The endocannabinoid system and stroke: A focused review
Stroke is an important cause of morbidity and mortality worldwide. Development of novel neuroprotectants is of paramount importance. This review seeks to summarize the recent evidence for the role of the endocannabinoid signaling system in stroke pathophysiology, as well as the evidence from preclinical studies regarding the efficacy of cannabinoids as neuroprotective therapies in the treatment of stroke. Recent evidence from rodent models implicating cannabinoid 1 receptor (CB1R), cannabinoid 2 receptor (CB2R), and CB1R and CB2R co-antagonism as neuroprotective strategies in stroke are reviewed. Rodent evidence for the therapeutic role of the endocannabinoid system in treating poststroke depression is reviewed. Finally, evidence for the role of cannabidiol, a publicly available cannabinoid that does not bind directly to known endocannabinoid receptors, as a stroke neuroprotectant is also reviewed. The review closes with a consideration of the role of human cannabinoid abuse in stroke and considers future directions for research on endocannabinoid-based stroke therapeutics.
Globally, overall stroke mortality has declined from 142/100,000 person-years in 1990–110/100,000 person-years in 2013, but the number of people affected or disabled from stroke has increased 1.4–1.8 folds over the same time period. In 2013, there were 25.7 million stroke survivors worldwide, with 6.5 million deaths and 10.3 million new strokes. Recent advancements in acute stroke treatment such as mechanical thrombectomy have fundamentally reshaped the treatment paradigm for ischemic stroke (IS) caused by large-vessel occlusion. On the other hand, novel neuroprotectants and rehabilitative facilitators for IS, although well-studied in preclinical settings, have yet to demonstrate major impact in the clinical setting. Targeting of the endocannabinoid system for IS protection and rehabilitation is one such area that has received a significant recent attention in the basic science literature, with emerging applicability to human patients.
Cannabis is widely considered one of the first plants cultivated by man. The use of hemp fibers derived from cannabis for rope, textile, and the paper has been dated as far back as 4000 BC in China. Cannabis also has a long history of medicinal use in various cultures, including as a treatment for rheumatic pain, constipation, female reproductive problems, and even malaria. The main psychoactive constituent of cannabis, delta-9-tetrahydrocannabinol (THC), was characterized in 1964. The endocannabinoid signaling system, consisting mainly of two cell-surface cannabinoid receptors, termed CB1R and CB2R, as well as endogenously produced ligands, known as the endocannabinoids, occurred in the late 1980s and early 1990s.[5,6,7,8] Therapeutic modulation of the endocannabinoid system to treat disease can occur in a variety of dimensions, either by agonism or antagonism of cannabinoid receptors themselves, or by targeted interaction with the various endocannabinoid pathway synthetic and degradative enzymes such as N-acylphosphatidylethanolamine-selective phospholipase D, fatty acid amide hydrolase, diacylglycerol lipase isozymes α and β, and monoacylglycerol lipase.
Alteration of the endocannabinoid signaling system has been implicated in a vast array of human diseases, including neurological disorders such as Parkinson’s, Alzheimer’s, and multiple sclerosis. Recent evidence has shown that simple medicinal cannabis formulations can function as efficacious neuroprotectants. For instance, Sativex, an oral medicinal spray containing both THC as well as nonpsychoactive cannabidiol (CBD), has been found to decrease spasticity in multiple sclerosis. A recent randomized controlled trial demonstrated that Epidiolex, a nonpsychoactive CBD formulation, is safe and effective in reducing seizures in Lennox–Gastaut syndrome. Adverse events were reported in 86% of patients; however, most were mild. Medical cannabis has also been found in a small study to improve the Unified Parkinson’s Disease Rating Scale scores in Parkinson’s in addition to rigidity, tremor, and bradykinesia.
