Impaired release of corticosterone from adrenals contributes to impairment of circadian rhythms of activity in hyperammonemic rats

Patients with liver cirrhosis may present impaired sleep-wake and circadian rhythms, relative adrenal insufficiency and altered hypothalamus–pituitary–adrenal gland (HPA) axis. The underlying mechanisms remain unclear. Circadian rhythms are modulated by corticosteroids which secretion is regulated by HPA axis. Hyperammonemia alters circadian rhythms of activity and corticosterone in rats.The aims were: (1) assessing whether corticosterone alterations are responsible for altered circadian rhythm in hyperammonemia: (2) to shed light on the mechanism by which corticosterone circadian rhythm is altered in hyperammonemia.The effects of daily corticosterone injection at ZT10 on circadian rhythms of activity, plasma corticosterone, adreno-corticotropic hormone (ACTH) and hypothalamic corticotropic releasing hormone (CRH) were assessed in control and hyperammonemic rats. ACTH-induced corticosterone release was analyzed in cultured adrenal cells.Corticosterone injection restores the corticosterone peak in hyperammonemic rats and their activity and circadian rhythm. Plasma ACTH and CRH in hypothalamus are increased in hyperammonemic rats. Corticosterone injection normalizes ACTH.Chronic hyperammonemia impairs adrenal function, reduces corticosterone content and ACTH-induced corticosterone release in adrenals, leading to reduced feedback modulation of HPA axis by corticosterone which contributes to impair circadian rhythms of activity. Impaired circadian rhythms and motor activity may be corrected in hyperammonemia and hepatic encephalopathy by corticosterone treatment.

► Hyperammonemia impairs adrenal function and ACTH-induced corticosterone release.
► This reduces feedback modulation of the hypothalamic–pituitary–adrenocortical axis.
► Chronic hyperammonemia increases CRH and ACTH.
► Reduced release of corticosterone contributes to impairment of circadian rhythms.
► Daily treatment with corticosterone restores circadian rhythms and motor activity.