Neuroprotective Effects of MAGL (Monoacylglycerol Lipase) Inhibitors in Experimental Ischemic Stroke.

Posted on February 15, 2018 by David

American Heart Association Learn and Live

“MAGL (monoacylglycerol lipase) is an enzyme that hydrolyzes the endocannabinoid 2-arachidonoylglycerol and regulates the production of arachidonic acid and prostaglandins-substances that mediate tissue inflammatory response. Here, we have studied the effects of the selective MAGL inhibitors JZL184 and MJN110 and their underlying molecular mechanisms on 3 different experimental models of focal cerebral ischemia.

Pharmacological inhibition of MAGL significantly attenuated infarct volume and hemispheric swelling. MAGL inhibition also ameliorated sensorimotor deficits, suppressed inflammatory response, and decreased the number of degenerating neurons. These beneficial effects of MAGL inhibition were not fully abrogated by selective antagonists of cannabinoid receptors, indicating that the anti-inflammatory effects are caused by inhibition of eicosanoid production rather than by activation of cannabinoid receptors.

Our results suggest that MAGL may contribute to the pathophysiology of focal cerebral ischemia and is thus a promising therapeutic target for the treatment of ischemic stroke.”

https://www.ncbi.nlm.nih.gov/pubmed/29440474

http://stroke.ahajournals.org/content/early/2018/02/12/STROKEAHA.117.019664

Long-term depression induced by endogenous cannabinoids produces neuroprotection via astroglial CB1R after stroke in rodents.

Posted on February 14, 2018 by David

“Ischemia not only activates cell death pathways but also triggers endogenous protective mechanisms. However, it is largely unknown what is the essence of the endogenous neuroprotective mechanisms induced by preconditioning. In this study we demonstrated that systemic injection of JZL195, a selective inhibitor of eCB clearance enzymes, induces in vivo long-term depression at CA3-CA1 synapses and at PrL-NAc synapses produces neuroprotection. JZL195-elicited long-term depression is blocked by AM281, the antagonist of cannabinoid 1 receptor (CB₁R) and is abolished in mice lacking cannabinoid CB₁ receptor (CB₁R) in astroglial cells, but is conserved in mice lacking CB₁R in glutamatergic or GABAergic neurons. Blocking the glutamate NMDA receptor and the synaptic trafficking of glutamate AMPA receptor abolishes both long-term depression and neuroprotection induced by JZL195. Mice lacking CB₁R in astroglia show decreased neuronal death following cerebral ischemia. Thus, an acute elevation of extracellular eCB following eCB clearance inhibition results in neuroprotection through long-term depression induction after sequential activation of astroglial CB₁R and postsynaptic glutamate receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/29432698

http://journals.sagepub.com/doi/abs/10.1177/0271678X18755661?journalCode=jcba

Surprising outcomes in cannabinoid CB1/CB2 receptor double knockout mice in two models of ischemia.

Posted on December 31, 2017 by David

Cover image

“Although the number of individuals suffering from stroke in the United States and worldwide will continue to grow, therapeutic intervention for treatment following stroke remains frustratingly limited.

Both the cannabinoid 1 receptor (CB1R) and the cannabinoid 2 receptor (CB2R) have been studied in relationship to stroke. Deletion of the CB2R has been shown to worsen outcome, while selective CB2R agonists have been demonstrated to be neuroprotective following stroke.

We tested the hypothesis that CB1/CB2 receptor double knockout would produce significant increases in infarct size and volume and significant worsening in clinical score, using two mouse models, one of permanent ischemia and one of ischemia/reperfusion.

The results surprisingly revealed that CB1/CB2 double knockout mice showed improved outcomes, with the most improvements in the mouse model of permanent ischemia.

Although initial studies of CB1R knockout mice demonstrated increased injury following stroke, indicating that activation of the CB1R was neuroprotective, later studies of selective antagonists of the CB1R also demonstrated a protective effect.

Surprisingly the double knockout animals had improved outcome.

Since the phenotype of the double knockout is not dramatically changed, significant changes in the contribution of other homeostatic pathways in compensation for the loss of these two important receptors may explain these apparently contradictory results.”

https://www.ncbi.nlm.nih.gov/pubmed/29288767

http://www.sciencedirect.com/science/article/pii/S002432051730677X

Translating Endocannabinoid Biology into Clinical Practice: Cannabidiol for Stroke Prevention.

