Category Archives: Stroke

Therapeutic Potential of Non-Psychotropic Cannabidiol in Ischemic Stroke.

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“Cannabis contains the psychoactive component delta⁸-tetrahydrocannabinol (delta⁸-THC), and the non-psychoactive components cannabidiol (CBD), cannabinol, and cannabigerol.

It is well-known that delta⁸-THC and other cannabinoid CB₁ receptor agonists are neuroprotective during global and focal ischemic injury.

Additionally, delta⁸-THC also mediates psychological effects through the activation of the CB₁ receptor in the central nervous system.

In addition to the CB₁ receptor agonists, cannabis also contains therapeutically active components which are CB₁ receptor independent.

Of the CB₁ receptor-independent cannabis, the most important is CBD.

In the past five years, an increasing number of publications have focused on the discovery of the anti-inflammatory, anti-oxidant, and neuroprotective effects of CBD.

In particular, CBD exerts positive pharmacological effects in ischemic stroke and other chronic diseases, including Parkinson’s disease, Alzheimer’s disease, and rheumatoid arthritis.

The cerebroprotective action of CBD is CB₁ receptor-independent, long-lasting, and has potent anti-oxidant activity. Importantly, CBD use does not lead to tolerance.

In this review, we will discuss the therapeutic possibility of CBD as a cerebroprotective agent, highlighting recent pharmacological advances, novel mechanisms, and therapeutic time window of CBD in ischemic stroke.”

https://www.ncbi.nlm.nih.gov/pubmed/27713349

Delayed treatment with cannabidiol has a cerebroprotective action via a cannabinoid receptor-independent myeloperoxidase-inhibiting mechanism.

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“We examined the neuroprotective mechanism of cannabidiol, non-psychoactive component of marijuana, on the infarction in a 4 h mouse middle cerebral artery (MCA) occlusion model in comparison with Delta(9)-tetrahydrocannabinol (Delta(9)-THC).

Both pre- and post-ischemic treatment with cannabidiol resulted in potent and long-lasting neuroprotection, whereas only pre-ischemic treatment with Delta(9)-THC reduced the infarction.

Unlike Delta(9)-THC, cannabidiol did not affect the excess release of glutamate in the cortex after occlusion.

Cannabidiol suppressed the decrease in cerebral blood flow by the failure of cerebral microcirculation after reperfusion and inhibited MPO activity in neutrophils.

Furthermore, the number of MPO-immunopositive cells was reduced in the ipsilateral hemisphere in cannabidiol-treated group.

Cannabidiol provides potent and long-lasting neuroprotection through an anti-inflammatory CB(1) receptor-independent mechanism, suggesting that cannabidiol will have a palliative action and open new therapeutic possibilities for treating cerebrovascular disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/17437545

Cannabis compound benefits blood vessels

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This computer rendition shows how fatty deposits can narrow blood vessels.

“Low dose helps combat formation of arterial blockages.

A compound derived from the cannabis plant protects blood vessels from dangerous clogging, a study of mice has shown.

The compound, called delta-9-tetrahydrocannabinol (THC), combats the blood-vessel disease atherosclerosis in mice.

The discovery could lead to new drugs to ward off heart disease and stroke.”

http://www.nature.com/news/2005/050404/full/news050404-7.html

 

The CB1 Antagonist, SR141716A, Is Protective in Permanent Photothrombotic Cerebral Ischemia.

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“Modulation of the endocannabinoid system has been shown to have a significant impact on outcomes in animal models of stroke.

We have previously reported a protective effect of the CB1 antagonist, SR141716A, in a transient reperfusion mouse model of cerebral ischemia. This protective effect was in part mediated by activation of the 5HT1A receptor.

Here we have examined its effect in a mouse model of permanent ischemia induced by photoinjury.

The CB1 antagonist was found to be protective in this model.

As was the case following transient ischemia reperfusion, SR141716A (5mg/kg) resulted in smaller infarct fractions and stroke volumes when utilized both as a pretreatment and as a post-treatment. In contrast to the effect in a transient ischemia model, the pretreatment effect did not depend on the 5HT1A receptor.

