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Inverse Agonism of Cannabinoid Receptor Type 2 Confers Anti-inflammatory and Neuroprotective Effects Following Status Epileptics

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Abstract

Prolonged status epilepticus (SE) in humans causes high mortality and brain inflammation–associated neuronal injury and morbidity in survivors. Currently, the only effective treatment is to terminate the seizures swiftly to prevent brain damage. However, reliance on acute therapies alone would be imprudent due to the required short response time. Follow-on therapies that can be delivered well after the SE onset are in an urgent need. Cannabinoid receptor type 2 (CB2), a G protein-coupled receptor that can be expressed by activated brain microglia, has emerged as an appealing anti-inflammatory target for brain conditions. In the current study, we reported that the CB2 inverse agonism by our current lead compound SMM-189 largely prevented the rat primary microglia–mediated inflammation and showed moderate neuroprotection against N-methyl-d-aspartic acid (NMDA) receptor–mediated excitotoxicity in rat primary hippocampal cultures containing both neurons and glia. Using a classical mouse model of epilepsy, in which SE was induced by systemic administration of kainate (30 mg/kg, i.p.) and proceeded for 1 h, we demonstrated that SE downregulated the CB1 but slightly upregulated CB2 receptor in the hippocampus. Transient treatment with SMM-189 (6 mg/kg, i.p., b.i.d.) after the SE was interrupted by diazepam (10 mg/kg, i.p.) prevented the seizure-induced cytokine surge in the brain, neuronal death, and behavioral impairments 24 h after SE. Our results suggest that CB2 inverse agonism might provide an adjunctive anti-inflammatory therapy that can be delivered hours after SE onset, together with NMDA receptor blockers and first-line anti-convulsants, to reduce brain injury and functional deficits following prolonged seizures.

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Funding

This work was supported by the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) grants R00NS082379 (J.J.), R01NS100947 (J.J.), and R21NS109687 (J.J.).

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  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, USA

    Ying Yu, Lexiao Li, Davis T. Nguyen, Suni M. Mustafa, Bob M. Moore & Jianxiong Jiang

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Correspondence to Jianxiong Jiang.

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Yu, Y., Li, L., Nguyen, D.T. et al. Inverse Agonism of Cannabinoid Receptor Type 2 Confers Anti-inflammatory and Neuroprotective Effects Following Status Epileptics. Mol Neurobiol 57, 2830–2845 (2020). https://doi.org/10.1007/s12035-020-01923-4

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