Category Archives: Brain Trauma

Cannabinoid Type 2 Receptors Mediate a Cell Type-Specific Plasticity in the Hippocampus

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“Endocannabinoids (eCBs) exert major control over neuronal activity by activating cannabinoid receptors (CBRs).

The functionality of the eCB system is primarily ascribed to the well-documented retrograde activation of presynaptic CB1Rs.

We find that action potential-driven eCB release leads to a long-lasting membrane potential hyperpolarization in hippocampal principal cells that is independent of CB1Rs.

The hyperpolarization, which is specific to CA3 and CA2 pyramidal cells (PCs), depends on the activation of neuronal CB2Rs, as shown by a combined pharmacogenetic and immunohistochemical approach.

Upon activation, they modulate the activity of the sodium-bicarbonate co-transporter, leading to a hyperpolarization of the neuron.

CB2R activation occurred in a purely self-regulatory manner, robustly altered the input/output function of CA3 PCs, and modulated gamma oscillations in vivo.

To conclude, we describe a cell type-specific plasticity mechanism in the hippocampus that provides evidence for the neuronal expression of CB2Rs and emphasizes their importance in basic neuronal transmission.”

http://www.cell.com/neuron/abstract/S0896-6273(16)30025-3

ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

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“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

Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways.

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“Emerging evidence suggests a complex interplay between the endocannabinoid system, omega-3 fatty acids and the immune system in the promotion of brain self-repair.

However, it is unknown if all omega-3 fatty acids elicit similar effects on adult neurogenesis and if such effects are mediated or regulated by interactions with the endocannabinoid system. This study investigated the effects of DHA and EPA on neural stem cell (NSC) fate and the role of the endocannabinoid signalling pathways in these effects.

EPA, but not DHA, significantly increased proliferation of NSCs compared to controls, an effect associated with enhanced levels of the endocannabinoid 2-arachidonylglycerol (2-AG) and p-p38 MAPK, effects attenuated by pre-treatment with CB1 (AM251) or CB2 (AM630) receptor antagonists.

Furthermore, in NSCs derived from IL-1β deficient mice, EPA significantly decreased proliferation and p-p38 MAPK levels compared to controls, suggesting a key role for IL-1β signalling in the effects observed. Although DHA similarly increased 2-AG levels in wild-type NSCs, there was no concomitant increase in proliferation or p-p38 MAPK activity. In addition, in NSCs from IL-1β deficient mice, DHA significantly increased proliferation without effects on p-P38 MAPK, suggesting effects of DHA are mediated via alternative signalling pathways.

These results provide crucial new insights into the divergent effects of EPA and DHA in regulating NSC proliferation and the pathways involved, and highlight the therapeutic potential of their interplay with endocannabinoid signalling in brain repair.”

http://www.ncbi.nlm.nih.gov/pubmed/27044662

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

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“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

Plant-derived, synthetic and endogenous cannabinoids as neuroprotective agents. Non-psychoactive cannabinoids, ‘entourage’ compounds and inhibitors of N-acyl ethanolamine breakdown as therapeutic strategies to avoid pyschotropic effects.

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“There is good evidence that plant-derived and synthetic cannabinoids possess neuroprotective properties.

These compounds, as a result of effects upon CB(1) cannabinoid receptors, reduce the release of glutamate, and in addition reduce the influx of calcium following NMDA receptor activation.

The major obstacle to the therapeutic utilization of such compounds are their psychotropic effects, which are also brought about by actions on CB(1) receptors. However, synthesis of the endogenous cannabinoids anandamide and 2-arachidonoylglycerol, which also have neuroprotective properties, are increased under conditions of severe inflammation and ischemia, raising the possibility that compounds that prevent their metabolism may be of therapeutic utility without having the drawback of producing psychotropic effects.

In this review, the evidence indicating neuroprotective actions of plant-derived, synthetic and endogenous cannabinoids is presented. In addition, the pharmacological properties of endogenous anandamide-related compounds that are not active upon cannabinoid receptors, but which are also produced during conditions of severe inflammation and ischemia and may contribute to a neuroprotective action are reviewed.”

http://www.ncbi.nlm.nih.gov/pubmed/12505646

Endocannabinoid system in the brain…and elsewhere.

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“The endocannabinoid system is a complex system with endogenous ligands, synthesis and transport processes, specific receptors (CB1 and CB2) and intracellular degrading enzymes.

It is widely distributed in the central nervous system, but also in peripheral organs.

In the brain, endocannabinoids and CB1 receptors are almost ubiquitous and play a role in synaptic plasticity: they modulate, through an inhibitory retrograde action, the release of classical neurotransmitters such as amines, acetylcholine or amino acids.

They may exert a neuroprotective effect, but are also involved in appetite and alcohol/drug dependence.

At the periphery, they are present (and overexpressed in case of abdominal obesity) in various organs involved in energy control and metabolic regulation.

Furthermore, CB2 receptors are also present in the brain, although less numerous than CB1 receptors.

They could attenuate pain and also be neuroprotective.

Selective agonists, antagonists and inverse agonists of CB1 and CB2 receptors are currently developed and open new interesting therapeutic perspectives.”

http://www.ncbi.nlm.nih.gov/pubmed/18669206

Functions of the CB1 and CB 2 receptors in neuroprotection at the level of the blood-brain barrier.

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“The cannabinoid (CB) receptors are the main targets of the cannabinoids, which include plant cannabinoids, endocannabinoids and synthetic cannabinoids. Over the last few years, accumulated evidence has suggested a role of the CB receptors in neuroprotection.

The blood-brain barrier (BBB) is an important brain structure that is essential for neuroprotection. A link between the CB receptors and the BBB is thus likely, but this possible connection has only recently gained attention.

Cannabinoids and the BBB share the same mechanisms of neuroprotection and both protect against excitotoxicity (CB1), cell death (CB1), inflammation (CB2) and oxidative stress (possibly CB independent)-all processes that also damage the BBB.

Several examples of CB-mediated protection of the BBB have been found, such as inhibition of leukocyte influx and induction of amyloid beta efflux across the BBB.

Moreover, the CB receptors were shown to improve BBB integrity, particularly by restoring the tightness of the tight junctions. This review demonstrated that both CB receptors are able to restore the BBB and neuroprotection, but much uncertainty about the underlying signaling cascades still exists and further investigation is needed.”

http://www.ncbi.nlm.nih.gov/pubmed/24929655

Neuroprotective effects of the synthetic cannabinoid HU-210 in primary cortical neurons are mediated by phosphatidylinositol 3-kinase/AKT signaling.

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“Cannabinoids (CBs) are neuroprotective in vivo and in vitro.

…the PI 3-K/AKT signaling pathway mediates the neuroprotective effect of exogenous cannabinoids in primary CNS neurons.”

http://www.ncbi.nlm.nih.gov/pubmed/15607953

Cannabidiol, neuroprotection and neuropsychiatric disorders.

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“Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid derived from Cannabis sativa.

It has possible therapeutic effects over a broad range of neuropsychiatric disorders.

CBD attenuates brain damage associated with neurodegenerative and/or ischemic conditions.

It also has positive effects on attenuating psychotic-, anxiety- and depressive-like behaviors.

Moreover, CBD affects synaptic plasticity and facilitates neurogenesis.

The mechanisms of these effects are still not entirely clear but seem to involve multiple pharmacological targets.

In the present review, we summarized the main biochemical and molecular mechanisms that have been associated with the therapeutic effects of CBD, focusing on their relevance to brain function, neuroprotection and neuropsychiatric disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26845349

Prior Cannabis Use Is Associated with Outcome after Intracerebral Hemorrhage.

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“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