Abstracts

Rationale: WWe have developed and validated a model of cryptogenic infantile spasms responding to acute as well as chronic ACTH treatment. We have identified that ACTH anti-spasm effects mainly involve agonistic action on central melanocortin (MC) receptors, especially on the MC4 isoform. The purpose of this study was to determine effects of different MC receptor agonists with particular interest in MC4 activity after either intracranial or systemic administration in our model.Methods: Sprague-Dawley timed pregnant rats (Taconic Farms) received two doses of betamethasone (0.4 mg/kg i.p. at 8:00 and 18:00) on day 15 of pregnancy. This prenatal priming is essential for increased susceptibility to develop spasms after postnatal trigger and also for development of ACTH efficacy. On postnatal day 13 (P13) some rats had intracerebroventricular (i.c.v.) cannula implanted in the lateral ventricle (unilaterally) for intracranial delivery of drugs. On P15, the rats were i.c.v. microinfused either with the drugs in 0.5 l of saline or with vehicle. The following drugs were used: THIQ, Ro 27-3225, alpha-MSH, and melanotan II. In additional groups of rats, these drugs were injected systemically (i.p.), controls received vehicle. Group sizes were n=5-11. One hour later, the rats were challenged with 15 mg/kg of N-methyl-D-aspartic acid (NMDA) to trigger spasms. We used systemic administration of ACTH as a reference for efficacy.Results: Intracerebroventricular administration of alpha-MSH, THIQ (both 1 nmol/0.5 l) and Ro 27-3225 (6.5 nmol/0.5 l) significantly delayed latency to onset of spasms (nonparametric Kaplan-Meier survival statistics with Mantel-Cox test; p<0.05). In addition, alpha-MSH also suppressed the number of spasms. Following systemic administration, there were no effects of THIQ (1 mg/kg) or Ro 27-3225 (0.1-1.0 mg/kg). In fact, THIQ even had some proconvulsant effects. On the other hand, we found significant and powerful effects of melanotan II (a cyclic MC receptor agonist; 1 mg/kg) against the spasms after systemic administration. Conclusions: Our data corroborate the findings that some of the proposed MC receptor agonists may have additional effects (such as THIQ, which should be a pure MC4 receptor agonist). Second, several MC receptor agonists have different effect after i.c.v. administration (during which they bath periventricular organs) compared to systemic administration, which likely involves entire brain. Finally, comparison of the properties of the tested substances indicates that those with additional MC3 receptor activity (besides the MC4 receptors) may have superior effects against the spasms. Our results demonstrate that the search for new treatments against infantile spasms is possible among peptidic agonists of melanocortin receptors.