Cannabinoids in the Brain: New Vistas on an Old Dilemma

“The use of cannabis as a therapeutic and recreational substance goes back to thousands of years throughout Asia, Middle East, Southern Africa, and South America.

The discovery of Δ-9-tetrahydrocannabinol (Δ9-THC) by Mechoulam and Gaoni in the midsixties as the major psychoactive constituent of cannabis sativa led to another important discovery, namely, its specific binding site that was isolated and cloned in 1990. This first cannabinoid receptor was coined CB1R and triggered a number of investigations on its expression, localization, and function within the body tissue including the brain, in various species. This was followed by the discovery in 1992 of the first endocannabinoid (eCB), anandamide, followed by another cannabinoid receptor CB2R and a second endocannabinoid called 2-arachidonoylglycerol (2-AG). Later on, some of the enzymes responsible for their synthesis (N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD); diacylglycerol lipase (DAGL)) and degradation (fatty acid amide hydrolase (FAAH); monoacylglycerol lipase (MAGL)) were identified.

Studies on the expression and localization of the cannabinoid receptors in the brain have burgeoned in the last decade and have furnished valuable data on their putative involvement in various sensory-motor and cognitive functions in diverse animal species, including Man. These studies have recently received substantial attention from pharmaceutical companies as a potential source for novel treatments. Additionally, the dilemma of legalizing the use of cannabis in some countries makes the investigation on cannabinoid systems more momentous. This special issue is therefore timely and brings historical and groundbreaking novel research on the role of these cannabinoid receptors in the mammalian central nervous system (CNS).

We hope that the collected papers in this special issue will contribute to the understanding of the various mechanisms involved in the functions of the endocannabinoid system and the development of new pharmaceutical tools to treat visual disorders.”

http://www.hindawi.com/journals/np/2016/9146713/

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

Cannabinoid Receptors CB1 and CB2 Modulate the Electroretinographic Waves in Vervet Monkeys.

“The expression patterns of the cannabinoid receptor type 1 (CB1R) and the cannabinoid receptor type 2 (CB2R) are well documented in rodents and primates.

In vervet monkeys, CB1R is present in the retinal neurons (photoreceptors, horizontal cells, bipolar cells, amacrine cells, and ganglion cells) and CB2R is exclusively found in the retinal glia (Müller cells). However, the role of these cannabinoid receptors in normal primate retinal function remains elusive.

Using full-field electroretinography in adult vervet monkeys, we recorded changes in neural activity following the blockade of CB1R and CB2R by the intravitreal administration of their antagonists (AM251 and AM630, resp.) in photopic and scotopic conditions.

Our results show that AM251 increases the photopic a-wave amplitude at high flash intensities, whereas AM630 increases the amplitude of both the photopic a- and b-waves.In scotopic conditions, both blockers increased the b-wave amplitude but did not change the a-wave amplitude.

These findings suggest an important role of CB1R and CB2R in primate retinal function.”

http://www.ncbi.nlm.nih.gov/pubmed/27069692

The Endocannabinoid System as a Therapeutic Target in Glaucoma.

“Glaucoma is an irreversible blinding eye disease which produces progressive retinal ganglion cell (RGC) loss. Intraocular pressure (IOP) is currently the only modifiable risk factor, and lowering IOP results in reduced risk of progression of the disorder.

The endocannabinoid system (ECS) has attracted considerable attention as a potential target for the treatment of glaucoma, largely due to the observed IOP lowering effects seen after administration of exogenous cannabinoids.

However, recent evidence has suggested that modulation of the ECS may also be neuroprotective.

This paper will review the use of cannabinoids in glaucoma, presenting pertinent information regarding the pathophysiology of glaucoma and how alterations in cannabinoid signalling may contribute to glaucoma pathology.

Additionally, the mechanisms and potential for the use of cannabinoids and other novel agents that target the endocannabinoid system in the treatment of glaucoma will be discussed.”

http://www.ncbi.nlm.nih.gov/pubmed/26881140

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

Endogenous and Synthetic Cannabinoids as Therapeutics in Retinal Disease.

“The functional significance of cannabinoids in ocular physiology and disease has been reported some decades ago.

In the early 1970s, subjects who smoked Cannabis sativa developed lower intraocular pressure (IOP). This led to the isolation of phytocannabinoids from this plant and the study of their therapeutic effects in glaucoma.

The main treatment of this disease to date involves the administration of drugs mediating either the decrease of aqueous humour synthesis or the increase of its outflow and thus reduces IOP. However, the reduction of IOP is not sufficient to prevent visual field loss.

Retinal diseases, such as glaucoma and diabetic retinopathy, have been defined as neurodegenerative diseases and characterized by ischemia-induced excitotoxicity and loss of retinal neurons. Therefore, new therapeutic strategies must be applied in order to target retinal cell death, reduction of visual acuity, and blindness.

