Abstracts

Infantile spasms belong to the catastrophic epileptic syndromes of childhood and consist of flexion seizures, interictal chaotic EEG (hypsarrhythmia), and mental retardation. Standard antiepileptic drugs have limited efficacy; ACTH and vigabatrine are used, but both have serious side effects. Development of new therapies is restricted because there are no appropriate animal models. Previously, we suggested a model of flexion seizures induced by systemic of N-methyl-D-aspartate (NMDA) in immature rats with strong similarities to infantile spasms: Spasms occur in clusters only early postnatally. Interictally, chaotic large-amplitude waves appear in the EEG. The spasms are associated with long-term cognitive deficits in Morris Water Maze. However, a serious shortcoming of the model is the ACTH insensitivity. The efficacy of ACTH suggests predisposing alterations in the hypothalmo-pituitary-adrenal axis. Here, we propose an ACTH-sensitive model based on prenatally compromised brain., Pregnant rats were injected with betamethasone (0.4 mg/kg i.p.) on the morning and evening of day 15 of gestation. Control mothers received saline and the study also included offspring of untreated mothers. The offspring was injected with NMDA (7.5-30 mg/kg i.p.) on postnatal day 15. We recorded latency to onset of NMDA-specific phenomena: tail twists, body flexion with preserved righting ability and flexion spasms with loss of righting with EEG correlates. Some rats were pretreated with ACTH (0.1-0.4 mg/kg i.p.) 30-60 min prior to NMDA. Other groups were injected with NMDA and brains processed for c-fos immunohistochemistry to determine region activation after the flexion spasms. Some rats received [14C]2-deoxyglucose s.c. to examine metabolic patterns., Prenatal betamethasone exposure significantly accelerated the onset of NMDA-induced spasms compared to immature rats with prenatal saline exposure. More importantly, ACTH delayed the onset of spasms only in prenatal betamethasone-exposed pups but not in prenatal saline-exposed controls or naive, prenatally unexposed rats. EEG recordings were similar in all NMDA-treated groups, i.e., periods of large chaotic waves interictally and EEG suppression or discharges ictally. C-fos immunohistochemistry identified three major regions activated in association with flexion spasms: limbic (septum and medial amygdaloid nuclei, but NO hippocampus), hypothalamic (supraoptic, paraventricular, arcuate and medial tuberal nuclei), and brain stem (pedunculopontine tegmental, pontine, and raphe magnus nuclei as well as ventral tegmental area). 2DG autoradiography confirmed c-fos findings., We present a new model of infantile spasms based on prenatal corticosteroid exposure, clinically similar to human infantile spasms, and responding to ACTH. This model may bring new insights into the pathophysiology of infantile spasms and may open avenues for testing new effective anticonvulsant strategies., (Supported by NIH NS-41366, CURE, and AECOM.)