Neuroprotection by the cannabidiol aminoquinone VCE-004.8 in experimental ischemic stroke in mice.

Abstract

Synthetic cannabidiol (CBD) derivative VCE-004.8 is a peroxisome proliferator-activated receptor gamma (PPARγ) and cannabinoid receptor type 2 (CB2) dual agonist with hypoxia mimetic activity. The oral formulation of VCE-004.8, termed EHP-101, possesses anti-inflammatory properties and is currently in phase 2 clinical trials for relapsing forms of multiple sclerosis. The activation of PPARγ or CB2 receptors exerts neuroprotective effects by dampening neuroinflammation in ischemic stroke models. However, the effect of a dual PPARγ/CB2 agonist in ischemic stroke models is not known. Here, we demonstrate that treatment with VCE-004.8 confers neuroprotection in young mice subjected to cerebral ischemia. Male C57BL/6J mice, aged 3-4 months, were subjected to 30-min transient middle cerebral artery occlusion (MCAO). We evaluated the effect of intraperitoneal VCE-004.8 treatment (10 or 20 mg/kg) either at the onset of reperfusion or 4h or 6h after the reperfusion. Seventy-two hours after ischemia, animals were subjected to behavioral tests. Immediately after the tests, animals were perfused, and brains were collected for histology and PCR analysis. Treatment with VCE-004.8 either at the onset or 4h after reperfusion significantly reduced infarct volume and improved behavioral outcomes. A trend toward reduction in stroke injury was observed in animals receiving the drug starting 6h after recirculation. VCE-004.8 significantly reduced the expression of pro-inflammatory cytokines and chemokines involved in BBB breakdown. Mice receiving VCE-004.8 had significantly lower levels of extravasated IgG in the brain parenchyma, indicating protection against stroke-induced BBB disruption. Lower levels of active matrix metalloproteinase-9 were found in the brain of drug-treated animals. Our data show that VCE-004.8 is a promising drug candidate for treating ischemic brain injury. Since VCE-004.8 has been shown to be safe in the clinical setting, the possibility of repurposing its use as a delayed treatment option for ischemic stroke adds substantial translational value to our findings.

• Authors: Bianca P Lavayen, Changjun Yang, Jonathan Larochelle, Lei Liu, Ryland J Tishko, Antonio Carlos Pinheiro de Oliveira, Eduardo Muñoz, Eduardo Candelario-Jalil
• Journal: Neurochemistry international (Neurochem Int) Vol. 165 Pg. 105508 (05 2023) ISSN: 1872-9754 [Electronic] England
• PMID: 36863495 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier Ltd. All rights reserved.

Chemical References

• Cannabidiol
• PPAR gamma
• Neuroprotective Agents

Topics

• Mice
• Animals
• Male
• Cannabidiol (pharmacology, therapeutic use)
• Neuroprotection
• PPAR gamma (metabolism)
• Ischemic Stroke (drug therapy)
• Mice, Inbred C57BL
• Brain Ischemia (metabolism)
• Stroke (drug therapy, metabolism)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Infarction, Middle Cerebral Artery (drug therapy)
• Disease Models, Animal