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

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.

SUBMITTER: Yu Y

PROVIDER: S-EPMC7282534 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Targeting pro-inflammatory events to reduce seizures is gaining momentum. Experimentally, antagonism of inflammatory processes and of blood-brain barrier (BBB) damage has been demonstrated to be beneficial in reducing status epilepticus (SE). Clinically, a role of inflammation in the pathophysiology of drug resistant epilepsies is suspected. However, the use anti-inflammatory drug such as glucocorticosteroids (GCs) is limited to selected pediatric epileptic syndromes and spasms. Lack of animal data may be one of the reasons for the limited use of GCs in epilepsy. We evaluated the effect of the CG dexamethasone in reducing the onset and the severity of pilocarpine SE in rats. We assessed BBB integrity by measuring serum S100? and Evans Blue brain extravasation. Electrophysiological monitoring and hematologic measurements (WBCs and IL-1?) were performed. We reviewed the effect of add on dexamethasone treatment on a population of pediatric patients affected by drug resistant epilepsy. We excluded subjects affected by West, Landau-Kleffner or Lennox-Gastaut syndromes and Rasmussen encephalitis, known to respond to GCs or adrenocorticotropic hormone (ACTH). The effect of two additional GCs, methylprednisolone and hydrocortisone, was also reviewed in this population. When dexamethasone treatment preceded exposure to the convulsive agent pilocarpine, the number of rats developing status epilepticus (SE) was reduced. When SE developed, the time-to-onset was significantly delayed compared to pilocarpine alone and mortality associated with pilocarpine-SE was abolished. Dexamethasone significantly protected the BBB from damage. The clinical study included pediatric drug resistant epileptic subjects receiving add on GC treatments. Decreased seizure frequency (? 50%) or interruption of status epilepticus was observed in the majority of the subjects, regardless of the underlying pathology. Our experimental results point to a seizure-reducing effect of dexamethasone. The mechanism encompasses improvement of BBB integrity. Our results also suggest that add on GCs could be of efficacy in controlling pediatric drug resistant seizures.

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

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