A mechanism for glucocorticoid toxicity in the hippocampus: increased neuronal vulnerability to metabolic insults

Abstract

Glucocorticoids appear capable of damaging or destroying hippocampal neurons. There is a progressive loss of such neurons with age, and the process can be prevented by adrenalectomy at mid-age or accelerated by prolonged exposure to high circulating titers of glucocorticoids. The present study examines possible mechanisms for this steroid action. Rats were either adrenalectomized, intact, or treated with corticosterone (CORT) sufficient to produce prolonged elevations of titers in the high physiological range. After 1 week, unilateral hippocampal microinfusions were made with either kainic acid (KA) or 3-acetylpyridine (3-AP). Doses of these hippocampal neurotoxins were chosen to produce small-sized lesions. Treatment with CORT exacerbated the extent of damage following neurotoxin infusion, whereas adrenalectomy attenuated the damage. Additional studies eliminated some potential mechanisms for this phenomenon. CORT did not directly alter the intrinsic toxicity of the compounds but, rather, altered the sensitivity of target cells to them. As evidence, no potentiation of damage in CORT-treated animals occurred in KA-sensitive brain regions lacking CORT receptors. Since CORT did not increase the diffusion or binding of [3H]KA in the hippocampus, it appears unlikely that CORT potentiated toxin-induced damage by influencing the specific mechanism of action of any toxin. Finally, the general nature of the CORT potentiation of damage was supported by the markedly different postulated mechanisms of toxicity of KA and 3-AP. We hypothesize that CORT exerts its extensive catabolic effects upon target cells to produce generalized metabolic vulnerability in hippocampal neurons possessing high concentrations of CORT receptors, thereby sensitizing them to varied metabolic insults.

Mineralocorticoid and glucocorticoid receptors in the brain. Implications for ion permeability and transmitter systems

“…MORPHOLOGY There are indications that prolonged elevation of plasma corticosterone, in contrast to the limited exposure discussed above, even without additional major challenges to the brain, result over time in neuronal cell damage. Chronic treatment of rats with high cortieosterone levels resulted after 3 weeks in atrophy of the dendritic tree of CA3 hippocampal neurons and after a 3 month period even in the actual loss of neurons in this area (Sapolsky et al, 1985). The neuronal loss was reminiscent of the cell loss observed in aged animals.…”

“…calpains, endonucleases, phospholypase C, oxygen radical formation and severe acidosis eventually leads to delayed neuronal death (Siesjo and Bengtsson, 1989;Choi, 1988Choi, , 1990Meyer, 1989;Erecinska and Silver, 1989). Glucocorticoid hormones do not seem to reduce cellular metabolism to an extent that they are damaging by themselves, but they can clearly exacerbate the vulnerability to excitotoxins (Sapolsky, 1985), hypoxia/ischemia (Sapolsky and Pulsinelli, 1985;Koide et al, 1986) and hypoglycemia (Sapolsky, 1985) in hippocampal tissue. They do so regardless of their peripheral catabolic actions, since the aggrevation of induced lesions was also observed in isolated brain preparations Tombaugh et al, 1992).…”

Interleukin-1β Biosynthesis Inhibition Reduces Acute Seizures and Drug Resistant Chronic Epileptic Activity in Mice

“…Besides its established anti-inflammatory properties, dexamethasone anticonvulsant effect may be mediated by its ability to reverse the increased serum corticosterone concentrations, which are elicited by elevated IL-1β brain levels via activation of the hypothalamic-pituitary adrenal axis (HPA) axis [47,48]. Thus, chronic high levels of glucorticoids can produce proinflammatory effects in the brain [49] and increase neuronal vulnerability to injury [50,51]. This mechanism, although still speculative, may also play a role in the anticonvulsant activity of VX-765.…”

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

“…154 Animal studies show that stress induces an enhanced expression of proinflammatory factors such as IL-1b, 155,156 macrophage migration inhibitory factor [157][158][159] and COX-2 160 in the brain. Elevation of these proinflammatory factors is accompanied with dendritic atrophy and neuronal death within the hippocampus, 161,162 which are also found in brains of subjects with MD. These detrimental effects of glucocorticoids in the CNS are mediated by a rise in extracellular glutamate 163,164 and subsequent overstimulation of the NMDA receptor.…”