ADRENALECTOMY ATTENUATES KAINIC ACID-INDUCED SPECTRIN PROTEOLYSIS ANDHEAT-SHOCK PROTEIN-70 INDUCTION IN HIPPOCAMPUS AND CORTEX

Citation
Mt. Lowy et al., ADRENALECTOMY ATTENUATES KAINIC ACID-INDUCED SPECTRIN PROTEOLYSIS ANDHEAT-SHOCK PROTEIN-70 INDUCTION IN HIPPOCAMPUS AND CORTEX, Journal of neurochemistry, 63(3), 1994, pp. 886-894
Citations number
57
Categorie Soggetti
Biology,Neurosciences
Journal title
ISSN journal
00223042
Volume
63
Issue
3
Year of publication
1994
Pages
886 - 894
Database
ISI
SICI code
0022-3042(1994)63:3<886:AAKASP>2.0.ZU;2-Q
Abstract
Glucocorticoids have been shown to exacerbate the damaging effects of a variety of neurotoxic insults in the hippocampus and other brain are as. Evidence suggests that the endangering effects of glucocorticoids may be due to augmenting the cascade of events, such as elevations in intracellular calcium levels, because of excitatory amino acid (EAA) r eceptor stimulation. A potential mechanism responsible for EAA-induced neuronal damage is activation of calcium-sensitive proteases, such as calpain, which then proteolytically degrade cytoskeleton structural p roteins, such as spectrin. The present study was designed to determine if glucocorticoids can regulate the spectrin proteolysis produced by the EAA agonist, kainic acid. Rats were adrenalectomized (ADX) or sham operated and 7 days later injected with kainic acid (10 mg/kg). Twent y-four hours later rats were killed and tissues obtained for western b lot analyses of the intact spectrin molecule and the proteolytically d erived breakdown products. Kainic acid produced an approximate sevenfo ld increase in the 145-155-kDa spectrin breakdown products in the hipp ocampus relative to ADX or sham rats injected with vehicle. ADX attenu ated the kainic acid-induced increase in breakdown products by 43%. In a similar way, kainic acid produced a large 10-fold increase in spect rin breakdown products in the frontal cortex, which was also significa ntly attenuated (-80%) by ADX. Induction of heat shock protein 70 (hsp 70) by neurotoxic insults has been suggested to be a sensitive indicat or of cellular stress in neurons. Kainic acid induced large amounts of hsp70 in both hippocampus and frontal cortex of sham-operated rats th at was markedly attenuated (85-95%) by ADX. There was a strong positiv e correlation between the amount of spectrin proteolysis and the degre e of hsp70 induction in both the hippocampus and frontal cortex. In co ntrast, kainic acid did not significantly produce spectrin proteolysis and induced only a very modest and inconsistent increase of hsp70 in the hypothalamus. This is consistent with the observation that the hyp othalamus is relatively insensitive to the neurotoxic effects of syste mically administered kainic acid. The dose of kainic acid (10 mg/kg) u sed in this experiment produces a 10-fold elevation in circulating cor ticosterone levels at both 1 and 3 h after administration. These resul ts suggest that part of the endangering effects of glucocorticoids on hippocampal and cortical neurons may be due to augmentation of calpain -induced spectrin proteolysis. The attenuation of kainic acid-induced synthesis of hsp70 by ADX indicates that the cellular stress produced by EAAs is regulated in part by glucocorticoids. In addition, the elev ation in endogenous corticosterone levels produced by kainic acid appe ars to be a significant factor contributing to the neuronal damage pro duced by this agent.