Pharmacological hypothermia: a potential for future stroke therapy?

“Mild physical hypothermia after stroke has been associated with positive outcomes.

Pharmacologically induced hypothermia has been explored as a possible treatment option following stroke in animal models.

Currently, there are eight classes of pharmacological agents/agonists with hypothermic effects affecting a multitude of systems including cannabinoid, opioid, transient receptor potential vanilloid 1 (TRPV1), neurotensin, thyroxine derivatives, dopamine, gas, and adenosine derivatives.

This review offers the opinion that these agents may be useful in combination therapies with physical hypothermia to achieve faster and more stable temperature control in hypothermia.”

http://www.ncbi.nlm.nih.gov/pubmed/27320243

No Link Between Marijuana Use and Stroke Risk

Medpage Today

“There was no evidence that marijuana use was associated with an increased risk of ischemic stroke in adolescents and young adults, a researcher said here.

“Our data did not support” a link between the drug and stroke risk”

http://www.medpagetoday.com/meetingcoverage/aan/45577

“Cannabinoids in experimental stroke: a systematic review and meta-analysis. Cannabinoids (CBs) show promise as neuroprotectants with some agents already licensed in humans for other conditions. Cannabinoids reduced infarct volume in transient and permanent ischemia and in all subclasses: endocannabinoids, CB1/CB2 ligands, CB2 ligands, cannabidiol, Δ9-tetrahydrocannabinol, and HU-211. Overall, CBs significantly reduced infarct volume and improve functional outcome in experimental stroke.” http://www.ncbi.nlm.nih.gov/pubmed/25492113

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

Phytocannabinoids and cannabimimetic drugs: recent patents in central nervous system disorders.

“Starting from the chemical structure of phytocannabinoids, isolated from Cannabis sativa plant, research groups designed numerous cannabimimetic drugs.

These compounds according to their activities can be partial, full agonists and antagonists of cannabinoid receptors.

Anecdotal reports and scientific studies described beneficial properties of cannabinoids and their derivatives in several pathological conditions like neurological and neuropsychiatric disorders, and in many other diseases ranging from cancer, atherosclerosis, stroke, hypertension, inflammatory related disorders, and autoimmune diseases.

The cannabinoid CB1 receptor was considered particularly interesting for therapeutic approaches in neurological diseases, because primarily expressed by neurons of the central nervous system. In many experimental models, these drugs act via this receptor, however, CB1 receptor independent mechanisms have been also described. Furthermore, endogenous ligands of cannabinoid receptors, the endocannabinoids, are potent modulators of the synaptic function in the brain. In neurological diseases, numerous studies reported modulation of the levels of endocannabinoids according to the phase of the disease and its progression.

CONCLUSIONS:

Finally, although the study of the mechanisms of action of these compounds is still unsolved, many reports and patents strongly suggest therapeutic potential of these compounds in neurological diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/27184693

Stimulated CB1 Cannabinoid Receptor Inducing Ischemic Tolerance and Protecting Neuron from Cerebral Ischemia.

“Anandamide system is mainly made up of cannabinoid receptors, their endogenous ligands and some related enzymes. Activation of the system mediates various molecular events, thereafter leading to vasodilation, bradycardia and anti-inflammation.

The stimulated cannabinoid receptors may take part in protection of endothelial cells from injury and therefore can be potential targets in therapy for some diseases, especially cardio or cerebral vascular disturbances.

Cerebral ischemia is a deadly disease that modern people have to face and will probably face for a long period of time. Ischemic tolerance has the protective effect of brain as an endogenous event in cerebral ischemia, in which variety of inducers such as transient cerebral ischemia, hypoxia, hypothermia and drug agents are involved.

Most of cannabinoid 1 receptors (CB1Rs), a member in G protein-coupled receptor family, exist in central nervous systems.

