Abstracts

Rationale: Infantile spasms (IS) is a devastating epileptic syndrome of infancy. The hallmarks of the syndrome are clusters of spasms, interictal hypsarrythmia, and progressing mental retardation. Effectiveness of ACTH therapy against IS suggests the involvement of HPA axis as one of the underlying mechanisms of IS. Our group has established the rat model for cryptogenic IS involving prenatal priming with a synthetic glucocorticoid (betamethasone) and postnatal induction of spasms by NMDA. The model shows clusters of NMDA-induced spasms as well as interictal hypsarrythmia-like EEG and ictal EEG electrodecrements, and responsiveness to acute and chronic ACTH treatments. In this study, we focused on corticotropin releasing factor (CRF - a hypothalamic molecule controlling HPA axis), which has been suggested as a candidate molecule in pathophysiology of IS because of its excitatory properties in developing brain, and on methylprednisolone (MPD) - the synthetic corticosteroid with negative feedback on the CRF release. Methods: Pregnant Sprague-Dawley dams received betamethasone or saline ip injections at G15. The offspring were subjected to NMDA (15 mg/kg ip) on postnatal day (P)15 to induce the flexion spasms. We tested: (1) Effects of prenatal betamethasone exposure on postnatal expression of CRF in the CNS of P15 pups; (2) Effects of microinfusions (into the hypothalamic arcuate nucleus - Arc or lateral ventricle - LV) or systemic administration (ip) of CRF1 receptor antagonist CP376395 or (3) Effects of acute or chronic pretreatments (ip) with MPD on the prenatally betamethasone primed NMDA-induced spasms. Results: (1) The expression of CRF in the Arc areas and the paraventricular hypothalamic nucleus (a major source of CRF for the ventral hypothalamus) was increased after prenatal betamethasone priming but before seizures. (2) Administration of CP376395 had region specific effects. Microinfusion of CP376395 in the Arc area delayed initiation of the spasms and decreased their number compared to vehicle infusion, but it had no effect on the spasms when microinfused into the LV or following systemic injection. (3) While the acute treatments with MPD 1h prior to NMDA administration did not affect the spasms, chronic high dose MPD significantly delayed onset of spasms and even significantly decreased the incidence of spasms. Conclusions: Our results demonstrate the important role of the ventral hypothalamic area (Arc) in the control/modulation of spasms and provide the evidence of disturbances in the CRF regulation in our model of cryptogenic IS. These findings suggest that the CRF system may serve as a potential region-specific therapeutic target for IS.