Effects Of Long-term Adrenalectomy Research Articles

Increased pro-inflammatory cytokines, glial activation and oxidative stress in the hippocampus after short-term bilateral adrenalectomy.

BackgroundBilateral adrenalectomy has been shown to damage the hippocampal neurons. Although the effects of long-term adrenalectomy have been studied extensively there are few publications on the effects of short-term adrenalectomy. In the present study we aimed to investigate the effects of short-term bilateral adrenalectomy on the levels of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α; the response of microglia and astrocytes to neuronal cell death as well as oxidative stress markers GSH, SOD and MDA over the course of time (4 h, 24 h, 3 days, 1 week and 2 weeks) in the hippocampus of Wistar rats.ResultsOur results showed a transient significant elevation of pro-inflammatory cytokines IL-1β and IL-6 from 4 h to 3 days in the adrenalectomized compared to sham operated rats. After 1 week, the elevation of both cytokines returns to the sham levels. Surprisingly, TNF-α levels were significantly elevated at 4 h only in adrenalectomized compared to sham operated rats. The occurrence of neuronal cell death in the hippocampus following adrenalectomy was confirmed by Fluoro-Jade B staining. Our results showed a time dependent increase in degenerated neurons in the dorsal blade of the dentate gyrus from 3 days to 2 weeks after adrenalectomy. Our results revealed an early activation of microglia on day three whereas activation of astroglia in the hippocampus was observed at 1 week postoperatively. A progression of microglia and astroglia activation all over the dentate gyrus and their appearance for the first time in CA3 of adrenalectomized rats hippocampi compared to sham operated was seen after 2 weeks of surgery. Quantitative analysis revealed a significant increase in the number of microglia (3, 7 and 14 days) and astrocytes (7 and 14 days) of ADX compared to sham operated rats. Our study revealed no major signs of oxidative stress until 2 weeks after adrenalectomy when a significant decrease of GSH levels and SOD activity as well as an increase in MDA levels were found in adrenalectomized compared to sham rats.ConclusionOur study showed an early increase in the pro-inflammatory cytokines followed by neurodegeneration and activation of glial cells as well as oxidative stress. Taking these findings together it could be speculated that the early inflammatory components might contribute to the initiation of the biological cascade responsible for subsequent neuronal death in the current neurodegenerative animal model. These findings suggest that inflammatory mechanisms precede neurodegeneration and glial activation.

Hippocampal Neuroinflammation, Neurodegeneration, Gliosis in Wistar rats Following Adrenal Gland Removal.

Hippocampal Neuroinflammation, Neurodegeneration, Gliosis in Wistar rats Following Adrenal Gland Removal.

Effects of maternal corticosterone and stress on behavioral and hormonal indices of formalin pain in male and female offspring of different ages