Current evidence for the neuroprotectant efficacy of cannabinoids in IS is predicated on preclinical work in animals. A 2015 meta-analysis examined 34 preclinical studies examining CBD for poststroke neuroprotection. The authors concluded that cannabinoids were able to statistically reduce infarct volume and improve functional outcomes in experimental stroke, with activity at both cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors associated with positive outcomes. For instance, one early study showed that CB1 knockout mice undergoing transient or permanent cerebral ischemia had larger infarct volumes, worse neurological deficits, decreased cerebral blood flow (CBF) to the penumbra on reperfusion, as well as increased N-methyl-D-aspartate (NMDA) excitotoxicity compared to CB1 wild-type mice, suggesting that the endocannabinoid system is intricately leaked with neuronal and endothelial behavior. Building on these results, Zhang et al. noted that CB1 antagonists coupled with CB2 agonists reduced inflammation and leukocyte rolling while also increasing blood flow during occlusion, possibly through collaterals. These and other studies have contributed to optimism regarding the possible applicability to cannabinoids in the treatment of stroke patients. To review the state of the literature, since the publication of the 2015 meta-analysis by England et al., we searched the PubMed/Medline database using the Thomson Reuters Web of Science for articles published within the last 5 years using the search term“TITLE: ((stroke) OR ischemi*) AND (((((((cannabinoid) OR cannabidiol) OR delta-9-tetrahydrocannabinoid) OR WIN 55212-2) OR “2-arachidonoylglycerol”) OR endocannabinoid*) OR CB1) OR CB2)).” In what follows, we provide a focused review of the results of this literature search, with special emphasis on clinically relevant findings [ Table 1 ].
Cannabinoid Receptor Agonists and Antagonists as Stroke Neuroprotectants
Evidence that CB1R antagonism is neuroprotective
In a human autopsy study, Caruso et al. have shown an increase in CB1R expression in the ischemic regions of the brain tissue, using both neuronal and nonneuronal cell staining and CB1R antibodies. It has also recently been shown that mice lacking CB1R expression on astrocytes demonstrate decreased neuronal death in a mouse model of stroke. Knowles et al. administered a CB1 receptor antagonist to rats 30 min prior to induction of transient global cerebral ischemia and assessed the effects of CB1 blockage on hormone expression and neuronal damage, finding that CB1 antagonist pretreatment counteracted ischemia-associated changes in corticotropin-releasing hormone, vesicular glutamate transporter 2, tyrosine hydroxylase, and dopamine receptor 1 expression throughout the rat brain. Reichenbach et al. have also found that CB1R antagonism used as both a pretreatment and a posttreatment is neuroprotective in a mouse model of permanent ischemia through photoinjury. However, there is at least one recent study that suggests that CB1R agonism can also play a neuroprotective role in rodent models of stroke. Caltana et al. have demonstrated that CB1 agonists administered poststroke in mice reduces deleterious effects on astrocytes, neurons, and dendrites, while also counteracting stroke-associated deterioration in motor activity, suggesting that agonism at CB1R poststroke in mice is neuroprotective. Further work is needed to fully determine the therapeutic possibilities of modulating activity at CB1R to treat stroke. For a summary of recent evidence related to the neuroprotective effects of CB1R antagonism see [ Table 2 ].
Evidence that CB2R agonism is neuroprotective
Recent work has examined the effects of CB2R agonism in a rat model of stroke when used as a pretreatment versus as a poststroke treatment.[21,22] When used as a pretreatment, CB2R agonists were able to suppress neurodegeneration in rat model of large-vessel IS created by occlusion of the right middle cerebral artery (MCA), whereas this effect was lost when the CB2R agonist was used in the 2–5-day period immediately following ischemic insult. Ronca et al. were able to demonstrate significantly smaller infarct volumes in a mouse model of IS in which mice received pre- and posttreatment with a selective cannabinoid CB2R agonist. Importantly, this animal model, rather than using transient middle cerebral occlusion to model ischemia/reperfusion injury, used a photoinjury method to model permanent ischemia. These results build on previously published data from the same group, demonstrating a similar effect in mice experiencing transient MCA occlusion rather than permanent photoinjury. In addition to animal model data suggesting that CB2R agonism is neuroprotective, there is also data that suggests that CB2R antagonism is neuroharmful. For example, administration of a CB2R antagonist in a mouse model of chronic IS resulted in decreased neuroblast migration toward the infarct boundary, while both mice treated with a CB2R antagonist and mice with deletion of the CB2R gene demonstrated decreased numbers of new neurons and worse sensorimotor performance 28 days poststroke, when compared to controls. The authors also demonstrated that CB2R agonists, but not CB2R antagonists, increased neural progenitor cell migration in vitro. Taken together, these results suggest that signaling interactions at the CB2R receptor play a critical role in poststroke neurogenesis, but further experiments are needed to determine whether this observation can be therapeutically leveraged, whether by pretreatment or poststroke treatment with CB2R agonists.
