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
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.