Differential neuroprotection from human heat shock protein 70 overexpression in in vitro and in vivo models of ischemia and ischemia-like conditions

We previously showed that overexpressing the 70-kDa inducible heat shock pr otein in primary astrocyte cultures and in a rodent stroke model using vira l vectors resulted in protection from ischemia and ischemia-like injury. Ho wever, viral transfection could potentially provoke a stress response itsel f; therefore, we examined whether transgenic mice constitutively expressing human heat shock protein 70 were protected from ischemic insults. Astrocyt e cultures from brains of heat shock protein 70 transgenic mice were resist ant to hydrogen peroxide injury in a dose-dependent fashion, but were less resistant to hypoglycemia and oxygen-glucose deprivation. Because hydrogen peroxide exposure and glucose deprivation are partially dependent on glutat hione levels, we determined whether heat shock protein 70 transgenic cultur es had altered glutathione levels under normal growth conditions, However, there was no significant difference in glutathione levels between heat shoc k protein 70 transgenic and wildtype astrocytes. Hippocampal, but not corti cal neuron cultures from these same transgenic mice were also protected aga inst oxygen-glucose deprivation and glutamate toxicity. In an in vivo model of permanent focal cerebral ischemia, there was no significant difference in infarct size assessed 24 h post-insult, These results suggest that heat shock protein 70 protects against some but not all kinds of central nervous system injury. The protective effects may be related to the nature and sev erity of the insults, as well as subpopulations of brain cells and dose-dep endent effects of HSP70 overexpression. (C) 2001 Academic Press.