF-1α, metallothionein-3, ZnT-1 and ZIP-6 were examined in the hippocampal region of brain.ResultsHypobaric hypoxia resulted in increased expression of metallothionein-3 and zinc transporters (ZnT-1 and ZIP-6). Hypobaric hypoxia elicited an oxidative stress and inflammatory response characterized by elevated NADPH oxidase activity and up-regulation of iNOS, COX-2 and TNF-α. Furthermore, hypobaric hypoxia induced HIF-1α protein expression, PARP activation and apoptosis in the hippocampus. Administration of Ca2EDTA significantly attenuated the hypobaric hypoxia induced oxidative stress, inflammation and apoptosis in the hippocampus.ConclusionWe propose that hypobaric hypoxia/reperfusion instigates free chelatable zinc imbalance in brain associated with neuroinflammation and neuronal apoptosis. Therefore, zinc chelating strategies which block zinc mediated neuronal damage linked with cerebral hypoxia and other neurodegenerative conditions can be designed in future.
Highlights
Hypobaric hypoxia experienced at high altitude has deleterious effects on the Central Nervous System (CNS) mediated through glutamate excitotoxicity, cholinergic dysfunction, oxidative stress and neurodegeneration, [1], [2], [3]
We observed that hypobaric hypoxia significantly (P,0.01) up-regulated hippocampal mRNA expression of ZIP-6 as compared to normoxia and normoxia treated groups (one-way analysis of variance (ANOVA): F(3,17) = 80.07)
We observed that hypobaric hypoxia upregulated the expression of ZIP-6 and zinc transporter-1 (ZnT-1), which act by transporting zinc from extracellular space to cytoplasm and vice-versa, respectively
Summary
Hypobaric hypoxia experienced at high altitude has deleterious effects on the Central Nervous System (CNS) mediated through glutamate excitotoxicity, cholinergic dysfunction, oxidative stress and neurodegeneration, [1], [2], [3]. Glutamate mediated calcium excitoxicity and subsequent neurodegeneration is associated with memory dysfunction on exposure to hypobaric hypoxia [2], [15]. Present study was designed to investigate the effect of Ca2EDTA, a specific zinc chelator, on the mechanism underlying hypobaric hypoxia induced neuronal inflammation and apoptosis in Balb/c mice. We reported that free chelatable zinc released during hypobaric hypoxia mediates neuronal damage and memory impairment. We investigated the underlying role of free chelatable zinc in hypobaric hypoxia-induced neuronal inflammation and apoptosis resulting in hippocampal damage
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