Adrenalectomy Attenuates Kainic Acid‐Induced Spectrin Proteolysis and Heat Shock Protein 70 Induction in Hippocampus and Cortex

Abstract

Glucocorticoids have been shown to exacerbate the damaging effects of a variety of neurotoxic insults in the hippocampus and other brain areas. 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) receptor 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 proteins, 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). Twenty‐four hours later rats were killed and tissues obtained for western blot analyses of the intact spectrin molecule and the proteolytically derived breakdown products. Kainic acid produced an approximate sevenfold increase in the 145–155‐kDa spectrin breakdown products in the hippocampus relative to ADX or sham rats injected with vehicle. ADX attenuated the kainic acid‐induced increase in breakdown products by 43%. In a similar way, kainic acid produced a large 10‐fold increase in spectrin breakdown products in the frontal cortex, which was also significantly attenuated (−80%) by ADX. Induction of heat shock protein 70 (hsp70) by neurotoxic insults has been suggested to be a sensitive indicator of cellular stress in neurons. Kainic acid induced large amounts of hsp70 in both hippocampus and frontal cortex of sham‐operated rats that was markedly attenuated (85–95%) by ADX. There was a strong positive correlation between the amount of spectrin proteolysis and the degree of hsp70 induction in both the hippocampus and frontal cortex. In contrast, 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 hypothalamus is relatively insensitive to the neurotoxic effects of systemically administered kainic acid. The dose of kainic acid (10 mg/kg) used in this experiment produces a 10‐fold elevation in circulating corticosterone levels at both 1 and 3 h after administration. These results 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 elevation in endogenous corticosterone levels produced by kainic acid appears to be a significant factor contributing to the neuronal damage produced by this agent.

The anterior attention network: Associations with temperament and neuroendocrine activity in 6‐year‐old children

“…It has been demonstrated that lesioning the ACC disrupts regulation of the HPA system's response to psychological stress in rats (Diorio, Viau, & Meaney, 1993). Evidence suggests that these relations are reciprocal in nature as GCs also affect the functioning of the prefrontal cortex, including the ACC (e.g., Karreman, Moghaddam, 1996;Lowy, 1994). Research involving experimental administration of exogenous GCs to adult human and nonhuman primates indicates that highly elevated levels of GCs interfere with frontal processes, such as inhibitory control, attention regulation, and planning (Kopell, Wittner, Lunde, Warrick, & Edwards, 1970;Lupien, Gillin, & Hauger, 1999;Lyons, Lopez, Yang, & Schatzberg, 2000;Young, Sahakian, Robbins, & Cowen, 1999).…”

Metyrapone, an inhibitor of corticosterone synthesis, blocks the kainic acid-induced expression of HSP 70

“…Although most of this evidence comes from studies conducted on adrenalectomized rats, it suggests that substances or procedures capable of decreasing the level of circulating corticosterone or preventing its excessive release during insults described above may have potential neuroprotective properties. It should be stressed here clearly that insults such as cerebral ischemia or kainic acid seizures induce marked secretion of glucocorticoids (Lowy et al, 1994).…”

“…Brain areas engaged in the kainic acid injury show significant changes in cytoskeletal proteins (Elliott et al, 1993;Lowy et al, 1994;Wang et al, 1993) and are marked, among others, by the robust appearance of HSP 70 (Armstrong et al, 1996;Planas et al, 1994;Sanz et al, 1997;Schreiber et al, 1993;Zhang et al, 1996). Considering such a profile of effects, kainic acid is widely used as a convenient tool in experiments studying the pharmacology of epilepsy as well as mechanisms of neurodegeneration associated with this type of seizure (Ben-Ari, 1985).…”

“…Available experimental data show that glucocorticoids, liberated under various stressful conditions, may damage brain structures, particularly those containing relatively high levels of receptors for corticosterone, e.g., hippocampus and selected cortical areas such as the frontal cortex (Lowy et al, 1994;Sapolsky, 1985;Stein-Behrens et al, 1994a, b;Wolley et al, 1990). It has been suggested that glucocorticoids account for loss of hippocampal neurons during aging (Lowy et al, 1995;Meaney et al, 1988;Talmi et al, 1993).…”

“…Moreover, it has been shown that in circumstances when the exposure of tissue to glucocorticoids is not sufficient per se to induce degeneration, they may exacerbate neuronal loss induced by such insults as hypoxia-ischemia, seizures/epilepsy (induced by kainic acid), hyperglycemia, and antimetabolite stress (Elliott et al, 1993;Elliott and Sapolsky, 1992;Sanz et al, 1997;Sapolsky, 1985;Stein and Sapolsky, 1988;Stein-Behrens et al, 1992;Talmi et al, 1995). In general, it has been demonstrated that the excess of glucocorticoids at the time of neuronal insult increases the amount of damage; conversely, the removal of corticosterone attenuates the neurotoxicity (Elliott et al, 1993;Elliott and Sapolsky, 1992;Lowy et al, 1994;Smith-Swintosky et al, 1996;Stein and Sapolsky, 1988). Although most of this evidence comes from studies conducted on adrenalectomized rats, it suggests that substances or procedures capable of decreasing the level of circulating corticosterone or preventing its excessive release during insults described above may have potential neuroprotective properties.…”