Category Archives: Stroke

Exploring the neuroprotective effects of phytocannabinoids on oxygen-glucose deprived neurons in an in vitro model of stroke

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“Stroke is a leading cause of death and disability worldwide, but therapeutic options to reduce or prevent neuronal damage are extremely limited.

Cannabinoids exhibit antioxidant, anti-inflammatory, and receptor modulatory actions that may offer neuroprotection.

While research on the potential of cannabinoids has expanded in epilepsy and neurodegeneration, the neuroprotective potential of this class of natural compounds in stroke remains underexplored. Here, we evaluated a panel of phytocannabinoids (PCs) for their ability to mitigate ischemia–reperfusion injury in an in vitro human model of stroke.

Methods

Human induced pluripotent stem cell (iPSC)-derived cortical neurons were subjected to 60 min of oxygen–glucose deprivation (OGD) followed by reperfusion. Neuronal survival was quantified over seven days using longitudinal live-cell imaging. Twenty-eight PCs were screened for their effect on reducing neuronal death.

Results

Among 28 PCs screened, seven demonstrated modest effects, with cannabigerorcinic acid (CBGOA) significantly improving post-OGD neuronal survival. While OGD exposure led to increased cell death via activation of caspase 3, CBGOA treatment did not impact that pathway, suggesting that other caspase-independent pathways may be implicated.

Conclusions

This pilot study identifies CBGOA as a candidate cannabinoid with neuroprotective potential in an in vitro model of ischemic stroke. The use of iPSC-derived human cortical neurons strengthens translational relevance, but the modest effects observed, and the limitations of in vitro systems, underscore the need for in vivo validation and further mechanistic studies.

Collectively, these results provide a foundation for exploring CBGOA and related cannabinoids as potential neuroprotective agents in stroke.”

https://pubmed.ncbi.nlm.nih.gov/41578349

https://link.springer.com/article/10.1186/s42238-026-00393-0

Exploring the neuroprotective effects and underlying mechanisms of medical cannabinoids in ischemic stroke: a systematic meta-analysis with bibliometric mapping of cerebral ischemia research

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“Background: Ischemic stroke is an acute neurological disorder with limited treatment options. Medical cannabinoids (MCs), primary bioactive compounds extracted from cannabis plants, have shown therapeutic prospects for ischemic stroke. This study integrates bibliometrics and meta-analysis to comprehensively summarize the research landscape of MCs in cerebral ischemia and thoroughly investigate their role and potential mechanisms in ischemic stroke.

Methods: Bibliometric analysis was performed based on literature retrieved from Web of Science Core Collection (WoSCC), PubMed, and Scopus. For meta-analysis, a comprehensive search was conducted across four databases (WoSCC, PubMed, Embase, and Cochrane Library) and grey literature repositories. Studies were screened according to predefined criteria. Pooled standardized mean differences with 95% confidence interval were calculated, followed by subgroup analysis.

Results: A total of 241 publications were identified for bibliometric analysis. From 2000 to June 2025, the annual publication output on MCs in cerebral ischemia displayed a fluctuating yet overall upward trend. Keyword co-occurrence analysis revealed three major research topics: neuroprotective mechanisms of MCs, pathological models of cerebral ischemia, and bioactive components of MCs. Meta-analysis of 26 studies demonstrated that MCs provided significant neuroprotection in animal models of ischemic stroke, including cerebral infarct volume, neurological function score (NFS), cerebral blood flow (CBF), blood-brain barrier (BBB) permeability, brain water content, apoptosis (TUNEL-positive cells), oxidative stress markers, inflammation (TNF-α, IL-1β), and excitotoxicity (Glu/NAA, Lac/NAA ratio). Subgroup analysis revealed that intraperitoneal administration and a full-course of cannabidiol (CBD) treatment were associated with reduced heterogeneity and enhanced therapeutic benefit. Isoflurane was identified as a potentially suitable anesthetic.

