Caspase activation contributes to delayed death of heat-stressed striatal neurons.
Hyperthermia can contribute to brain damage both during development and post-natally. We used rat embryonic striatal neurons in culture to study mechanisms underlying hyperthermia-induced neuronal death. Heat stress at 43 degrees C for 2 h produced no obvious signs of damage during the first 12 h after the stress, but more than 50% of the neurons died during the next 3 days. More than 40% of the neurons had activated caspases 24 h following the heat stress. Caspase-3 activity increased with a delay of more than 10 h following cessation of the heat stress, reaching a peak at approximately 18 h. Neuronal death measured 1-3 days after the stress was reduced by the general caspase inhibitors qVD-OPH (10-20 microm) and zVAD-fmk (50-100 microm). These inhibitors were protective even when added 9 h after cessation of the heat stress, consistent with the delayed activation of caspases. In contrast, blockers of Na+ channels and ionotropic glutamate receptors did not reduce the heat-induced death, indicating that glutamate excitotoxicity was not required for this neuronal death. These results show that the neuronal death produced by heat stress has characteristics of apoptosis, and that caspase inhibitors can delay this death.
White
Michael G
MG
Department of Physiology and Biophysics, University of Miami School of Medicine, Miami, Florida 33101, USA.
Emery
Michael
M
Nonner
Doris
D
Barrett
John N
JN
D000818:Animals; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018882:Heat Stress Disorders / Q000201:enzymology*; D006358:Hot Temperature / Q000009:adverse effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013997:Time Factors
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D026941:Sodium Channel Blockers; D020169:Caspases