In previous studies, we showed for the first time that prenatal stress in rats produces long-term alterations of formalin-induced pain behavior that are dependent on age and sex, and we demonstrated an important role of the serotonergic system in mechanisms of prenatal stress (Butkevich, I.P. and Vershinina, E.A., 2001; Butkevich, I.P. and Vershinina, E.A., 2003; Butkevich, I.P., Mikhailenko, V.A., Vershinina, E.A., Khozhai, L.I., Grigorev, I.P., Otellin, V.A., 2005; Butkevich, I.P., Mikhailenko, V.A., Khozhai, L.I., Otellin, V.A., 2006). In the present study, we focus on the influence of the maternal corticosterone milieu and its role in the effects of stress during pregnancy on formalin-induced pain and the corticosterone response to it in male and female offspring of different ages. For this purpose, we used adrenalectomy (AD) in female rats 3–4 weeks before mating (as distinct from AD typically performed at the beginning of pregnancy). Since AD is considered a reliable method to treat hypercortisolism, researches on the effects of long-term AD in dams on the systems responsible for adaptive behavior in offspring are important (such studies are not described in the literature). The results demonstrate that the differences in the corticosterone response to injection of formalin and saline are obvious in 90-day-old (adult) female offspring but masked in 25-day-old ones. AD promoted the corticosterone response to formalin-induced pain but not to injection of saline in prenatally non-stressed female offspring of both ages. Prenatal stress canceled the differences in corticosterone response to injection of formalin and saline in 25-day-old offspring of AD dams and in adult offspring of sham-operated (SH) dams but caused similar differences in adult offspring of AD dams. Sex differences were found in basal corticosterone levels in AD prenatally stressed rats of both age groups, with a higher level in females, and in the corticosterone response to formalin-induced pain in the adult rats of all groups investigated, with higher corticosterone levels in females. In regard to pain behavior, AD induced significant changes in flexing + shaking in prenatally non-stressed adult offspring and canceled the differences in this behavior between non-stressed and stressed 25-day-old offspring. There were sex differences in pain behavior of the adult rats: greater flexing + shaking in AD non-stressed males but in SH non-stressed females; greater licking in prenatally-stressed AD and SH females. These results indicate that the long-term influences of maternal corticosterone on formalin-induced pain and the corticosterone response to it are determined by the sex and age of the offspring and suggest that other mechanisms, including serotonergic ones revealed in our previous studies, are involved in the effects of prenatal stress on inflammatory pain behavior.

The effects of long-term adrenalectomy on 5-HT 1B receptors mRNA expression in cerebellum, striatum, frontal cortex and hippocampus of rats

The brain serotonin (5-HT) system and circulating corticosteroids are in close interaction and both implicated in the pathogenesis of affective disorders. We evaluated the effects of adrenalectomy (ADX) on 5-HT 1B receptors mRNA expression in cerebellum, frontal cortex, striatum and hippocampus in rats, using the RNase protection assay technique. Eight weeks after bilateral adrenalectomy, 5-HT 1B receptor mRNA levels were decreased in the cerebellum and in the frontal cortex. The expression of 5-HT 1B receptors mRNA was unchanged in the hippocampus and in the striatum. This data indicates regional differences in the effects of long term adrenalectomy on the expression of 5-HT 1B receptors.

Long-term adrenalectomy decreases NMDA receptors in rat hippocampus.

The effect of long-term adrenalectomy on NMDA receptors in the rat hippocampus was studied. Hippocampal sections of control and adrenalectomized rats were incubated with [3H]MK-801, a radiolabeled non-competitive inhibitor of the NMDA receptor. Analysis by in vitro autoradiography showed a significant decrease in [3H]MK-801 binding in the dentate gyrus, CA1 and CA4 areas, as well as the temporal cortex. Results of this study suggest that glucocorticoids are vital for the regulation of the NMDA receptors.

Behavioural deficits in adult rats following long-term adrenalectomy

Long-term adrenalectomy results in loss of neurones in the hippocampal formation of the adult rat. The effects of long-term adrenalectomy on spatial learning and exploratory behaviour in adrenalectomized (ADX), adrenalectomized normal weight gain (ADXNW), sham operated and naive control male Sprague-Dawley rats were investigated in this study. The ADX rats had significantly longer latencies in the Morris maze task compared to the other groups. In the open-field situation, as a novel finding, the ADX rats showed significantly lower rearing scores compared to other groups. These data indicate that long-term adrenalectomy causes impairment in spatial learning and explorative behaviour in the rat.

Cellular nuclear binding and retention of glucocorticoids in rat lymphoid cells: effect of long-term adrenalectomy.

In the present study we have shown for the first time that lymphocytes from the spleen, thymus and mesenteric lymph nodes can specifically bind and retain 3H-dexamethasone in the nuclear fraction. The use of the specific corticosteroid receptor antagonists, RU28362 and RU38486, for the displacement of labeled dexamethasone revealed that binding was mainly of type-II glucocorticoids receptors. In lymphocytes obtained from mesenteric lymph nodes, binding was significantly higher than in cells obtained from spleen and thymus. Long-term adrenalectomy (up to 30 days), which markedly elevated serum ACTH, caused a time-dependent increase in binding in all lymphoid cells. No increase in binding was found in lymphocytes obtained from rats hypophysectomized for 15 days, in which neither serum ACTH nor corticosterone could be measured. These results suggest that the cellular nuclear binding in lymphocytes may be regulated by a pituitary factor.