Regarding CB2R agonism is a stroke therapeutic, an important question to consider is how durable any observed positive effects are over time. Rivers-Auty et al. have shown that a CB2 agonist failed to show positive histological and behavioral effects at 15 days after injury in an animal model of cerebral hypoxia-ischemia. This important article suggests that many of the neuroprotective properties associated with CB2 agonists or other endocannabinoid signaling molecules may be early and transient and that further rigorous experimentation is needed to assess the exact properties of CB2 agonists with respect to stroke neuroprotection in animal models, let alone in humans.
Another important question for researchers to answer is the exact mechanism by which CB2R agonism provides a neuroprotective effect. One possible mechanism by which the putative neuroprotective effects of cannabinoids are achieved is through the endocannabinoid-mediated modulation of the poststroke inflammatory response. Using CB2R tracers and positron emission tomography, Hosoya et al. have demonstrated increased levels of the CB2 receptor in the cerebral cortex surrounding ischemic lesions in rats undergoing photothrombotic stroke surgery. The authors were also able to demonstrate using immunohistochemistry that there was an elevation in CB2R expression within the microglia around the peri-infarct area, suggesting that the CB2R receptor may mediate microglia recruitment and activity in the postischemic inflammatory response. However, there are also data that suggest that decreased activity at CB2R also promotes inflammation. For instance, Kossatz et al. have shown that CB2R knockout mice demonstrate increased levels of HIF-1-alpha and TIM-3 expression by infiltrating microglia. Further work is needed to determine the exact role of CB2R signaling in poststroke inflammation. For a summary of recent evidence regarding the neuroprotective effects of CB2R agonism and antagonism see [ Table 3 ].
Evidence that altered activity at CB2R is neuroprotective, neuroharmful, or has no effect in rodent models of stroke
Evidence that co-antagonism at CB1R and CB2R is neuroprotective
The primary CB1 and CB2 endogenous agonist 2-arachidonoylglycerol (2-AG) is difficult to measure in vivo, and Brose et al. have recently shown that brain 2-AG levels rise dramatically following global ischemia, which both demonstrate the intimate connection between endocannabinoid signaling and brain ischemia as well as the importance of developing novel laboratory techniques to prevent ischemia-associated surges when measuring endocannabinoid levels in experimental animal models. Jalin et al. have shown that postischemic treatment with the nonselective CB1R and CB2R antagonist hinokiresinols reduced infarct volume as well as infiltration by inflammatory cells into ischemic lesions, while co-administration of 2-AG abolished these positive effects, elegantly demonstrating the important role the endocannabinoid system plays in poststroke inflammation. After administration of 2-AG to rats receiving permanent MCA occlusion surgery, Shearer et.al. performed blinded measurements of CBF. They found that CBF was severely reduced in the 2-AG group when compared to vehicle controls for up to 4 h following the ischemic insult. These results further suggest that blocking the effects of 2-AG, the main endogenous ligand for CB1R and CB2R could play a neuroprotective role in stroke. Finally, in a recent study published by Ward et al., it was shown that CB1R/CB2R double-knockout mice showed improved poststroke outcomes in both permanent and transient MCA occlusions, further suggesting that agonist activity at CB1R and CB2R may be driving deleterious physiological processes in the poststroke brain microenvironment. Future research is needed to explore the full therapeutic possibilities of counteracting 2-AG signaling in the poststroke microenvironment. For a summary of recent evidence that co-antagonism CB1R and CB2R is neuroprotective in rodent models of stroke [ Table 4 ].