Mechanism of neuroprotection mediated by the receptor is considered through facilitating neurotransmitter release and regulating other molecular events. In this review, advance of the neuroprotection against cerebral ischemia and the mechanism of the action are overviewed.”

http://www.ncbi.nlm.nih.gov/pubmed/27142423

“Cerebral ischemia or brain ischemia, is a condition that occurs when there isn’t enough blood flow to the brain to meet metabolic demand. This leads to limited oxygen supply or cerebral hypoxia and leads to the death of brain tissue, cerebral infarction, or ischemic stroke. It is a sub-type of stroke along with subarachnoid hemorrhage and intracerebral hemorrhage. There are two kinds of ischemia: focal ischemia: confined to a specific region of the brain; global ischemia: encompasses wide areas of brain tissue.”  http://www.columbianeurosurgery.org/conditions/cerebral-ischemia/

ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

Image result for Curr Clin Pharmacol.

“Cannabis sativa is also popularly known as marijuana. It is being cultivated and used by man for recreational and medicinal purposes from many centuries.

Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries.

The research of drugs acting on endocannabinoid system has seen many ups and down in recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve “protective role” in many medical conditions.

Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and Tourette’s syndrome could possibly be treated by drugs modulating endocannabinoid system.

Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008.

Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite of some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish the therapeutic targets for both cannabinoid receptor agonists and antagonists.

One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that acts selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted.

Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids.

In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as “protective” and “disease inducing substance”, time-dependent changes in the expression of cannabinoid receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27086601

Experimental cannabinoid 2 receptor inhibition in CNS injury-induced immunodeficiency syndrome.

“Severe central nervous system (CNS) injury, such as stroke, traumatic brain injury or spinal cord injury, is known to increase susceptibility to infections. The increased susceptibility to infection is due to an impaired immune response and is referred to as CNS injury-induced immune deficiency syndrome (CIDS).

The cannabinoid 2 receptor (CB2 R) on immune cells presents a potential therapeutic target in CIDS as activation of this receptor has been shown to be involved in immunosuppression.

Our findings suggest that inhibition of CB2 R signaling in animals with CIDS challenged with endotoxin restored peripheral leukocyte recruitment without detrimental impact on infarct size.

We conclude that the endocannabinoid system is involved in the impaired immune response following CNS injury and future studies should further explore the CB2 R pathway in order to develop novel therapies for CIDS.”

http://www.ncbi.nlm.nih.gov/pubmed/26999797

The molecular mechanism and effect of cannabinoid-2 receptor agonist on the blood-spinal cord barrier permeability induced by ischemia-reperfusion injury.

“Previous studies have shown that modulation of the receptor-mediated endocannabinoid system during ischemia injury can induce potent neuroprotective effects.

However, little is known about whether cannabinoid-2 (CB2) receptor agonist would produce a protective effect on blood-spinal cord barrier (BSCB) during ischemia.

Taken together, all of these results suggested that JWH-015 might regulate the BSCB permeability and this effect could be related to paracellular and transcellular pathway.

And pharmacological CB2R ligands offer a new strategy for BSCB protection during ischemic injury.”

http://www.ncbi.nlm.nih.gov/pubmed/26835555

Prior Cannabis Use Is Associated with Outcome after Intracerebral Hemorrhage.

“The purpose of this study was to determine the implications of cannabis use in intracerebral hemorrhage (ICH) patients.

CONCLUSION:

In this multinational cohort, cannabis use was discovered in nearly 10% of patients with spontaneous ICH. Although there was no relationship between cannabis use and specific ICH characteristics, CB+ patients had milder ICH presentation and less disability at discharge.”

http://www.ncbi.nlm.nih.gov/pubmed/26820826

Role of hypothalamic cannabinoid receptors in post-stroke depression in rats.

“One of the most common psychological consequences of stroke is post-stroke depression (PSD). While more than 30 percent of stroke patients eventually develop PSD, the neurobiological mechanisms underlying such a phenomenon have not been well investigated.

Given the critical involvement of hypothalamic-pituitary-adrenal axis and endocannabinoid system in response to stressful stimuli, we evaluated the hypothesis that cannabinoid receptors in the hypothalamus are critical for modulation of post-stroke depression-like behaviors in rats.

Taken together, these results suggest that decreased CB1 receptor expression is likely associated with the development of post-stroke depression, and CB2 receptor may be a potential therapeutic target for the treatment post-stroke depressive disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26778127

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

“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.

These data suggest that activity at the BBB could represent an as yet unrecognised mechanism of CBD-induced neuroprotection in ischaemic stroke, mediated by PPARγ and 5-HT1A .”

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