Adrenalectomy-induced Cell Death Research Articles

3α,5α-THP mediates progestins' effects to protect against adrenalectomy-induced cell death in the dentate gyrus of female and male rats

Progestins have neuroprotective effects in several in vitro models of neurodegeneration and in vivo in seizure models. The extent to which progesterone's in vivo protective effects may generalize to models not involving seizure processes and whether progesterone's protective effects are modulated by its metabolites have not been comprehensively investigated. The present experiments investigated the effects of progesterone and its metabolites, dihydryoprogesterone (DHP) and 5α-pregnan-3α-ol-20-one (3α,5α-THP), to protect the hippocampus from damage induced by adrenalectomy (ADX). In Experiments 1 and 2, progesterone, DHP, or 3α,5α-THP administration (1 mg/kg sc) to female (Experiment 1) or male (Experiment 2) rats similarly reduced the total number of ADX-induced pyknotic cells in the dentate gyrus compared with vehicle administration. In Experiment 3, blocking progesterone's metabolism to 3α,5α-THP with coadministration of a 5α-reductase inhibitor, finasteride (10 mg/kg sc), in female rats attenuated progesterone's protective effects on cell death in the dentate gyrus. Together, these data suggest that progestins can protect against ADX-induced cell death and that the actions of the progesterone metabolite, 3α,5α-THP, may underlie these effects.

Adrenalectomy-induced cell death in the dentate gyrus: further characterisation using TUNEL and effects of the Ginkgo biloba extract, EGb 761, and ginkgolide B.

This study investigated the potential neuroprotective effects of the Ginkgo biloba extract, EGb-761, and ginkgolide B, on adrenalectomy (ADX)-induced cell death in the dentate gyrus (DG). Adrenalectomised, sham surgery-treated, and naive controls received either EGb-761 (25, 50, or 100 mg/kg), 0.9% saline vehicle control, ginkgolide B (10 or 25 mg/kg), or a polyethylene glycol vehicle control, i.p, daily for 6 days postsurgery. Cell death in the DG was determined by in situ labelling of DNA fragments, using the TUNEL method; sections were counterstained with hematoxylin. Radioimmunoassay was used to confirm a decrease in plasma corticosterone (CORT) after ADX. TUNEL-positive granule cells were observed in the DG at 1 week, but not at 24 h, post-ADX. The rate of granule cell death at this time was highest in the suprapyramidal blade and increased in a crest tip and a rostrotemporal gradient. Whereas CORT replacement completely prevented the occurrence of TUNEL-positive granule cells, EGb-761 and ginkgolide B did not, at any of the doses used. These results suggest that these drugs may not have substantial neuroprotective effects in the ADX model of neurodegeneration.

Electroshock seizures protect against apoptotic hippocampal cell death induced by adrenalectomy

Seizures evoked by electroshock induce rapid changes in the expression of several genes in the adult brain, including those encoding for neurotrophic factors. Some of the neurotrophic factors induced by brief seizures such as basic fibroblast growth factor and nerve growth factor have been shown to have neuroprotective action. We reasoned therefore that these seizures may protect against neural injury. To test this hypothesis, we examined the effect of electroshock-induced seizures on the vulnerability to cell death in the hippocampus. Cell death was induced by adrenalectomy, which results in a highly selective apoptotic neuronal death in the dentate granule cell layer of the hippocampus. Daily electroshock seizures were administered for seven days to sham-operated and adrenalectomized rats. Neuronal degeneration was evaluated by the highly sensitive and reliable cupric-silver impregnation method. Animals experiencing electroshock seizures were completely protected against adrenalectomy-induced cell death, whereas adrenalectomized animals not exposed to electroshock seizures exhibited substantial neuronal cell degeneration in the dentate granule cell layer. Daily restraint stress did not prevent the adrenalectomy-induced neuronal death, indicating that the neuroprotective effect of the seizure treatment is not accounted for by stress. We conclude that brief controlled seizure-evoked neural activation may allow the sparing of otherwise vulnerable neuronal populations in the injured adult brain. This prompts a need to explore the possibility that controlled administration of electroshock seizures may have therapeutic potential in treating neurodegenerative disorders.

Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus

The dentate gyrus of the rat produces new granule neurons well into adulthood. In the adult, newly born granule neurons migrate from the hilus to the granule cell layer, receive synaptic input, extend axons into the mossy fiber pathway, and express a neuronal marker. No previous studies have identified factors that regulate neuronal birth in the adult dentate gyrus. In order to determine whether glucocorticoids control neurogenesis in the adult dentate gyrus, the effects of adrenal steroid manipulations on neuronal birth were assessed using [ 3H]thymidine autoradiography and immunohistochemistry for the neuronal marker neuron specific enolase. Acute treatment with corticosterone produced a significant decrease in the density of [ 3H]thymidine-labeled cells in the hilus of the dentate gyrus. In contrast, removal of endogenous adrenal steroids stimulated increased neuronal birth; adrenalectomy resulted in a significant increase in the number of neuron specific enolase-immunoreactive [ 3H]thymidine labeled cells in the granule cell layer compared to sham operation. Replacement of corticosterone to adrenalectomized rats after [ 3H]thymidine injection did not substantially alter the increase in neurogenesis observed following adrenalectomy, even though this replacement protects cells from adrenalectomy-induced cell death. These results indicate that the rate of neurogenesis in the dentate gyrus of the adult rat is dependent upon the levels of circulating adrenal steroids.

Effects of aldosterone or RU28362 treatment on adrenalectomy-induced cell death in the dentate gyrus of the adult rat

Previous studies have shown that granule cells of the adult dentate gyrus require adrenal steroids for their survival. In order to investigate whether activation of type I or type II adrenal steroid receptors can mediate granule cell survival, we have analyzed the density of pyknotic cells in the granule cell, CA1 and CA3 pyramidal cell layers in Nissl stained hippocampal sections from adult male rats which were either sham operated, adrenalectomized, or adrenalectomized and treated with aldosterone as a specific type I receptor agonist or RU28362 as a specific type II receptor agonist. Aldosterone treatment completely protected the dentate gyrus from adrenalectomy-induced cell death, while treatment with RU28362 resulted in only a partial protection against cell death in this region. These results indicate that type I adrenal steroid receptor activation is sufficient to protect against adrenalectomy-induced cell death.