Evidence that altered activity at CB1R and CB2R is neuroprotective or neuroharmful in rodent models of stroke
The Endocannabinoid System and Poststroke Depression
In a rat model of poststroke depression, Wang et al. found that CB1 receptor expression was downregulated in the hypothalamus of rats subjected to MCA occlusion following by chronic unpredictable mild stress (CUMS), while also showing that intraperitoneal injections of CB1 and CB2 receptor agonists during the administration of CUMS were able to attenuate poststroke depression behavior in rats. These data suggest a possible role for cannabinoid receptor agonists in the treatment of poststroke depression in humans. Zhang et al. have also investigated the role of the endocannabinoid system in poststroke depression, showing that interaction between sevoflurane and the CB1R resulted in a reduction in depressive-like behavior in rats following transient occlusion of bilateral common carotid arteries.
Cannabidiol as a Stroke Neuroprotectant
Unlike experimental CB1R agonists and antagonists, CBD is a widely available cannabinoid that does not bind directly to CB1R or CB2R, and its specific target has yet to be established. It has also received attention for its possible neuroprotective properties. Khaksar and Bigdeli have shown that infusion of CBD into the lateral ventricle through a surgically implanted cannula for 5 days resulted in reduction in neurological deficit, infarction, edema, and blood–brain barrier permeability at 24 h following 60 min of MCA occlusion.[35,36] Recent work in a neonatal rat model of IS has demonstrated that CBD administration following MCA occlusion for 3 h increased neurobehavioral function at 1 week and 1 month without reducing the volume of infarct. Using a mouse model of cerebral ischemia induced by bilateral common carotid artery occlusion, Mori et al. have demonstrated that CBD aids in global function recovery following ischemic insult while also resulting in reduced hippocampal neurodegeneration, reduced white matter injury, reduced glial response, while also demonstrating increased levels of the brain-derived neurotrophic factor. Rodríguez-Muñoz et al. have recently shown that the poststroke neuroprotective effects of CBD may be mediated by an antagonist-like activity at the sigma-1 receptor, which itself is known to inhibit NMDA receptor activity, suggesting that the neuroprotective effects of CBD may result from counteracting the effects of NMDA receptor overactivity in the brain. Building on the above results, Lafuente et al. have shown that co-therapy with CBD and hypothermia in neonatal piglets subjected to hypoxic-ischemic insult reduced excitotoxicity, inflammation, oxidative stress, and cell damage more than either alone. Similar results have been reported in newborn mice as well, with the therapeutic window for CBD administration stretching to 18 h posthypoxia-ischemia. In conflict with these results, Garberg et al. demonstrated in newborn piglets that the administration of CBD alone did not have significant effects on postischemia neuropathology scores, S100B levels in the CSF, hippocampal proton magnetic resonance spectroscopy biomarks, plasma troponin-T, or urinary neutrophil gelatinase-associated lipocalin, whereas the administration of CBD plus hypothermia reduced urinary neutrophil gelatinase-associated lipocalin compared to hypothermia alone. These conflicting results suggest that further research is needed to understand the role of CBD signaling in ischemic brain injury, both in the context of adult stroke and neonatal hypoxia-ischemia.
Human Studies of Cannabinoid Use in Stroke
Despite considerable number of animal and preclinical studies, there are only a limited number of clinical studies assessing cannabinoids in human ischemic cerebral injury. Keles et al. noted significant increases in oxygenated hemoglobin in the prefrontal cortex after THC use, as well as increased prefrontal blood flow on near-infrared spectroscopy. These physiological effects associated with THC use could be therapeutically leveraged in the appropriate setting. In addition to its effects on brain oxygenation, cannabinoids have also received recent attention as a treatment for various types of spasticity. Along these lines, a double-blind, placebo-controlled, crossover trial is currently recruiting patients to investigate the efficacy of cannabinoids in reducing poststroke spasticity.
Cannabinoid Abuse and the Risk of Stroke
Prior studies have shown a complex and varied interaction between cerebrovascular system regulatory pathways and cannabinoids. In a recent detailed review of literature from animal models, Richter et al. demonstrated that administration of cannabinoids can lead to vasodilation or vasoconstriction in the animal depending on the experiment. Of a total of nine studies addressing the effect of cannabinoids on cerebral vasculature, three indicated vasoconstriction in response to the drug, while others showed vasodilatory effects. Depending on the timepoint, at which vasodilation is activated, this protection may be beneficial in early stages of ischemia. If it occurs at a later stage, it might accelerate the recuperation of cerebral function.