Conclusion: MCs exert multi-target neuroprotection in ischemic stroke by improving CBF, reducing brain edema and BBB permeability, and inhibiting oxidative stress, neuroinflammation, apoptosis, and excitotoxicity. Future research should focus on high-quality clinical trials to validate these findings and translate MCs into clinical practice.”

https://pubmed.ncbi.nlm.nih.gov/41551042

“THC produces anti-inflammatory effects, reduces neuronal damage, and promotes hippocampal neurogenesis.”

“CBD acts as a negative allosteric modulator of cannabinoid receptors (CBR) and exerts brain-protective effects through multi-target regulatory properties “

 “Moreover, the results of meta-analysis consolidate preclinical evidence, demonstrating that MCs confer neuroprotection by mitigating multiple pathological processes, including cerebral tissue perfusion, BBB permeability and cerebral edema, oxidative stress, excitotoxicity, inflammatory responses, and apoptosis.”

https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2025.1731738/full

Administration of Δ9-Tetrahydrocannabinol Following Controlled Cortical Impact Restores Hippocampal-Dependent Working Memory and Locomotor Function

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“Hypothesis: Administration of the phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) will enhance brain repair and improve short-term spatial working memory in mice following controlled cortical impact (CCI) by upregulating granulocyte colony-stimulating factor (G-CSF) and other neurotrophic factors (brain-derived neurotrophic factor [BDNF], glial-derived neurotrophic factor [GDNF]) in hippocampus (HP), cerebral cortex, and striatum. 

Materials and Methods: C57BL/6J mice underwent CCI and were treated for 3 days with Δ9-THC 3 mg/kg intraperitoneally (i.p.). Short-term working memory was determined using the spontaneous alternations test during exploratory behavior in a Y-maze. Locomotor function was measured as latency to fall from a rotating drum (rotometry). These behaviors were recorded at baseline and 3, 7, and 14 days after CCI. Groups of mice were euthanized at 7 and 14 days. Extent of microgliosis, astrocytosis, and G-CSF, BDNF, and GDNF expression were measured at 7 and 14 days in cerebral cortex, striatum, and HP on the side of the trauma. Levels of the most abundant endocannabinoid (2-arachidonoyl-glycerol [2-AG]) was also measured at these times. 

Results: Δ9-THC-treated mice exhibited marked improvement in performance on the Y-maze indicating that treatment with the phytocannabinoid could reverse the deficit in working memory caused by the CCI. Δ9-THC-treated mice ran on the rotarod longer than vehicle-treated mice and recovered to normal rotarod performance levels at 2 weeks. Δ9-THC-treated mice, compared with vehicle-treated animals, exhibited significant upregulation of G-CSF as well as BDNF and GDNF in the cerebral cortex, striatum, and HP. Levels of 2-AG were also increased in the Δ9-THC-treated mice. 

Conclusion: Administration of the phytocannabinoid Δ9-THC promotes significant functional recovery from traumatic brain injury (TBI) in the realms of working memory and locomotor function. This beneficial effect is associated with upregulation of brain 2-AG, G-CSF, BDNF, and GDNF. The latter three neurotrophic factors have been previously shown to mediate brain self-repair following TBI and stroke.”

https://pubmed.ncbi.nlm.nih.gov/34747647

https://www.liebertpub.com/doi/10.1089/can.2021.0053

Cannabidiol releases CB1R from A2AR repression in ischemic stroke

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“Cannabidiol (CBD) is a phytocannabinoid with potential in one of the most prevalent syndromes occurring at birth, the hypoxia of the neonate.

CBD targets a variety of proteins, adenosine A2AR and cannabinoid CB1R receptors included. These two receptors may interact to form heteromers (A2AR-CB1R Hets) that are also a target of CBD. Thus, we aimed to assess whether the expression and function of A2AR-CB1R-Hets is affected by CBD in animal models of hypoxia of the neonate and in glucose- and oxygen deprived (GOD) neurons and microglial cells.