Posted on November 4, 2017 by David

Mary Ann Liebert, Inc. publishers

“Introduction: The endocannabinoid system (ECS) regulates functions throughout human physiology, including neuropsychiatric, cardiovascular, autonomic, metabolic, and inflammatory states. The complex cellular interactions regulated by the ECS suggest a potential for vascular disease and stroke prevention by augmenting central nervous and immune cell endocannabinoid signaling.

Discussion: The endocannabinoid N-arachidonoylethanolamine (anandamide) plays a central role in augmenting these processes in cerebrovascular and neurometabolic disease. Furthermore, cannabidiol (CBD), a nonpsychoactive constituent of Cannabis, is an immediate therapeutic candidate both for potentiating endocannabinoid signaling and for acting at multiple pharmacological targets.

Conclusion: This speculative synthesis explores the current state of knowledge of the ECS and suggests CBD as a therapeutic candidate for stroke prevention by exerting favorable augmentation of the homeostatic effects of the ECS and, in turn, improving the metabolic syndrome, while simultaneously stalling the development of atherosclerosis.”

https://www.ncbi.nlm.nih.gov/pubmed/29098188

http://online.liebertpub.com/doi/10.1089/can.2017.0033

Treatment of human spasticity with delta 9-tetrahydrocannabinol.

Posted on September 9, 2017 by David

Image result for J Clin Pharmacol.

“Spasticity is a common neurologic condition in patients with multiple sclerosis, stroke, cerebral palsy or an injured spinal cord. Animal studies suggest that THC has an inhibitory effect on polysynaptic reflexes.

Some spastic patients claim improvement after inhaling cannabis. We tested muscle tone, reflexes, strength and performed EMGs before and after double-blinded oral administration of either 10 or 5 mg THC or placebo.

10 mg THC significantly reduced spasticity by clinical measurement (P less than 0.01).

Responses varied, but benefit was seen in three of three patients with “tonic spasms.””

https://www.ncbi.nlm.nih.gov/pubmed/6271839

Intra-cerebral cannabidiol infusion-induced neuroprotection is partly associated with the TNF-α/TNFR1/NF-кB pathway in transient focal cerebral ischaemia.

Posted on September 7, 2017 by David

Publication Cover

“Stroke is a neurological disease, which, in addition to high mortality, imposes many financial and mental burdens on families and the society.

The main objective of this study was to investigate the effect of cannabidiol (CBD) on one of the major inflammatory pathways in cerebral ischaemia.

RESULTS:

Administration of CBD (100 and 200 ng/rat) caused a significant reduction in infarction, brain oedema, and BBB permeability compared with the vehicle-received group. Down-regulation of TNF-α, TNFR1, and NF-кB expression was also observed by CBD.

CONCLUSION:

The results achieved in this study support the idea that CBD has a cerebroprotective effect (partly through suppression of TNF-α, TNFR1, and NF-кB) on ischaemic injury.”

https://www.ncbi.nlm.nih.gov/pubmed/28872345

http://www.tandfonline.com/doi/abs/10.1080/02699052.2017.1358397?journalCode=ibij20

Smoking Marijuana Can Reduce Risk Of Stroke, Study Finds.

Posted on August 18, 2017 by David

Image result for university texas dallas

“Smoking marijuana can reduce the risk of a stroke to a large extent, a new study has found. In the states where marijuana use is legal, strains of the drug are prescribed to cure chronic pain, anxiety, and epilepsy. A new study conducted by the University of Texas at Dallas has found cannabis can improve a person’s health by enhancing the blood and oxygen flow, thus reducing the risk of blood clots and the possibility of a stroke.” http://www.ibtimes.com/smoking-marijuana-can-reduce-risk-stroke-study-finds-2579489

“Study Connects Chronic Cannabis Use to Oxygen Changes in Brain” http://www.utdallas.edu/news/2017/8/14-32651_Study-Connects-Chronic-Cannabis-Use-to-Oxygen-Chan_story-wide.html?WT.mc_id=NewsHomePage

“Residual Effects of THC via Novel Measures of Brain Perfusion and Metabolism in a Large Group of Chronic Cannabis Users” https://www.nature.com/npp/journal/vaop/ncurrent/full/npp201744a.html

“Could cannabis PROTECT you from a stroke? People who smoke marijuana every day have better blood flow and oxygen to the brain, controversial study claims. A study by the University of Texas at Dallas has found the drug can improve oxygen and blood flow to the brain, reducing the risk of clots that cause a brain attack. In fact, the research team found chronic cannabis users have the most efficient brain blood flow of all, suggesting their stroke risk is lowest.” http://www.dailymail.co.uk/health/article-4797444/Cannabis-PROTECTS-stroke-study-claims.html

http://www.thctotalhealthcare.com/category/stroke-2/

Modulation of Astrocyte Activity by Cannabidiol, a Nonpsychoactive Cannabinoid.