These data from animal models are important when putting in the context of recent concern over an apparent clinical connection between cannabinoid use and IS. A recent study reviewed possible stroke-related complications in the young and reported a temporal relationship between cannabinoids’ use, whether natural or synthetic, and the occurrence of stroke. Reversible cerebral vasoconstriction triggered by cannabinoid use has been reported as a possible underlying factor predisposing these patients to ischemic complications. Generation of reactive oxygen species leading to an oxidative stress and mitochondrial damage is other postulated underlying mechanisms that have been reported as a possible predisposing factor for cerebrovascular complications following chronic cannabinoid use. However, despite the widespread use of cannabinoids, the low number of their ischemic complications has raised the possibility for a genetic predisposition for cerebrovascular complications in these patients. Future randomized or well-designed population-based epidemiologic studies are required to assess the association of cannabinoids with the risk of IS in general population.
A great deal of supporting evidence exists for the involvement of the endocannabinoid system in IS pathophysiology. While no definitive human studies demonstrating poststroke benefit yet exist, the available preclinical data are promising. However, recent work has also demonstrated that the role of the endocannabinoid system in stroke is more complex than initially thought. First, the 2018 study by Shearer et al. has demonstrated an intimate connection between poststroke CBF and 2-AG signaling, and further work should be done to unpack this relationship in order to better predict the full effects of endocannabinoid therapeutics in human. Second, Rivers-Auty et al. have cast doubt on the idea that CB2 agonism can reduce brain damage associated with hypoxia-ischemia, and further work is needed to examine the true potential of CB2 agonism as a promising poststroke neuroprotectant. Finally, the endogenous ligands for CBD have yet to be determined, and conflicting evidence for the neuroprotective effects of CBD in animal models of stroke have recently been published.[39,42] In our opinion, further work is required to establish satisfactory answers to these CBD-related questions before human trials. In sum, more studies will be needed to determine more precisely which cannabinoid receptors are most beneficial to neural recovery, the optimum timing of administration, and whether THC, CBD, or another synthetic agonist or antagonist will be the most efficacious agent with the least amount of adverse effects for stroke treatment.
Cannabis-based medicines–GW pharmaceuticals: high CBD, high THC, medicinal cannabis–GW pharmaceuticals, THC:CBD
GW Pharmaceuticals is undertaking a major research programme in the UK to develop and market distinct cannabis-based prescription medicines [THC:CBD, High THC, High CBD] in a range of medical conditions. The cannabis for this programme is grown in a secret location in the UK. It is expected that the product will be marketed in the US in late 2003. GW’s cannabis-based products include selected phytocannabinoids from cannabis plants, including D9 tetrahydrocannabinol (THC) and cannabidiol (CBD). The company is investigating their use in three delivery systems, including sublingual spray, sublingual tablet and inhaled (but not smoked) dosage forms. The technology is protected by patent applications. Four different formulations are currently being investigated, including High THC, THC:CBD (narrow ratio), THC:CBD (broad ratio) and High CBD. GW is also developing a specialist security technology that will be incorporated in all its drug delivery systems. This technology allows for the recording and remote monitoring of patient usage to prevent any potential abuse of its cannabis-based medicines. GW plans to enter into agreements with other companies following phase III development, to secure the best commercialisation terms for its cannabis-based medicines. In June 2003, GW announced that exclusive commercialisation rights for the drug in the UK had been licensed to Bayer AG. The drug will be marketed under the Sativex brand name. This agreement also provides Bayer with an option to expand their license to include the European Union and certain world markets. GW was granted a clinical trial exemption certificate by the Medicines Control Agency to conduct clinical studies with cannabis-based medicines in the UK. The exemption includes investigations in the relief of pain of neurological origin and defects of neurological function in the following indications: multiple sclerosis (MS), spinal cord injury, peripheral nerve injury, central nervous system damage, neuroinvasive cancer, dystonias, cerebral vascular accident and spina bifida, as well as for the relief of pain and inflammation in rheumatoid arthritis and