The aim of the present review is to address the neuroprotective and therapeutic potential of cannabinoids in retinal disease.”

http://www.ncbi.nlm.nih.gov/pubmed/26881135

The Endocannabinoid System in the Retina: From Physiology to Practical and Therapeutic Applications.

“Cannabis is one of the most prevalent drugs used in industrialized countries.

The main effects of Cannabis are mediated by two major exogenouscannabinoids: ∆9-tetrahydroxycannabinol and cannabidiol. They act on specific endocannabinoid receptors, especially types 1 and 2.

Mammals are endowed with a functional cannabinoid system including cannabinoid receptors, ligands, and enzymes.

This endocannabinoid signaling pathway is involved in both physiological and pathophysiological conditions with a main role in the biology of the central nervous system.

As the retina is a part of the central nervous system due to its embryonic origin, we aim at providing the relevance of studying the endocannabinoid system in the retina. Here, we review the distribution of the cannabinoid receptors, ligands, and enzymes in the retina and focus on the role of the cannabinoid system in retinal neurobiology.

This review describes the presence of the cannabinoid system in critical stages of retinal processing and its broad involvement in retinal neurotransmission, neuroplasticity, and neuroprotection.

Accordingly, we support the use of synthetic cannabinoids as new neuroprotective drugs to prevent and treat retinal diseases.

Finally, we argue for the relevance of functional retinal measures in cannabis users to evaluate the impact of cannabis use on human retinal processing.”

http://www.ncbi.nlm.nih.gov/pubmed/26881099

Cannabinoids for treatment of glaucoma.

“The purpose of this article is to review the current status of cannabis in the treatment of glaucoma, including the greater availability of marijuana in the USA.

The pharmacology of marijuana and its effect on intraocular pressure has not changed since the research in the 1970s and 1980s.

Marijuana is an effective ocular hypotensive agent.

However, cardiovascular and neurological effects are observed at the same dose, and may theoretically reduce the beneficial effect of lowering intraocular pressure by reducing ocular blood flow. The clinician must be cognizant of this potential in diagnosis, prognosis, and therapy.”

http://www.ncbi.nlm.nih.gov/pubmed/26840343

Expression and Function of the Endocannabinoid System in the Retina and the Visual Brain.

“Endocannabinoids are important retrograde modulators of synaptic transmission throughout the nervous system.

Cannabinoid receptors are seven transmembrane G-protein coupled receptors favoring Gi/o protein. They are known to play an important role in various processes, including metabolic regulation, craving, pain, anxiety, and immune function.

In the last decade, there has been a growing interest for endocannabinoids in the retina and their role in visual processing.

The purpose of this review is to characterize the expression and physiological functions of the endocannabinoid system in the visual system, from the retina to the primary visual cortex, with a main interest regarding the retina, which is the best-described area in this system so far.

It will show that the endocannabinoid system is widely present in the retina, mostly in the through pathway where it can modulate neurotransmitter release and ion channel activity, although some evidence also indicates possible mechanisms via amacrine, horizontal, and Müller cells.

The presence of multiple endocannabinoid ligands, synthesizing and catabolizing enzymes, and receptors highlights various pharmacological targets for novel therapeutic application to retinal diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/26839718

Seeing over the horizon – targeting the endocannabinoid system for the treatment of ocular disease.

“The observation that marijuana reduces intraocular pressure was made by Hepler and Frank in the 1970s. Since then, there has been a significant body of work investigating cannabinoids for their potential use as therapeutics.

To date, no endocannabinoid system (ECS)-modulating drug has been approved for clinical use in the eye; however, recent advances in our understanding of the ECS, as well as new pharmacological tools, has renewed interest in the development of ocular ECS-based therapeutics.

This review summarizes the current state-of-affairs for the use of ECS-modulating drugs for the treatment of glaucoma and ocular inflammatory and ischemic disease.”

http://www.ncbi.nlm.nih.gov/pubmed/26565550

[CANNABIS AND GLAUCOMA: AN ANCIENT LEGEND OR A NOVEL THERAPEUTIC HORIZON?].

“Glaucoma causes damage to the optic nerve and compromises the visual field. The main risk factor of the disease is the level of the intra-ocular pressure. Therapeutic options include medical and surgical treatment, aimed to lower the intra-ocular pressure.

Consumption of the cannabis plant (Cannabis Satival has been known since ancient times. It can be consumed orally, topically, intra-venous or by inhalation.

The main active ingredient of cannabis is THC (Tetra-Hydro-Cannabinol). One of THC’s reported effects is the reduction of intra-ocular pressure.

Several studies have demonstrated temporary intra-ocular pressure decrease in both healthy subjects and glaucoma patients following topical application or systemic consumption.

Cannabis may be considered as a therapeutic option in glaucoma.”

http://www.ncbi.nlm.nih.gov/pubmed/26281086