Category Archives: Endocannabinoid System

Increasing levels of the endocannabinoid 2-AG is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease.

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“Parkinson’s disease (PD) is a common chronic neurodegenerative disorder, usually of idiopathic origin. Symptoms including tremor, bradykinesia, rigidity and postural instability are caused by the progressive loss of dopaminergic neurons in the nigrostriatal region of the brain.

Symptomatic therapies are available but no treatment slows or prevents the loss of neurons.

Neuroinflammation has been implicated in its pathogenesis.

To this end, the present study utilises the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to reproduce the pattern of cell death evident in PD patients.

Herein, the role of a potential regulator of an immune response, the endocannabinoid system (ECS), is investigated.

The most prevalent endocannabinoid, 2-arachidonoylglycerol (2-AG) (3 and 5mg/kg), was added exogenously and its enzymatic degradation inhibited to provide protection against MPTP-induced cell death.

Furthermore, the addition of DFU (25mg/kg), a selective inhibitor of inflammatory mediator cyclooxygenase-2 (COX-2), potentiated these effects.

Levels of 2-AG were shown to be upregulated in a time- and region-specific manner following MPTP administration, indicating that the ECS represents a natural defence mechanism against inflammation, potentiation of which could provide therapeutic benefits.

The results expand the current understanding of the role that this signalling system has and its potential influence in PD.”

Age-related changes in the endocannabinoid system in the mouse hippocampus.

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“Previous studies have demonstrated that the endocannabinoid system significantly influences the progression of brain ageing, and the hippocampus is one of the brain regions most vulnerable to ageing and neurodegeneration.

We have further examined age-related changes in the hippocampalendocannabinoid system by measuring the levels of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in young and old mice from two different mouse strains.

We found a decrease in 2-AG but not AEA levels in aged mice.

In order to identify the cause for 2-AG level changes, we investigated the levels of several enzymes that contribute to synthesis and degradation of 2-AG in the hippocampus.

We found a selective decrease in DAGLα mRNA and protein levels as well as an elevated MAGL activity during ageing.

We hypothesize that the observed decrease of 2-AG levels is probably caused by changes in DAGLα expression and MAGL activity.

This finding can contribute to the existing knowledge about the processes underlying selective vulnerability of the hippocampus to ageing and age-related neurodegeneration.”

http://www.ncbi.nlm.nih.gov/pubmed/26278494

Effect of anandamide on endometrial adenocarcinoma (Ishikawa) cell numbers: implications for endometrial cancer therapy.

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“We have previously shown that patients with endometrial carcinoma express elevated concentrations of the endocannabinoid, anandamide (AEA), in both their plasma and their endometrial tissue and that the endometrial carcinoma cell line, Ishikawa, contains the receptors to which AEA binds.

Several studies have reported that human and rodent cancer cell lines die in response to high AEA concentrations.

The incidence of endometrial carcinoma continues to escalate and, although surgical treatment has improved, morbidity and mortality rates have not. A move towards a novel non-surgical therapeutic option is thus required, and the endocannabinoid system provides a good candidate target.

We aimed to investigate the effects of AEA on the survival and proliferation of an endometrial carcinoma cell model.

Our results show that AEA induces a decrease in Ishikawa cell number probably through inhibition of cell proliferation rather than cell death.

These data suggest that the increased plasma and tissue AEA concentrations observed in patients with endometrial cancer is a counter mechanism against further cancer growth and points to the endocannabinoid system as a potentially new therapeutic target.”

http://www.ncbi.nlm.nih.gov/pubmed/26312842

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60335-X/fulltext

Cannabinoids and Schizophrenia: Risks and Therapeutic Potential.

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“The endocannabinoid system has been implicated in psychosis both related and unrelated to cannabis exposure, and studying this system holds potential to increase understanding of the pathophysiology of schizophrenia.

Anandamide signaling in the central nervous system may be particularly important.

Δ9-Tetrahydrocannabinol in cannabis can cause symptoms of schizophrenia when acutely administered, and cannabidiol (CBD), another compound in cannabis, can counter many of these effects.

CBD may have therapeutic potential for the treatment of psychosis following cannabis use, as well as schizophrenia, possibly with better tolerability than current antipsychotic treatments. CBD may also have anti-inflammatory and neuroprotective properties.

Establishing the role of CBD and other CBD-based compounds in treating psychotic disorders will require further human research.”

http://www.ncbi.nlm.nih.gov/pubmed/26311150

http://www.thctotalhealthcare.com/category/schizophrenia/

Pregnenolone can protect the brain from cannabis intoxication.

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“Pregnenolone is considered the inactive precursor of all steroid hormones, and its potential functional effects have been largely uninvestigated.

The administration of the main active principle of Cannabis sativa (marijuana), Δ(9)-tetrahydrocannabinol (THC), substantially increases the synthesis of pregnenolone in the brain via activation of the type-1 cannabinoid (CB1) receptor.

