Tag Archives: therapeutic

The therapeutic potential of the cannabinoids in neuroprotection.

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Abstract

“After thousands of years of interest the last few decades have seen a huge increase in our knowledge of the cannabinoids and their mode of action. Their potential as medical therapeutics has long been known. However, very real concerns over their safety and efficacy have lead to caution and suspicion when applying the legislature of modern medicine to these compounds. The ability of this diverse family of compounds to modulate neurotransmission and act as anti-inflammatory and antioxidative agents has prompted researchers to investigate their potential as neuroprotective agents. Indeed, various cannabinoids rescue dying neurones in experimental forms of acute neuronal injury, such as cerebral ischaemia and traumatic brain injury. Cannabinoids also provide symptomatic relief in experimental models of chronic neurodegenerative diseases, such as multiple sclerosis and Huntington’s disease. This preclinical evidence has provided the impetus for the launch of a number of clinical trials in various conditions of neurodegeneration and neuronal injury using compounds derived from the cannabis plant. Our understanding of cannabinoid neurobiology, however, must improve if we are to effectively exploit this system and take advantage of the numerous characteristics that make this group of compounds potential neuroprotective agents.”

http://www.ncbi.nlm.nih.gov/pubmed/12387700

Cannabinoids and neuroprotection.

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Abstract

“Cannabinoid compounds are endowed with pharmacological properties that make them interesting candidates for therapeutic development. These properties have been known since antiquity. However, in the last decade extremely important advances in the understanding of the physiology, pharmacology, and molecular biology of the cannabinoid system have given this field of research fresh impetus and have renewed the interest in the possible clinical exploitation of these compounds. In the present review we summarize the effects elicited, at the cellular level, by cannabinoids acting through receptor-dependent and receptor-independent mechanisms. These data suggest different ways by which cannabinoids may act as neuroprotective agents (prevention of excitotoxicity by inhibition of glutamate release, antioxidant effects, anti-inflammatory actions, etc.). The experimental evidence supporting these hypotheses are presented and discussed with regard to both preclinical and clinical studies in disease states such as cerebral ischemia, brain trauma, and Multiple Sclerosis.”

http://www.ncbi.nlm.nih.gov/pubmed/11831553

Delta 9-tetrahydrocannabinol inhibits cell cycle progression by downregulation of E2F1 in human glioblastoma multiforme cells.

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“The active components of Cannabis sativa L., Cannabinoids, traditionally used in the field of cancer for alleviation of pain, nausea, wasting and improvement of well-being have received renewed interest in recent years due to their diverse pharmacologic activities such as cell growth inhibition, anti-inflammatory activity and induction of tumor regression. Here we used several experimental approaches, which identified delta-9-tetrahydrocannabinol (Delta(9)-THC) as an essential mediator of cannabinoid antitumoral action.”

“CONCLUSIONS:

Delta(9)-THC is shown to significantly affect viability of GBM cells via a mechanism that appears to elicit G(1) arrest due to downregulation of E2F1 and Cyclin A. Hence, it is suggested that Delta(9)-THC and other cannabinoids be implemented in future clinical evaluation as a therapeutic modality for brain tumors.”

http://www.ncbi.nlm.nih.gov/pubmed/17934890

Cannabinoids Inhibit the Vascular Endothelial Growth Factor Pathway in Gliomas

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“Cannabinoids, the active components of Cannabis sativa L. (marijuana), and their derivatives exert a wide array of effects by activating their specific G protein-coupled receptors CB1 and CB2, which are normally engaged by a family of endogenous ligands–the endocannabinoids. Marijuana and its derivatives have been used in medicine for many centuries, and there is currently a renaissance in the study of the therapeutic effects of cannabinoids. Today, cannabinoids are approved to palliate the wasting and emesis associated with cancer and AIDS chemotherapy, and ongoing clinical trials are determining whether cannabinoids are effective agents in the treatment of pain, neurodegenerative disorders such as multiple sclerosis, and traumatic brain injury . In addition, cannabinoid administration to mice and/or rats induces the regression of lung adenocarcinomas, gliomas, thyroid epitheliomas, lymphomas, and skin carcinomas. These studies have also evidenced that cannabinoids display a fair drug safety profile and do not produce the generalized cytotoxic effects of conventional chemotherapies, making them potential antitumoral agents.” 

