ACTH Directly Down-Regulates CRH Expression in the Immature Amygdala, Independent of Steroid Receptor Activation: A Mechanism of ACTH Action on Infantile Spasms?
Abstract number :
3.075
Submission category :
Year :
2000
Submission ID :
3312
Source :
www.aesnet.org
Presentation date :
12/2/2000 12:00:00 AM
Published date :
Dec 1, 2000, 06:00 AM
Authors :
Kristen L Brunson, Najeeb Khan, Mariam Eghbal-Ahmadi, Tallie Z Baram, Univ of CA, Irvine, CA.
RATIONALE: ACTH and glucocorticoids (GCs) are effective for the therapy of Infantile Spasms (IS; West syndrome). In addition, controlled prospective studies suggest that high doses of ACTH may be more potent than GCs. However, the mechanisms by which ACTH eliminates IS, and specifically, whether ACTH influences neurons by mechanisms that are independent from those of GCs remains unresolved. ACTH and GCs, being stress hormones, are expected to influence the production and levels of the key central nervous system (CNS) stress mediator, corticotropin releasing hormone (CRH). CRH, an excitatory neuropeptide expressed in amygdala and hippocampus, causes severe seizures in the immature CNS. Do ACTH and GCs improve IS by downregulating CRH levels in seizure-prone CNS regions? Here we tested the hypothesis that ACTH suppresses CRH-expression in immature rat amygdala directly, via activation of melanocortin receptors (MCRs). METHODS: To distinguish the direct effects of ACTH from those mediated by GCs, intact rats were compared to those in whom GCs were eliminated by adrenalectomy. In situ hybridization was used to determine the effects of both peripheral and central ACTH administration and of specific MCR- and GC- receptor blockers on CRH-messenger RNA (mRNA) expression in amygdala. RESULTS: Systemically given ACTH (ACTHARGEL), in doses equivalent to those used for IS, reduced amygdala-CRH-mRNA levels significantly in both intact and adrenalectomized rats, indicating that GCs were not required for this effect. In addition, a centrally infused ACTH analog that does not promote GC secretion also reduced CRH-mRNA levels. Finally, selective blocking of MCR type 4, but not of GC receptors, prevented the down-regulation of CRH, strongly implicating activation of specific MCRs in the mechanism for this effect of ACTH. CONCLUSIONS: ACTH activates central MCRs to modulate CRH gene expression in amygdala, supporting the notion that direct,GC- independent actions of ACTH may account for its efficacy in the treatment of IS. Supported by NS28912 and NS 39307.