Abstracts

Rationale: Neonatal seizures and seizures of infancy represent a significant cause of morbidity. 30-40% of infants and children with seizures will fail to achieve seizure remission with current anti-epileptic drug (AED) treatment. Moreover, less than half of electrographic neonatal seizures are effectively controlled with the current first (phenobarbital) or second (phenytoin) line drug treatments. Identification of new therapies for neonatal/infantile epilepsy syndromes is thus of high priority. Recent case reports have suggested that cannabis extracts, such as cannabidiol, may exert clinical anticonvulsant effects in young patients. While drugs targeting the cannabinoid system with cannabinoid receptor 1 (CB1) agonists display anticonvulsant efficacy in adult animal models of seizures/epilepsy, they remain unexplored in neonatal models. However, the cannabinoid system emerges and is active early in development across species, supporting the investigation of targeting this system in neonates. Methods: We examined the therapeutic potential of drugs targeting the cannabinoid system in two neonatal rodent models of seizures. In the first model, postnatal day (P) 10 or P20 male, Sprague-Dawley rat pups were challenged with the chemoconvulsant DMCM (300 ug/kg) or pentylenetetrazole (PTZ; 100mg/kg) 20 min after pretreatment. Rat pups received a high, mid-range, or low dose of either: CB1/2 mixed agonist (WIN 55,212-2), CB1 agonist (ACEA) or antagonist (AM-251), CB2 agonist (HU-308) or antagonist (AM-630), fatty acid amide hydrolase (FAAH) inhibitor (URB597), and GPR55 agonist (O-1602). After induction of complex partial seizures via DMCM or tonic-clonic seizures via PTZ, seizures were scored on a Racine scale modified for neonates (0.5: chew, facial clonus, tremors; 1: myoclonic jerks; 2: unilateral clonus, shuffling; 3: bilateral facial-forelimb clonus; 4: swimming with loss of righting; 4.5: running/bouncing clonic seizure; 5: tonic extension). In the second model, P10 male, Sprague-Dawley rat pups were pretreated with either saline vehicle or CB1/2 mixed agonist (WIN 55,212-2). Hypoxia was then induced and the presence of acute seizures were characterized by tremors, head bobbing, wet dogs shakes, and tonic-clonic movements. Results: Only the mixed CB1/2 agonist and the CB1 agonist displayed anticonvulsant effects against DMCM. The severity of seizures was significantly decreased and the latency to display behavioral seizure symptoms was increased. These effects were seen in P10 animals but not P20 animals. By contrast, both CB1 and CB2 antagonism increase seizure severity. The anticonvulsant effect of the mixed CB1/2 agonist persisted in the hypoxia model of neonatal seizures. Compared to vehicle treated animals (n=8), there was a significant (p = 0.0084) decrease in hypoxia-induced seizures in animals treated with the mixed CB1/2 agonist (n=8/dose). Conclusions: Together, these results indicate that in neonates, anticonvulsant action of the cannabinoid system is specific to CB1 receptor activation during a specific developmental window. These data provide justification for further examination of CB1 receptor agonists as novel antiepileptic drugs targeting epilepsy in infants and children. Funding: NIH: KL2TR001432