Results indicated that the formation of A2AR-CB1R heteromers increased A2AR affinity for its selective agonist CGS21680. Moreover, resonance energy transfer assays showed that CBD and cannabigerol (CBG) affected the structure of the heteromer. Regarding functionallity, CBD partially bloked A2AR induced signalling in transfected HEK-293 T cells, while it recovered CB1R signalling in glucose/oxygen-deprived neurons and microglial cells. The expression of A2AR-CB1R Hets increased in GOD neurons and microglial cells.

This increase was counteracted with a pre-treatment with CBD and CBG. Importantly, in brain sections of a hypoxia/ischemia animal model, administration of CBD led to a significant reduction in the expression of A2AR-CB1R Hets.

In conclusion, CBD effects in the hypoxia of the neonate can be mediated by A2AR-CB1R complex. CBD partially blocks A2AR signalling while potentiates the neuroprotective effect of CB1R in hypoxic-ischemic conditions.”

https://pubmed.ncbi.nlm.nih.gov/41046105/

“In conclusion, the relevance of A2A-CB1 heteromers formations lies in the fact that these receptors can regulate each other. At the first stages after the injury A2A acquires a more important role, while days after CB1R signalling would provide an improvement.

Interestingly, CBD treatment plays an important effect by controlling A2AR and CB1R competition. This compound could be really beneficial to fight ischemic stroke by regulating A1R-CB1R complex function in the different stages of the disease.”

https://www.sciencedirect.com/science/article/pii/S0969996125003481?via%3Dihub

Oromucosal as an Alternative Method for Administration of Cannabis Products in Rodents

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“Oral administration of drugs in laboratory rodents such as rats is conventionally performed using the gavage technique. Despite effectiveness, gavage can induce distress associated with restraint, especially following repeated animal handling.

To mitigate these adverse effects and reduce morbidity associated with traditional methods, we explored oromucosal/buccal administration of cannabidiol (CBD)-enriched Cannabis extract.

In this method, male rats were treated daily for 15 days with medium-chain triglycerides (TCM) derived from coconut oil or CBD-enriched Cannabis extract. Each treatment was administered individually while animals were gently immobilized using an affectionate touch technique. The administration involved the use of a micropipette to apply the oily formulation directly into the oral mucosa. The dosage was calculated based on the CBD concentration in the Cannabis extract, standardized at 3 mg/kg/day. To ensure accuracy, animals were weighed daily, allowing for dose adjustments in accordance with weight changes over the treatment period. This method offers non-invasive and stress-reducing treatment, potentially improving animal welfare in experimental settings.

The treatment with CBD-enriched Cannabis extract was safe, and the analysis of the hippocampus of these animals’ showed alterations in the expression levels of GluA1 and GFAP proteins, which are directly associated with glutamatergic receptor functionality and neuroinflammation, respectively. This suggests that Cannabis extract could be applied in pathological conditions where glutamatergic excitotoxicity and astrogliosis are observed.”

https://pubmed.ncbi.nlm.nih.gov/40920655/

https://app.jove.com/t/68104/oromucosal-as-an-alternative-method-for-administration-cannabis

Cannabinoid Receptor Modulation in Focal Ischemic Stroke: A Systematic Review and Meta-Analysis of Infarct Volume and Behavioral Deficits in Animal Models

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“Introduction: Stroke is a leading cause of morbidity and mortality worldwide, with ischemic stroke accounting for the majority of cases. The endocannabinoid system (ECS), comprising cannabinoid receptors CB1 and CB2, has been implicated in regulating physiological processes and has shown potential neuroprotective effects in preclinical studies. However, the precise impact of cannabinoid receptor modulation on stroke outcomes remains unclear. This systematic review and meta-analysis aimed to evaluate the impact of cannabinoid receptor modulation on infarct volume and behavioral deficits in animal models of focal ischemic stroke, with a primary focus on infarct outcomes.

Method: A comprehensive literature search was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, yielding 29 eligible studies for inclusion.

Results: The analysis revealed significant reductions in infarct volume with cannabinoid agonists, particularly CB1 and CB2 agonists, indicating their potential as neuroprotective agents. Subgroup analyses further highlighted specific agonists, such as ACEA and KN38-72717, as particularly effective in reducing infarct volume. Additionally, CB antagonists, particularly CB1 antagonists, such as SR141716, showed promising results in reducing infarct volume. Although improvements in neurological scores were observed with both agonists and antagonists, statistical significance was not reached, indicating the need for further investigation.

