Neuroprotective Mechanisms of Cannabinoids in Stroke: Preliminary Results of a Scoping Review

Abstract

Background. Stroke is a critical global public health challenge and one of the leading causes of long-term severe disability. Current therapeutic approaches primarily consist of thrombolysis and mechanical thrombectomy during the acute phase. However, there remains a critical lack of neuroprotective therapies capable of effectively improving patients’ quality of life following ischemic injury, which triggers a cascade of secondary damage characterized by glutamate-mediated excitotoxicity, oxidative stress, neuroinflammation, blood–brain barrier dysfunction, and neuronal death. Cannabinoids have emerged as a therapeutic strategy capable of modulating the pathophysiological processes involved in stroke. Nevertheless, a better understanding of the neuroprotective mechanisms underlying their therapeutic effects is needed to identify potential therapeutic targets that may support comprehensive rehabilitation after stroke. Objective. To describe the neuroprotective mechanisms that may explain the therapeutic potential of endocannabinoid system modulation in stroke. Methods. A literature search was conducted in PubMed using algorithms based on the following Medical Subject Headings (MeSH) and search terms: (Cannabinoids OR Cannabinoid) AND Stroke AND (“Glutamic Acid” OR “L-Glutamic Acid” OR “L Glutamic Acid” OR “Potassium Glutamate” OR “Aluminum L-Glutamate” OR “Aluminum L Glutamate” OR “D-Glutamate” OR “D Glutamate” OR “Glutamate” OR “L-Glutamate” OR “L Glutamate” OR “Oxidative Stress” OR CB2 OR “CB2 Receptor” OR “Cannabinoid Receptor CB2” OR CB1 OR “CB1 Receptor” OR “Cannabinoid Receptor CB1”). Clinical and preclinical studies involving patients with stroke or experimental stroke models that evaluated endocannabinoid levels or the effects of cannabinoids (phytocannabinoids or synthetic cannabinoids) through biochemical or imaging methods were included. Quantitative, qualitative, and mixed-methods studies were considered. Study selection was performed independently by two reviewers in two stages (title/abstract screening and full-text review). A narrative synthesis was conducted according to PRISMA guidelines. Results. A total of 208 articles were identified, of which 22 were included. Available evidence regarding cannabinoids in stroke is concentrated primarily in preclinical models of ischemic stroke, predominantly involving middle cerebral artery occlusion, ischemia–reperfusion, photothrombosis, neonatal hypoxia–ischemia, and oxygen–glucose deprivation models. Collectively, the included studies describe a potential neuroprotective effect of the endocannabinoid system mediated through CB1 receptor modulation, which appears to limit excessive glutamate release and reduce NMDA-mediated excitotoxicity, and through CB2 receptor activation, which appears to attenuate microglial and macrophage activation. Conclusions. Modulation of the endocannabinoid system may represent a promising neuroprotective target for ischemic stroke, primarily through its role in regulating glutamate-mediated excitotoxicity, neuroinflammatory responses, and neuronal survival. However, the available evidence remains predominantly preclinical, and translational clinical studies are required to confirm its efficacy, safety, and potential integration into neurological rehabilitation strategies.