Abstract
Objective: Evaluate CBD’s effect on GPR55 signalling.
Background: In CBD’s multimodal pharmacologic profile, one molecular target is antagonism of the orphan G-protein coupled receptor GPR55, activated by endogenous ligand lysophosphatidylinositol (LPI). Since LPI activation of GPR55 increases presynaptic Ca2+ and vesicular release at excitatory CA3-CA1 synapses, promoting the excitability of CA1 pyramidal neurons, antagonism of GPR55 may be a promising target for epilepsy management.
Design/Methods: Acute brain slices were taken from chronically epileptic animals following lithium-pilocarpine induced status epilepticus and non-epileptic controls (n=6–9/group). Whole-cell patch-clamp recordings of hippocampal CA1 pyramidal neurons and interneurons were made, and changes in LPI-mediated effects on frequency and waveform of miniature postsynaptic currents were examined in CBD-(10 μM) or CBD vehicle–treated slices. In vivo mouse models of acute seizure were used to assess the role of GPR55 in seizures and the effect of altered GPR55-mediated signaling upon CBD’s anticonvulsant potency. Results were compared using unpaired t-test and one way ANOVA statistical tests.
Results: Mean amplitude of miniature excitatory postsynaptic currents (mEPSCs) was decreased in epileptic vs non-epileptic slices (6.6±1.8 vs 14.9±5.6 pA; p<0.001). Mean mEPSC decay time constant was longer in epileptic vs non-epileptic slices (11.2±2.4 vs 14.5±0.9 ms; p<0.05), suggesting potential alterations in subunit composition of postsynaptic amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPARs). mEPSCs waveform changes in epileptic tissue were not affected by CBD (p>0.05). LPI mediated increase of mEPSCs frequency was potentiated in epileptic CA1 pyramidal cells (2.8±0.6) when compared to non-epileptic neurons (1.4±0.1, p<0.05); CBD fully inhibited this response.
Conclusions: These results show glutamatergic transmission at CA3-CA1 synapses is modified by epilepsy, potentially involving changes in AMPA receptor subunit composition. In addition, GPR55 function was enhanced by epilepsy in a manner that would worsen the disease state, but CBD remained fully potent in epileptic brains, suggesting a novel anticonvulsant mechanism of action of CBD.
Study Supported by:
GW Research Ltd
Disclosure: Dr. Whalley has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with GW PHARMACEUTIALS (EMPLOYMENT). Dr. Whalley holds stock and/or stock options in GW PHARMACEUTICALS, which sponsored research in which Dr. Whalley was involved as an investigator. Dr. Bazelot has nothing to disclose. Dr. Rosenberg has nothing to disclose. Dr. Tsien has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Receive quarterly payments for serving on the HHMI Scientific Advisor Board.
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