title: Effect of Ca2EDTA on zinc mediated inflammation and neuronal apoptosis in hippocampus of an in vivo mouse model of hypobaric hypoxia.
abstract: BACKGROUND
  Calcium 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.
  
  
  METHODS
  Adult 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.
  
  
  RESULTS
  Hypobaric 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.
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: Dr.B.R.Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India.
authors.forename: Udayabanu
authors.initials: U
authors.lastname: Malairaman
authors.affiliation: Dr.B.R.Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India.
authors.forename: Kumaran
authors.initials: K
authors.lastname: Dandapani
authors.affiliation: Dr.B.R.Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India.
authors.forename: Anju
authors.initials: A
authors.lastname: Katyal
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002614:Chelating Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004492:Edetic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000473:pathology*; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D000860:Hypoxia / Q000235:genetics / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008807:Mice, Inbred BALB C; D019255:NADPH Oxidases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015032:Zinc / Q000009:adverse effects*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D002614:Chelating Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D009573:Nitrites; D051028:bcl-2-Associated X Protein; D009569:Nitric Oxide; D004492:Edetic Acid; D019255:NADPH Oxidases; D011065:Poly(ADP-ribose) Polymerases; D015032:Zinc