Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model.

BACKGROUND AND PURPOSE:

A non-psychoactive phytocannabinoid, cannabidiol (CBD), shows promising results as an effective potential antiepileptic drug in some forms of refractory epilepsy. In an attempt to understand the mechanisms by which CBD exerts its anti-seizure effects, we investigated the effects of CBD at synaptic connections, and the intrinsic membrane properties of hippocampal CA1 pyramidal cells and two major inhibitory interneurons: fast spiking, parvalbumin -expressing (PV) and adapting, cholecystokinin-expressing (CCK) interneurons. We also investigated whether in vivo treatment with CBD altered the fate of CCK and PV interneurons using immunohistochemistry.

EXPERIMENTAL APPROACH:

Electrophysiological intracellular whole-cell recordings combined with neuroanatomy were performed in acute brain slices of rat temporal lobe epilepsy (in vivo kainic acid-induced) and in vitro (Mg²⁺ -free-induced) epileptic seizure models. For immunohistochemistry experiments, CBD was administered in vivo (100 mg kg^-1) at zero time and 90 minutes post status epilepticus (SE) induced with kainic acid.

KEY RESULTS:

Bath-application of CBD (10 μM), dampened excitability at unitary synapses between pyramidal cells, but enhanced inhibitory synaptic potentials elicited by fast spiking and adapting interneurons at postsynaptic pyramidal cells. Furthermore, CBD restored impaired membrane excitability of PV, CCK, and pyramidal cells in a cell type-specific manner. These neuroprotective effects of CBD were corroborated by immunohistochemistry experiments that revealed a significant reduction of atrophy and death of PV- and CCK-expressing interneurons after CBD treatment.

CONCLUSIONS & IMPLICATIONS:

In conclusion, our data suggest CBD restores excitability and morphological impairment in epileptic models to pre-epilepsy control levels through multiple mechanisms to restore normal network function.

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