Chronic Corticosterone Administration Dose‐Dependently Modulates Aβ_(1–42)− and NMDA‐Induced Neurodegeneration in Rat Magnocellular Nucleus Basalis

Abstract

The impact of glucocorticoids on beta-amyloid(1-42) (Abeta(1-42)) and NMDA-induced neurodegeneration was investigated in vivo. Abeta(1-42) or NMDA was injected into the cholinergic magnocellular nucleus basalis in adrenalectomized (ADX) rats, ADX rats supplemented with 25%, 100%, 2x100% corticosterone pellets, or sham-ADX controls. Abeta(1-42)- or NMDA-induced damage of cholinergic nucleus basalis neurones was assessed by quantitative acetylcholinesterase histochemistry. Plasma concentrations of corticosterone and cholinergic fibre loss after Abeta(1-42) or NMDA injection showed a clear U-shaped dose-response relationship. ADX and subsequent loss of serum corticosterone potentiated both the Abeta(1-42) and NMDA-induced neurodegeneration. ADX+25% corticosterone resulted in a 10-90 nM plasma corticosterone concentration, which significantly attenuated the Abeta(1-42) and NMDA neurotoxicity. ADX+100% corticosterone (corticosterone concentrations of 110-270 nM) potently decreased both Abeta(1-42)- and NMDA-induced neurotoxic brain damage. In contrast, high corticosterone concentrations of 310-650 nM potentiated Abeta(1-42)- and NMDA-triggered neurodegeneration. In conclusion, chronic low or high corticosterone concentrations increase the vulnerability of cholinergic cells to neurotoxic insult, while slightly elevated corticosterone levels protect against neurotoxic injury. Enhanced neurotoxicity of NMDA in the presence of high concentrations of specific glucocorticoid receptor agonists suggests that the corticosterone effects are mediated by glucocorticoid receptors.

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

“…57 Moreover, in vivo chronic corticosterone administration was shown to increase A␤ and N-methyl-D-aspartate-induced neurodegeneration in cholinergic neurons from the nucleus basalis in the rat. 56 In the present study, we obtained clear evidence that A␤ [25][26][27][28][29][30][31][32][33][34][35] increased the blood concentration of corticosterone from the first week and at least up to the third week. Note that plasma corticosterone levels observed in A␤ [25][26][27][28][29][30][31][32][33][34][35] -treated rats were in the same range as observed in chronically stressed rats, 58 which is consistent with the long-term hyperactivity of the hypothalamic-pituitary-adrenal axis.…”

“…Although no data are available on the effects of A␤ peptide injection on hypothalamic-pituitary-adrenal axis activity, several studies have demonstrated that glucocorticoids modulate APP processing, 55 increase A␤ 1-42 -induced neurodegeneration in basal nuclei of Meynert, 56 and increase A␤ [25][26][27][28][29][30][31][32][33][34][35] toxicity in hippocampus neurons. 57 Moreover, in vivo chronic corticosterone administration was shown to increase A␤ and N-methyl-D-aspartate-induced neurodegeneration in cholinergic neurons from the nucleus basalis in the rat.…”

Postnatal betamethasone vs dexamethasone in premature infants with bronchopulmonary dysplasia: a pilot study

“…16,35 Moreover, animal and cell culture experiments show that low-dose glucocorticoid is neuroprotective whereas high-dose is neurodegenerative. 15,36,37 In a similar but randomized trial using a low-dose dexamethasone protocol (0.15 mg kg À1 per day starting dose with a 10-day tapering course; total exposure: 0.88 mg kg À1 ), 35 ELBW neonates received glucocorticoid and 35 patients received placebo. The hormone-supplemented group showed: (1) facilitated weaning from the ventilator, (2) no significant elevation in blood glucose or blood pressure and (3) reduced postnatal weight gain (50% lower than the control group).…”

“…[12][13][14] Animal and tissue culture experiments show that low doses of glucocorticoids are neuroprotective whereas higher doses are neurodegenerative. 13,15 At least 11 systemic reviews on postnatal systemic glucocorticoids published between 1992 and 2001 showed a greater risk of cerebral palsy among premature infants treated with dexamethasone, for long duration (21 to 42 days) using a high dose (>0.5 mg kg À1 per day). 7 Surprisingly, betamethasone is not commonly used as a postnatal glucocorticoid to treat BPD in premature infants even though there is compelling evidence of its safety and efficacy in postnatal outcomes following antenatal betamethasone use during pregnancy.…”

Temporal control of glucocorticoid neurodynamics and its relevance for brain homeostasis, neuropathology and glucocorticoid-based therapeutics

“…The hippocampus appears to be particularly vulnerable to these neurotoxic effects, with CA3 pyramidal neurons being particularly more sensitive compared to CA1 pyramidal cells (Levy et al, 1994). Moreover, combination of differential GC levels with various noxious stimuli [Aβ-toxicity, hypoxia, N-methyl-Daspartate (NMDA)-induced excitotoxicity] leads to either an exacerbation of the neurodegenerative effects (when levels of GCs too low or too high) or an attenuation of the latter (under moderate corticosteroid levels) in a GC concentration-dependent manner (Abrahám et al, 2000). This latter effect has been also observed in animal models of cerebral ischemia, where chronic stress prior of neurovascular pathology was shown to increase stroke vulnerability, likely through GC-related endothelial dysfunction, since this effect was reversed by a GR antagonist (mifepristone) (Balkaya et al, 2011).…”