Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain.

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“Many patients with life-threatening diseases such as cancer experience severe symptoms that compromise their health status and deny them quality of life. Patients with cancer often experience cachexia, pain, and depression,which translate into an unacceptable quality of life. The discovery of the endocannabinoid system has led to a renewed interest in the use of cannabinoids for the management of nausea, vomiting, and weight loss arising either from cancer or the agents used to treat cancer. The endocannabinoid system has been found to be a key modulator of systems involved in pain perception, emesis, and reward pathways. As such, it represents a target for development of new medications for controlling the symptoms associated with cancer. Although the cannabinoid receptor agonist tetrahydrocannabinol and one of its analogs are currently the only agents approved for clinical use, efforts are under way to devise other strategies for activating the endocannabinoid system for therapeutic uses.”

http://www.ncbi.nlm.nih.gov/pubmed/15357514

Cannabinoid agonist WIN-55,212-2 partially restores neurogenesis in the aged rat brain

“A decline in neurogenesis in the hippocampus may underlie age-related memory impairment in rats and humans. We now show that WIN 55,212-2 administration for 3 weeks can partially restore neurogenesis in the hippocampus of aged rats. Cannabinoid receptor stimulation therapy may thus provide clinical benefit for humans with age-associated memory impairment.”

“This report shows for the first time the potential therapeutic efficacy of endocannabinoid receptor stimulation in stimulating neurogenesis from proliferation to engraftment during normal aging in vivo. The current results, coupled with our previous observations regarding the role of endocannabinoid receptors, underscores the potential clinical benefits of cannabinoid pharmacotherapies during normal and pathological brain aging.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3011092/

Anti-inflammatory property of the cannabinoid agonist WIN-55212-2 in a rodent model of chronic brain inflammation

“Cannabinoid receptors (CBr) stimulation induces numerous central and peripheral effects. A growing interest in the beneficial properties of manipulating the endocannabinoid system has lead to the possible involvement of CBr in the control of brain inflammation… Our results emphasize the potential use of CBr agonists in the regulation of inflammatory processes within the brain; this knowledge may lead to the use of CBr agonists in the treatment of neurodegenerative diseases associated with chronic neuroinflammation, such as Alzheimer disease.”

“The current report is the first to our knowledge to demonstrate the modulatory role of cannabinoids in an animal model of chronic neuroinflammation, pointing out the effectiveness of a CBr agonist on the consequences of LPS mediated neuroinflammation at a dose (0.5 mg/kg/day i.p. of WIN-55212-2) that does not impair performance in a patial memory task. These results further advocate for the manipulation of the endocannabinoid system to diminish the consequences of neuroinflammation in progression of AD and others inflammation-related diseases.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1852513/

Inflammation and aging: can endocannabinoids help?

“Aging often leads to cognitive decline due to neurodegenerative process in the brain. As people live longer, a growing concern exist linked to long-term, slowly debilitating diseases that have not yet found a cure, such as Alzheimer’s disease. Recently, the role of neuroinflammation has attracted attention due to its slow onset, chronic nature and its possible role in the development of many different neurodegenerative diseases. In the future, treatment of chronic neuroinflammation may help counteract aspects of neurodegenerative disease. Our recent studies have focused upon the endocannabinoid system for its unique effects on the expression of neuroinflammation. The basis for the manipulation of the endocannabinoid system in the brain in combination with existing treatments for Alzheimer’s disease will be discussed in this review.”

“Endocannabinoids

Cannabinoid refers to naturally occurring or synthetic molecules mimicking the activity of plant-derived cannabinoids from Cannabis Sativa. Two types of cannabinoid receptors have been so far identified in the body, named CB1 and CB2. Discovery of cannabinoid receptors (CBr) lead to the finding of endogenous agonists for these receptors called endocannabinoids (EC). EC are derived from arachidonic acid, arachidonoylethanolamide (anandamide), and 2-arachidonoyl glycerol (2-AG), synthesized on-demand post-synaptically and released in response to the entry of calcium ions. These EC in combination with the two known CBr constitute the endocannabinoid system (ECS). In the central nervous system (CNS), CB1 is overwhelmingly represented over CB2 and particularly abundant in cortical regions, the hippocampus, cerebellum and basal ganglia while CB2 may be restricted to microglia or neurons in the brainstem  and cerebellum. Deactivation of the EC is due to a rapid enzymatic degradation in the synaptic cleft or after membrane transport. The ECS is thought to be a neuromodulator and an immunomodulator. In the CNS, the ECS can influence food intake, endocrine release, motor control, cognitive processes, emotions and perception. Cannabinoids treatment has been shown to be neuroprotective under many experimental conditions. Drugs that manipulate the ECS are currently evaluated in various diseases ranging from cancer to AIDS for their peripheral analgesic and immunosuppressive properties. Their anti-inflammatory actions may make them useful in the treatment of multiple sclerosis, Parkinson’s disease and AD. Very little in vivo evidence to support the use of EC receptor agonists has been reported, although in vitro studies have found evidence for their anti-inflammatory effectiveness. Our recent work demonstrated the anti-inflammatory effect of a chronic treatment of a low dose of the CBr agonist WIN-55,212-2 (without psychoactive effects) on the consequences of chronic neuroinflammation induced by the infusion of LPS into the 4th ventricle of young rats. Moreover, that same anti-inflammatory effect was found using a non-psychoactive dose given by slow subcutaneous infusion of WIN-55,212-2 to healthy aged rats; these rats also demonstrated improved spatial memory. Our ongoing work in aged rats has shown that treatment with the CBr agonist WIN-55,212-2 increases neurogenesis in the hippocampus. Our preliminary data suggest that the neurogenic and anti-inflammatory effects in aged rats are due to the agonist/antagonist properties of WIN-55,212-2 at multiple receptors.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2408719/

Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb.

“Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions).

The well-known psychotropic effects of Delta(9)-tetrahydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetrahydrocannabinol.

Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol,

the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.”

http://www.ncbi.nlm.nih.gov/pubmed/19729208