Posted on August 10, 2017 by David

“The astrocytes have gained in recent decades an enormous interest as a potential target for neurotherapies, due to their essential and pleiotropic roles in brain physiology and pathology. Their precise regulation is still far from understood, although several candidate molecules/systems arise as promising targets for astrocyte-mediated neuroregulation and/or neuroprotection.

The cannabinoid system and its ligands have been shown to interact and affect activities of astrocytes. Cannabidiol (CBD) is the main non-psychotomimetic cannabinoid derived from Cannabis. CBD is devoid of direct CB1 and CB2 receptor activity, but exerts a number of important effects in the brain. Here, we attempt to sum up the current findings on the effects of CBD on astrocyte activity, and in this way on central nervous system (CNS) functions, across various tested models and neuropathologies.

The collected data shows that increased astrocyte activity is suppressed in the presence of CBD in models of ischemia, Alzheimer-like and Multiple-Sclerosis-like neurodegenerations, sciatic nerve injury, epilepsy, and schizophrenia. Moreover, CBD has been shown to decrease proinflammatory functions and signaling in astrocytes.”

https://www.ncbi.nlm.nih.gov/pubmed/28788104

http://www.mdpi.com/1422-0067/18/8/1669

Correlation Between Cannabidiol-Induced Reduction of Infarct Volume and Inflammatory Factors Expression in Ischemic Stroke Model.

Posted on May 26, 2017 by David

Image result for Basic Clin Neurosci.

“Recent studies demonstrated that cannabidiol had neuroprotective property. There is some evidence about effective role of cannabidiol in reduction of ischemic damages. It has been reported that infarct size is influenced by various factors after MCAO, including inflammatory factors. The aim of the present study was to evaluate the effect of cannabidiol on infarction volume and correlation of infarct size with tumor necrosis factor receptor 1 (TNFR1), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression.

RESULTS:

The present results indicate that in the MCAO-induced cerebral ischemia, administration of cannabidiol (100 and 200 ng/rat) causes a significant reduction in infarction volume in comparison with the vehicle group. Also, there were significant correlations between decrease of regional infarct volume and TNFR1/NF-κB expression.

CONCLUSION:

The results of this study indicate that cannabidiol reduced cerebral infarction possibly through diminishing TNFR1/NF-κB-induced neurotoxicity in transient focal cerebral ischemia.”

https://www.ncbi.nlm.nih.gov/pubmed/28539998

http://bcn.iums.ac.ir/article-1-708-en.html

Neuroprotection in oxidative stress-related neurodegenerative diseases: role of endocannabinoid system modulation.

Posted on May 13, 2017 by David

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“Redox imbalance may lead to overproduction of reactive oxygen and nitrogen species (ROS/RNS) and subsequent oxidative tissue damage which is a critical event in the course of neurodegenerative diseases. It is still not fully elucidated, however, whether oxidative stress is the primary trigger or a consequence in process of neurodegeneration.

Recent Advances: Increasing evidence suggests that oxidative stress is involved in the propagation of neuronal injury and consequent inflammatory response, which in concert promote development of pathological alterations characteristic of most common neurodegenerative diseases.

Critical Issue: Accumulating recent evidence also suggests that there is an important interplay between the lipid endocannabinoid system (ECS; comprising of the main cannabinoid 1 and 2 receptors (CB1 and CB2), endocannabinoids and their synthetic and metabolizing enzymes) and various key inflammatory and redox-dependent processes.

FUTURE DIRECTIONS:

Targeting the ECS in order to modulate redox state-dependent cell death, and to decrease consequent or preceding inflammatory response holds therapeutic potential in multitude of oxidative stress-related acute or chronic neurodegenerative disorders from stroke and traumatic brain injury to Alzheimer`s and Parkinson`s diseases, and multiple sclerosis, just to name a few, which will be discussed in this overview.”

https://www.ncbi.nlm.nih.gov/pubmed/28497982