Effect of long-term adrenalectomy on hippocampal neurons and cognitive behaviour

Effect of long-term adrenalectomy on hippocampal neurons and cognitive behaviour

Adrenalectomy and Experimental Hypercorticalism Modulate the Basal, Corticotropin-Releasing-Hormone- and Arginine-Vasopressin-Stimulated Release of Hypothalamic Beta-Endorphin

Recent in vitro studies have shown that the release of hypothalamic beta-endorphin (beta-END), like that of adenohypophysial origin, is enhanced by both corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). However, whereas AVP merely synergizes with CRH in the pituitary, it seems to be essential for the release of hypothalamic beta-END by CRH. The present paper reports on the effects of long-term adrenalectomy (ADX) and subsequent replacement with supraphysiological doses of corticosterone (compound B, CB) upon the in vitro basal and CRH- and AVP-stimulated release of beta-END from the rat hypothalamus. Basal release of beta-END was significantly elevated by ADX, and returned to control levels following CB overdosage. Both ADX and CB replacement significantly reduced the stimulatory effect of CRH (10(-8) M) upon beta-END release. ADX caused no significant change in the AVP (10(-6) M)-induced release of beta-END. However, the AVP-stimulated release of beta-END was completely abolished in ADX rats treated with a high dose of CB. The hypothalamic content of beta-END was also measured following ADX and subsequent CB treatment. Compared with control tissues, those from ADX animals had significantly greater contents of beta-END; the hypothalami from rats with experimentally induced hypercorticalism had markedly reduced concentrations of the opioid peptide. Measurements of basal release and content of AVP in the hypothalamus following long-term ADX and CB treatment revealed that AVP neuronal activity is also subject to manipulations of the glucocorticoid hormone environment.(ABSTRACT TRUNCATED AT 250 WORDS)

Significance of ACTH4-10 in the control of hippocampal corticosterone receptor capacity of hypophysectomized rats.

The effect of hypophysectomy on the number of corticosterone receptor sites was investigated in three rat brain regions and was compared with the effect of long-term adrenalectomy. Subsequently, the effect on receptor capacity was measured after the hypophysectomized rats had received as substitution therapy ACTH1-24 and smaller peptide fragments lacking corticotropic activity. All rats (sham and hypophysectomy) were adrenalectomized 24 h prior to sacrifice for depletion of endogenous adrenal hormones and replacement therapy was discontinued at that time. Extensive perfusion with saline was carried out at the time of sacrifice. 3H-corticosterone binding was measured in cytosol by means of an in vitro assay. 2 weeks after hypophysectomy, the apparent maximal binding capacity (Bmax) of the corticosterone receptor system was increased by 60, 36 and 72% in hippocampus, hypothalamus and septum, respectively. The increase in Bmax in the hippocampus of hypophysectomized rats was 30% higher than the increase in animals adrenalectomized 2 weeks previously. Replacement with ACTH1-24 markedly decreased the binding capacity in all brain regions investigated. Replacement with the behaviorally active ACTH4-10 sequence reduced the number of corticosterone receptor sites in the hippocampus by 21%, while the behaviorally inactive ACTH11-24 sequence was ineffective. Des-glycinamide-arginine-vasopressin was also ineffective. There were no alterations in binding affinity for corticosterone in hippocampal cytosol after the surgical procedures or after the different replacement therapies. It is concluded that the neurotropic ACTH4-10 sequence reduces the number of corticosterone receptor sites in the hippocampus of the hypophysectomized rat. The action of ACTH4-10 was specific for the hippocampus and was not observed in other brain regions or plasma transcortin.