Neurological function correlated favorably to the reduction in stroke size when SR141716A was given as a pretreatment.

With the incidence of stroke predicted to rise in parallel with an ever aging population, understanding mechanisms underlying ischemia and therapeutics remains a paramount goal of research.”

http://www.ncbi.nlm.nih.gov/pubmed/27453059

Expression of the Endocannabinoid Receptor 1 in Human Stroke: An Autoptic Study.

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“Stroke is one of the leading causes of disability and death in the world.

The endocannabinoid (eCB) system is upregulated in several neurological diseases including stroke. A previous animal study demonstrated an increased expression of the endocannabinoid receptor 1 (CB1R) in the penumbra area surrounding the ischemic core, suggesting a crucial role in inflammation/reperfusion after stroke. Regarding the localization of CB1/CB2 receptors, animal studies showed that cortical neurons, activated microglia, and astroglia are involved. Our aim was to evaluate the cerebral expression of CB1R in the ischemic brain areas of 9 patients who died due to acute cerebral infarction in the middle cerebral artery territory.

METHODS:

The cerebral autoptic tissue was collected within 48 hours since death. Ischemic and contralateral normal-appearing areas were identified. After tissue preprocessing, 4-µm-thick cerebral sections were incubated with the primary CB1R antibodies (Cayman Chemical Company, Ann Arbor, MI). Thereafter, all cerebral sections were hematoxylin treated. In each section, the total cell number and CB1R-positive cells were counted and the CB1R-positive cell count ratio was calculated. For statistical analysis, Student’s t-test was used.

RESULTS:

In normal tissue, CB1R-positive neurons were the majority; a few non-neuronal cells expressed CB1R. In the ischemic areas, a few neurons were detectable. A significant increase in total CB1R staining was found in the ischemic regions compared to contralateral areas.

CONCLUSIONS:

We found an increase in CB1R expression in the ischemic region (neuronal and non-neuronal cell staining), suggesting the inflammatory reaction to the ischemic insult. Whether such response might mediate neuroprotective actions or excitotoxicity-related detrimental effects is still unclear.”

http://www.ncbi.nlm.nih.gov/pubmed/27425766

Cannabidiol protects an in vitro model of the blood-brain barrier from oxygen-glucose deprivation via PPARγ and 5-HT1A receptors.

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“In vivo and in vitro studies have demonstrated a protective effect of cannabidiol (CBD) in reducing infarct size in stroke models and against epithelial barrier damage in numerous disease models.

We aimed to investigate whether CBD also affects blood-brain barrier (BBB) permeability following ischaemia.

CONCLUSIONS AND IMPLICATIONS:

These data suggest that preventing permeability changes at the BBB could represent an as yet unrecognized mechanism of CBD-induced neuroprotection in ischaemic stroke, a mechanism mediated by activation of PPARγ and 5-HT1A receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/26497782

Neuroprotective effect of endogenous cannabinoids on ischemic brain injury induced by the excess microglia-mediated inflammation.

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“Increasing evidence has demonstrated the role of endogenous cannabinoids system (ECS) on protecting brain injury caused by ischemia (IMI). Papers reported that microglia-mediated inflammation has become one of the most pivotal mechanisms for IMI. This study was aimed to investigate the potential roles of ECS on neuron protection under microglia-mediated inflammation. Inflammatory cytokines level both in vitro (BV-2 cells) and in vivo (brain tissue from constructed IMI model and brain-isolated microglia) was detected. ECS levels were detected, and its effects on inflammations was also analyzed. Influence of microglia-mediated inflammation on neuron injury was analyzed. Moreover, the effects of ECS on protecting neuron injury were also analyzed. Our results showed that the levels of inflammatory cytokines including TNFα and IL-1β were higher while IKBα was lower in IMI model brain tissue, brain-isolated microglia and BV-2 cells compared to the control. Inflammation was activated in microglia, as well as the activation of ECS characterized by the increasing level of AEA and 2-AG. Furthermore, the activated microglia-mediated self-inflammation performed harmful influence on neurons via suppressing cell viability and inducing apoptosis. Moreover, ECS functioned as a protector on neuron injury though promoting cell proliferation and suppressing cell apoptosis which were caused by the activated BV-2 cells (LPS induced for 3 h). Our data suggested that ECS may play certain neuroprotective effects on microglia-mediated inflammations-induced IMI through anti-inflammatory function.”

http://www.ncbi.nlm.nih.gov/pubmed/27398146

Endocannabionoid System in Neurological Disorders.