Pregnenolone then, acting as a signaling-specific inhibitor of the CB1 receptor, reduces several effects of THC.

This negative feedback mediated by pregnenolone reveals a previously unknown paracrine/autocrine loop protecting the brain from CB1 receptor overactivation that could open an unforeseen approach for the treatment of cannabis intoxication and addiction.

These data indicate that THC increases pregnenolone through activation of the CB1 receptor…

In conclusion, this new understanding of the role of pregnenolone has the potential to generate new therapies for cannabis dependence.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057431/

Pro-inflammatory obesity in aged cannabinoid-2 receptor deficient mice.

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“Cannabinoid-1 receptor signaling increases the rewarding effects of food intake and promotes the growth of adipocytes, whereas CB2 possibly opposes these pro-obesity effects by silencing the activated immune cells that are key drivers of the metabolic syndrome.

Pro- and anti-orexigenic cannabimimetic signaling may become unbalanced with age because of alterations of the immune and endocannabinoid system…

CB2 agonists may fortify CB2-mediated anti-obesity signaling without the risk of anti-CB1 mediated depression that caused the failure of rimonabant.”

http://www.ncbi.nlm.nih.gov/pubmed/26303348

[Neuroprotective mechanisms of cannabinoids in brain ischemia and neurodegenerative disorders].

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“One of the most important causes of morbidity and mortality is neurologic dysfunction; its high incidence has led to an intense research of the mechanisms that protect the central nervous system from hypoxia and ischemia. The mayor challenge is to block the biochemical events leading to neuronal death.

This may be achieved by neuroprotective mechanisms that avoid the metabolic and immunologic cascades that follow a neurological damage. When it occurs, several pathophysiological events develop including cytokine release, oxidative stress and excitotoxicity.

Neuroprotective effects of cannabinoids to all those mechanisms have been reported in animal models of brain ischemia, excitotoxicity, brain trauma and neurodegenerative disorders.

Some endocannabinoid analogs are being tested in clinical studies (I-III phase) for acute disorders involving neuronal death (brain trauma and ischemia).

The study of the cannabinoid system may allow the discovery of effective neuroprotective drugs for the treatment of neurological disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26299059

Cannabinoid receptor type 1 agonist ACEA improves motor recovery and protects neurons in ischemic stroke in mice.

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“Brain ischemia produces neuronal cell death and the recruitment of pro-inflammatory cells.

In turn, the search for neuroprotection against this type of insult has rendered results involving a beneficial role of endocannabinoid receptor agonists in the Central Nervous System.

In this work, to further elucidate the mechanisms associated to this neuroprotective effect…

Motor tests showed a progressive deterioration in motor activity in ischemic animals, which only ACEA treatment was able to counteract.

Our results suggest that CB1R may be involved in neuronal survival and in the regulation of neuroprotection during focal cerebral ischemia in mice.”

http://www.ncbi.nlm.nih.gov/pubmed/26296704

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

Clinical Use of Cannabinoids for Symptom Control in Multiple Sclerosis.

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“The endocannabinoid system was discovered in 1988 but has received little attention for its potential therapeutic possibilities.

That has started to change, and since 2000, a significant number of clinical trials of cannabinoids, principally for the control of spasticity in multiple sclerosis, have been undertaken. These studies have been difficult because of the nature of the disease and have involved patients for whom other therapies have failed or proved inadequate.

This paper outlines the background to the use of cannabinoids available and discusses the principles of practice associated with their safe use.

The focus has been on nabiximols, being the most studied and the only cannabinoid that has been both adequately researched for use in multiple sclerosis and granted a license by the regulators. However, what has emerged is that the effect for many patients can be much wider than just control of spasticity.

Within and outside of neurology there seems to be an expanding range of possibilities for the therapeutic use of cannabinoids.”

http://www.ncbi.nlm.nih.gov/pubmed/26289248

http://www.thctotalhealthcare.com/category/multiple-sclerosis-ms/

Cannabinoids and Glucocorticoids in the Basolateral Amygdala Modulate Hippocampal-Accumbens Plasticity after Stress.

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“Acute stress results in release of glucocorticoids which are potent modulators of learning and plasticity. This process is presumably mediated by the basolateral amygdala (BLA) where cannabinoids CB1 receptors play a key role in regulating the hypothalamic-pituitary-adrenal (HPA) axis.

Growing attention has been focused on nucleus accumbens (NAc) plasticity which regulates mood and motivation. The NAc integrates affective and context dependent input from the BLA and ventral subiculum (vSub), respectively.

Since our previous data suggest that the CB1/2 receptor agonist WIN55,212-2 (WIN) and glucocorticoid receptor (GR) antagonist RU-38486 (RU) can prevent the effects of stress on emotional memory, we examined whether intra-BLA WIN and RU can reverse the effects of acute stress on NAc plasticity…

The results suggest that glucocorticoid and cannabinoid systems in the BLA can restore normal function of the NAc and hence may play a central role in the treatment of a variety of stress-related disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26289146