Conclusion: These results highlight the potential of cannabinoid receptor modulation as a neuroprotective strategy in ischemic strokes and underscore the need for further research to elucidate the underlying mechanisms and optimize therapeutic approaches.”

https://pubmed.ncbi.nlm.nih.gov/40706582/

https://karger.com/mpp/article/doi/10.1159/000547277/930925/Cannabinoid-Receptor-Modulation-in-Focal-Ischemic

Full-spectrum Cannabis sativa extract enhances gut-peripheral organ integrity after experimental ischemic stroke

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“Objective: This study aims to investigate the impact of full-spectrum Cannabis sativa extract (FSC) treatment on gut and peripheral organ protection after ischemic stroke.

Main methods: Male Wistar rats were subjected to 60-min middle cerebral artery occlusion (MCAO) or sham surgery, and received FSC (15 or 30 mg/kg) or coconut oil by gavage at different time points post-MCAO. After 72 h, neurological score, infarct volume, blood cell count, thymus, spleen and adrenal gland size and weight, serum corticosterone, intestinal permeability, oxidative stress, and inflammatory cytokines in peripheral organs were assessed.

Key findings: The results show a significant improvement in neurological deficits, suggesting the therapeutic potential of FSC in post-stroke recovery. Additionally, a reduction in body mass, a decrease in blood cells related to the immune response, and atrophy of lymphoid organs, lower corticosterone levels, and reduced intestinal permeability were observed. FSC treatment also demonstrated a crucial role in protecting against oxidative stress and post-stroke lung inflammation.

Significance: The discovery of the positive impacts of FSC in this study represents an entry point for new explorations and perspectives within this field. With latent potential, these findings have the power to shape clinical research, especially in the realm of neurodegenerative diseases and innovative therapies. Therefore, the results highlight the promising role of FSC, paving the way for more effective and transformative clinical interventions.”

https://pubmed.ncbi.nlm.nih.gov/40389682/

https://link.springer.com/article/10.1007/s10787-025-01775-1

The Endocannabinoid System as a Target for Ischemic Stroke Therapy

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“Introduction: Cannabinoids are increasingly being explored as a potential treatment for neurodegenerative diseases. This article aims to provide a narrative review of available data on the treatment of neurological disorders with cannabis constituents, focusing on ischemic stroke. 

Methods: Selected articles are summarized to describe design, results, limitations, conclusions, and implications about this theme. 

Results: The growing understanding of the endocannabinoid system and the cannabinoid receptors distribution in all human body systems and organs and particularly in brain structures importantly involved in myelination processes, suggests potential benefits for stroke symptoms and overall patient improvement. However, the variety of studied compounds, the different administration routes, dosages, and timing complicates data comparison, especially due to limited studies about these compounds, peculiarly in stroke patients. Thereat, this review to showcase disparities in findings and to summarize current advancements in cannabinoid use for potential future treatments. 

Conclusion: This article offers a review of the current literature in the field and discuss a pragmatic approach to the clinical use of cannabinoids in patients with ischemic stroke.”

https://pubmed.ncbi.nlm.nih.gov/39951358/

The Effects of Cannabinoids on Ischemic Stroke-Associated Neuroinflammation: A Systematic Review

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“Stroke represents a significant burden on global health and the economy, with high mortality rates, disability, and recurrence. Ischemic stroke is a serious condition that occurs when a blood vessel in the brain is interrupted, reducing the blood supply to the affected area.

Inflammation is a significant component in stroke pathophysiology. Neuroinflammation is triggered following the acute ischemic ictus, where the blood-brain barrier (BBB) breaks down, causing damage to the endothelial cells. The damage will eventually generate oxidative stress, activate the pathological phenotypes of astrocytes and microglia, and lead to neuronal death in the neurovascular unit. As a result, the brain unleashes a robust neuroinflammatory response, which can further worsen the neurological outcomes.