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“Several studies support the evidence that the endocannabinoid system and cannabimimetic drugs might have therapeutic potential in numerous pathologies. These pathologies range from neurological disorders, atherosclerosis, stroke, cancer to obesity/metabolic syndrome and others.

In this paper we review the endocannabinoid system signaling and its alteration in neurodegenerative disorders like multiple sclerosis, Alzheimer’s disease, Parkinson’s disease and Huntington’s disease and discuss the main findings about the use of cannabinoids in the therapy of these pathologies.

Despite different etiologies, neurodegenerative disorders exhibit similar mechanisms like neuro-inflammation, excitotoxicity, deregulation of intercellular communication, mitochondrial dysfunction and disruption of brain tissue homeostasis.

Current treatments ameliorate the symptoms but are not curative.

Interfering with the endocannabinoid signaling might be a valid therapeutic option in neuro-degeneration.

To this aim, pharmacological intervention to modulate the endocannabinoid system and the use of natural and synthetic cannabimimetic drugs have been assessed. CB1 and CB2 receptor signaling contributes to the control of Ca2+ homeostasis, trophic support, mitochondrial activity, and inflammatory conditions.

Several studies and patents suggest that the endocannabinoid system has neuro-protective properties and might be a target in neurodegenerative diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/27364363

Cannabimimetic Drugs: Recent Patents in Central Nervous System Disorders.

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“Agents acting via cannabinoid receptors have been widely developed; starting from the chemical structure of phytocannabinoids isolated from cannabis sativa plant, specific and selective compounds of these receptors have been produced ranging from partial to full agonists and /or antagonists endowed with different potency.

The enhanced interest on developing such classes of drugs is due to the beneficial properties widely reported by both anecdotal reports and scientific studies describing the potential medicinal use of cannabinoids and their derivatives in numerous pathological conditions in both in vitro and in vivo models.

The use of these drugs has been found to be of benefit in a wide number of neurological and neuropsychiatric disorders, and in many other diseases ranging from cancer, atherosclerosis, stroke, hypertension, inflammatory related disorders, and autoimmune diseases, just to mention some.

In particular, being the cannabinoid CB1 receptor a central receptor expressed by neurons of the central nervous system, the attention for the treatment of neurological diseases has been mainly focused on compounds acting via this receptor, however some of these compounds has been showed to act by alternative pathways in some cases unrelated to CB1 receptors.

Nonetheless, endocannabinoids are potent regulators of the synaptic function in the central nervous system and their levels are modulated in neurological diseases.

In this study, we focused on endocannabinoid mechanism of action in neuronal signaling and on cannabimimetic drug potential application in neurological disorders.

Finally, novel patents on cannabis-based drugs with applicability in central nervous system disorders are highlighted, to suggest future potential therapeutic utility of derivatives of this ancient plant.”

http://www.ncbi.nlm.nih.gov/pubmed/27334611

Hypothermia induced by delta9-tetrahydrocannabinol in rats with electrolytic lesions of preoptic region.

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“The preoptic region (POR) is a primary central site for thermoregulation. Bilateral lesions of POR disrupt thermoregulation, and in rats, produce a characteristic syndrome including hyperthermia.

delta9-Tetrahydrocannabinol (delta9-THC), a potent hypothermic agent, appears to mediate this effect via some central mechanism. The studies reported here suggest that delta9-THC induces hypothermia at a site other than POR.

These data demonstrate that delta9-THC is able to induce a hypothermic response in rats whose body temperatures were elevated by POR ablation. Although delta9-THC does not appear to act primarily at POR to induce hypothermia, it is evident than an intact POR plays a role in modifying the duration and magnitude of delta9-THC induced hypothermia.”

http://www.ncbi.nlm.nih.gov/pubmed/996043