also pain relief in brachial plexus injury. The UK Government stated that it would be willing to amend the Misuse of Drugs Act 1971 to permit the introduction of a cannabis-based medicine. GW stated in its 2002 Annual Report that it was currently conducting five phase III trials of its cannabis derivatives, including a double-blind, placebo-controlled trial with a sublingual spray containing High THC in more than 100 patients with cancer pain in the UK. Also included is a phase III trial of THC:CBD (narrow ratio) being conducted in patients with severe pain due to brachial plexus injury, as are two more phase III trials of THC:CBD (narrow ratio) targeting spasticity and bladder dysfunction in multiple sclerosis patients. Another phase III trial of THC:CBD (narrow ratio) in patients with spinal cord injury is also being conducted. Results from the trials are expected during 2003. Three additional trials are also in the early stages of planning. These trials include a phase I trial of THC:CBD (broad ratio) in patients with inflammatory bowel disease, a phase I trial of High CBD in patients with psychotic disorders such as schizophrenia, and a preclinical trial of High CBD in various CNS disorders (including epilepsy, stroke and head injury). GW Pharmaceuticals submitted an application for approval of cannabis-based medicines to UK regulatory authorities in March 2003. Originally GW hoped to market cannabis-based prescription medicines by 2004, but is now planning for a launch in the UK towards the end of 2003. Several trials for GW’s cannabis derivatives have also been completed, including four randomised, double-blind, placebo-controlled phase III clinical trials conducted in the UK. The trials were initiated by GW in April 2002, to investigate the use of a sublingual spray containing THC:CBD (narrow ratio) in the following medical conditions: pain in spinal cord injury, pain and sleep in MS and spinal cord injury, neuropathic pain in MS and general neuropathic pain (presented as allodynia). Results from these trials show that THC:CBD (narrow ratio) caused statistically significant reductions in neuropathic pain in patients with MS and other conditions. In addition, improvements in other MS symptoms were observed as well. Phase II studies of THC:CBD (narrow ratio) have also been completed in patients with MS, spinal cord injury, neuropathic pain and a small number of patients with peripheral neuropathy secondary to diabetes mellitus or AIDS. A phase II trial of THC:CBD (broad ratio) has also been completed in a small number of patients with rheumatoid arthritis, as has a trial of High CBD in patients with neurogenic symptoms. A phase II trial has also been evaluated with High THC in small numbers of patients for the treatment of perioperative pain. The phase II trials provided positive results and confirmed an excellent safety profile for cannabis-based medicines. GW Pharmaceuticals received an IND approval to commence phase II clinical trials in Canada in patients with chronic pain, multiple sclerosis and spinal cord injury in 2002. Following meetings with the US FDA, Drug Enforcement Agency (DEA), the Office for National Drug Control Policy, and National Institute for Drug Abuse, GW was granted an import license from the DEA and has imported its first cannabis extracts into the US. Preclinical research with these extracts in the US is ongoing.
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Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice
Atherosclerosis is a chronic inflammatory disease, and is the primary cause of heart disease and stroke in Western countries. Derivatives of cannabinoids such as delta-9-tetrahydrocannabinol (THC) modulate immune functions and therefore have potential for the treatment of inflammatory diseases. We investigated the effects of THC in a murine model of established atherosclerosis. Oral administration of THC (1 mg kg(-1) per day) resulted in significant inhibition of disease progression. This effective dose is lower than the dose usually associated with psychotropic effects of THC. Furthermore, we detected the CB2 receptor (the main cannabinoid receptor expressed on immune cells) in both human and mouse atherosclerotic plaques. Lymphoid cells isolated from THC-treated mice showed diminished proliferation capacity and decreased interferon-gamma secretion. Macrophage chemotaxis, which is a crucial step for the development of atherosclerosis, was also inhibited in vitro by THC. All these effects were completely blocked by a specific CB2 receptor antagonist. Our data demonstrate that oral treatment with a low dose of THC inhibits atherosclerosis progression in the apolipoprotein E knockout mouse model, through pleiotropic immunomodulatory effects on lymphoid and myeloid cells. Thus, THC or cannabinoids with activity at the CB2 receptor may be valuable targets for treating atherosclerosis.
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