Neuroinflammation is a complex pathological process involved in ischemic damage and repair. Finding new neuroinflammation molecular targets is essential to develop effective and safe novel treatment approaches against ischemic stroke.

Accumulating studies have investigated the pharmacological properties of cannabinoids (CBs) for many years, and recent research has shown their potential therapeutic use in treating ischemic stroke in rodent models.

These findings revealed promising impacts of CBs in reducing neuroinflammation and cellular death and ameliorating neurological deficits.

In this review, we explore the possibility of the therapeutic administration of CBs in mitigating neuroinflammation caused by a stroke. We summarize the results from several preclinical studies evaluating the efficacy of CBs anti-inflammatory interventions in ischemic stroke.

Although convincing preclinical evidence implies that CBs targeting neuroinflammation are promising for ischemic stroke, translating these findings into the clinical setting has proven to be challenging. The translation hurdle is due to the essence of the CBs ability to cause anxiety, cognitive deficit, and psychosis. Future studies are warranted to address the dose-beneficial effect of CBs in clinical trials of ischemic stroke-related neuroinflammation treatment.”

https://pubmed.ncbi.nlm.nih.gov/39899062/

“Recently, there has been increased interest in the use of cannabinoids (CBs) in stroke and other neurological disorders with a robust neuroinflammatory component.”

“CBs are naturally occurring compounds derived from the cannabis plant (Cannabis sativa L.), which have been utilized historically for their therapeutic effects.”

“In this systematic review, CBs showed remarkable effects against ischemic stroke-induced neuroinflammation in animal models through selective and nonselective activation/inhibition of CB receptors. Most CBs have the advantage of working on multiple targets, affecting many aspects of stroke pathology (Fig. 2). However, a wide range of CBs modulating neuroinflammation were found to be acting more through CB2Rs than CB1Rs, which is attributed to the close involvement of CB2Rs with the inflammatory cascades. Interestingly, simultaneous activation, inhibition, or a combination of both effects on CB1R and CB2R has demonstrated potential neuroprotective effects. This phenomenon is attributed to the biphasic nature of CBs, which allows them to modulate excitatory and inhibitory neurotransmitters in the brain.”

https://link.springer.com/article/10.1007/s11481-025-10171-z

β-Caryophyllene mitigates ischemic stroke-induced white matter lesions by inhibiting pyroptosis

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“β-Caryophyllene (BCP), a selective agonist for cannabinoid receptor 2 (CB2R), has demonstrated promising protective effects in various pathological conditions. However, the neuroprotective effects of BCP on white matter damage induced by ischemic stroke have not been elucidated previously.

In this study, we find that BCP not only improves sensorimotor and cognitive function via CB2R but also mitigates white matter lesions in mice following ischemic stroke. Furthermore, BCP enhances the viability of MO3.13 oligodendrocytes after oxygen-glucose deprivation and reoxygenation (OGD/R), attenuating OGD/R-induced cellular damage and pyroptosis. Notably, these protective effects of BCP are partially enhanced by the NLRP3 inhibitor MCC950 and counteracted by the NLRP3 activator nigericin. In addition, nigericin significantly exacerbates neurological outcomes and increases white matter lesions following BCP treatment in middle cerebral artery occlusion (MCAO) mice.

These results suggest that BCP may ameliorate neurological deficits and white matter damage induced by cerebral ischemia through inhibiting NLRP3-mediated pyroptosis.”

https://pubmed.ncbi.nlm.nih.gov/39159913/

“In conclusion, our study provides compelling evidence that BCP can enhance motor and cognitive function outcomes via activating CB2R, as well as promote white matter integrity after ischemic stroke. Significantly, this research establishes, for the first time, the crucial role of inhibiting NLRP3-mediated pyroptosis in the therapeutic effects of BCP post-ischemic stroke.”

https://www.sciencedirect.com/science/article/abs/pii/S0014482724003057?via%3Dihub

“Beta-caryophyllene is a dietary cannabinoid.” https://www.ncbi.nlm.nih.gov/pubmed/18574142

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934