Hsp70 Involvement in Hyperthermic Preconditioning of Excitotoxic Neuronal Damage in the Hippocampus

Background: Hsp70 is an essential stress protein affording significant protection against adverse effects of hyperthermia and other insults. We used excitotoxic damage model in the hippocampus to elucidate if whole body hyperthermia (WBH) would precondition the excitotoxic neuronal damage.

Methods and findings: Rats were subjected to preconditioning heat stress (HS) (HS: 41.5°C × 30 min) and after 4 h, 24 h or 72 h they were intracerebroventricularly (icv) injected with different kainite (KA) doses (KA: 0.05, 0.15 or 0.6 μg). Then, the rats were sacrificed after 4 hours. Hippocampal tissue sections were immune-stained and evaluated quantitatively by image analysis and nonparametric statistics. KA-induced damage was dose dependent and extended through CA3 to CA4 and the hilus of the hippocampus with the highest KA dose (0.6 and 0.15 μg). The HS preconditioning decreased the hippocampal CA3a damage and c-Fos expression attenuation only after the lowest (0.05 μg) KA dosage by about 60% in 4 h and 72 h intervals investigated. Blocking of Hsp70 expression by quercetin injection pre- and post- HS significantly abolished the HS-induced protection at 4 h, but not at 72 h after HS. Furthermore, we injected the heat-stress preconditioned animals with 50 μg PES/ pifithrin μ icv, a new low molecular inhibitor of Hsp70 but this treatment did not attenuate heat induced tolerance to kainate. Then, injecting PES/pifithrin to rats treated only with kainate revealed that PES/pifithrin alone protected CA3a neurons against KA-induced excitotoxic damage.

Conclusions: These results suggest that Hsp70 might be responsible for the observed early protection against excitotoxicity.


Muna Alrumh, Waleed M Renno and Alfred Pavlik

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