Abstracts

Rationale: Infantile spasms are refractory to conventional antiepileptic drugs, while ACTH is a drug of choice. We developed a model of the cryptogenic infantile spasms, characterized by the spasms responding to ACTH (Ann Neurol 2007 (61)109-119). Recently we showed that melanocortin 4 receptors (MC4R) are responsible for the effect of ACTH against the spasms in our model (Epilepsia 2009 (50) Suppl. 11, 375). Here we examined other MC4R agonists against the spasms using our model. Methods: We used the offspring from mothers injected with betamethasone on G15. Prenatally betamethasone exposed rats were implanted with a guide cannula to the lateral ventricle on postnatal day (P)13. On P15, pups were pretreated with i.c.v. administered MC4R agonists; alpha-MSH (1nmol), THIQ (1nmol), or Ro273225 (6.5 nmol). Controls received 0.5 L saline (vehicle) i.c.v.. Additional prenatally betamethasone exposed rats were treated using systemic administration (i.p.) of THIQ (1mg/kg) or Ro273225 (100 g/kg). After 60min following any drug treatment, NMDA was administered intraperitoneally to trigger the spasms and the latency to onset of flexion spasms and the number of spasms were evaluated. Results: Intraventricular administration of THIQ, Ro273225 and alpha-MSH significantly delayed the onset of NMDA induced spasms (p <0.05) when compared to the saline-infused controls. On the other hand, systemic administration of THIQ or Ro 273225 had no specific effects on the latency to onset of spasms or the number of spasms (p >0.05). Conclusions: Despite of the lack of efficacy after the systemic administration, non-peptide MC4 receptor agonists and alpha-MSH significantly delayed the onset of spasms after i.c.v. administration. This suggests that the MC4 receptors play a significant role in regulation/modulation of cryptogenic infantile spasms in our model.