Abstracts

Rationale: In contrast to tetrahydrocannabinol (THC), cannabidiol (CBD) the major non-psychotropic cannabinoid constituent of cannabis sativa, has low affinity for endogenous cannabinoid receptors, but has anticonvulsant and immunosuppressive properties in adult experimental epilepsy models by unknown action. Less is known about anticonvulsant effects of CBD in the immature brain. We hypothesized that treatment of CBD will attenuate hippocampal seizures and prevent or reverse early onset of glutamate pathogenicity to vulnerable pyramidal neurons and subsequent cognitive co-morbidities of the early juvenile period. Methods: Two experimental models were tested on postnatal (P) day 20. Kainic (KA) acid (1.2 µg/µl) was either unilaterally injected (a) directly into the hippocampus (KAih) or (b) systemically (KAip) (8 mg/kg) to induce status epilepticus. Intrahippocampal CBD was co-administered (KA+CBDih) or followed KAih after onset to status epilepticus (KA/CBDih). Sytemic treatment followed KAip 30 min after onset to status epilepticus, KA/CBDip. All brains were histologically evaluated with NeuN immunohistochemistry and Nissl staining. Results: Co-administration, KA+CBDih, was most efficacious to lessen seizure severity scores but post-treatment was also anticonvulsant and protective, supporting its therapeutic potential at immature ages.The electroencephalogram (EEG) revealed reduced spike amplitude and frequency without high bursts (Table 1). Hyper-locomotion of open field activity was reversed also by KA+CBDih and systemic delivery. Nissl stains and NeuN immunohistochemistry revealed regular morphology of hippocampal neurons after KA+CBDih closely resembling vehicle injected controls. Similarly after KA+CBDih, there was less hyperbasophilia and a significant percentage of reactive astroglia were less intense and fewer in number within the CA1 and deep proliferative dentate hilar regions compared with the other treatments. Somatic labeling of interneurons with parvalbumin (PV) was hardly affected after KAip, whereas dendrtic staining was reduced or absent after KAih or KA/CBDih. In contrast, increases in ipsilateral dendritic/ neuropil density were observed suggesting GABergic activity may be affected by local hippocampal seizures. Cannabinoid receptor 1 (CB1) immunodensity was minimally affected after KAih or KA/CBDih and KA+CBDih contrasting elevations observed after KAip. Conclusions: Intracranial seizure data suggest that CBD is more effective in certain types of epilepsies with hippocampal origin and focus rather than when extra-hippocampal amygdala/cortical structures are triggered by systemic treatments. Higher and more frequent dosing may increase peripheral efficacy. The developmental stability of CB1 expression in both seizure models implies that they play important protective roles in regulating the hippocampal seizure threshold at young ages before neurotoxicity becomes progressive and irreversible. Further studies are still required to characterize the safety profile and true efficacy of this compound in the immature brain. Funding: none