“Gliomas are one of the most malignant forms of cancer, resulting in the death of affected patients within 1–2 two years after diagnosis. Current therapies for glioma treatment are usually ineffective or just palliative. Therefore, it is essential to develop new therapeutic strategies for the management of glioblastoma multiforme, which will most likely require a combination of therapies to obtain significant clinical results. In line with the idea that anti-VEGF treatments constitute one of the most promising antitumoral approaches currently available, the present laboratory and clinical findings provide a novel pharmacological target for cannabinoid-based therapies.”

“The use of cannabinoids in medicine is limited by their psychoactive effects mediated by neuronal CB1 receptors. Although these adverse effects are within the range of those accepted for other medications, especially in cancer treatment, and tend to disappear with tolerance on continuous use, it is obvious that cannabinoid-based therapies devoid of side-effects would be desirable. As glioma cells express functional CB2 receptors, we used a selective CB2 ligand to target the VEGF pathway. Selective CB2 receptor activation in mice also inhibits the growth and angiogenesis of skin carcinomas.”

“Cannabinoids inhibit tumor angiogenesis…”

“Cannabinoids Inhibit the Vascular Endothelial Growth Factor Pathway in Gliomas”

“Because blockade of the VEGF pathway constitutes one of the most promising antitumoral approaches currently available, the present findings provide a novel pharmacological target for cannabinoid-based therapies.”

http://cancerres.aacrjournals.org/content/64/16/5617.full

Role of the endocannabinoid system in depression and suicide.

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“Depression is one of the most prevalent forms of neuropsychiatric disorder and is a major cause of suicide worldwide. The prefrontal cortex is a crucial brain region that is thought to be involved in the regulation of mood, aggression and/or impulsivity and decision making, which are altered in suicidality.

Evidence of the role of the endocannabinoid (EC) system in the neurobiology of neuropsychiatric disorders is beginning to emerge. The behavioral effects of ECs are believed to be mediated through the central cannabinoid CB1 receptor. Alterations in the levels of ECs, and in the density and coupling efficacy of CB1 receptors, have been reported in the prefrontal cortex of depressed and alcoholic suicide victims.

These findings support our hypothesis that altered EC function contributes to the pathophysiological aspects of suicidal behavior. Here, we provide a brief overview of the role of the EC system in alcoholism, depression and suicide, and discuss possible therapeutic interventions and directions for future research.”

https://www.ncbi.nlm.nih.gov/pubmed/16919786

http://www.cell.com/trends/pharmacological-sciences/fulltext/S0165-6147(06)00186-6

 

Role of cannabinoids in the regulation of bone remodeling

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Abstract

“The endocannabinoid system plays a key role in regulating a variety of physiological processes such as appetite control and energy balance, pain perception, and immune responses. Recent studies have implicated the endocannabinoid system in the regulation of bone cell activity and bone remodeling. These studies showed that endogenous cannabinoid ligands, cannabinoid receptors, and the enzymes responsible for ligand synthesis and breakdown all play important roles in bone mass and in the regulation of bone disease. These findings suggest that the endocannabinoid pathway could be of value as a therapeutic target for the prevention and treatment of bone diseases. Here, we review the role of the skeletal endocannabinoid system in the regulation of bone remodeling in health and disease.”

http://www.ncbi.nlm.nih.gov/pubmed/23181053

CB1 and CB2 receptor agonists promote analgesia through synergy in a murine model of tumor pain

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“Pain associated with cancer and tumor growth is often difficult to manage.”

“Cannabis sativa has a long history of use for management of pain.”

“In light of the adverse side effects of opioids, cannabinoid (CB) receptor agonists may provide an effective alternative for the treatment of cancer pain. The present study examined the potency and efficacy of synthetic CB1 and CB2 receptor agonists in a murine model of tumor pain.”

“Co-administering both CB receptor agonists attenuated mechanical hyperalgesia through a synergistic mechanism.”

 

“Together these data support the use of combined CB1 and CB2 receptor agonists in the development of strategies for the treatment of tumor related pain.”

“These data extend our previous findings that the peripheral cannabinoid receptors are a promising target for the management of cancer pain and mixed cannabinoid receptor agonists may have a therapeutic advantage over selective agonists.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155626/

Toward Fulfilling the Promise of Molecular Medicine in Fragile X Syndrome

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“Fragile X syndrome (FXS) is the most common inherited form of mental retardation and a leading known cause of autism. It is caused by loss of expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein that negatively regulates protein synthesis. In neurons, multiple lines of evidence suggest that protein synthesis at synapses is triggered by activation of group 1 metabotropic glutamate receptors (Gp1 mGluRs) and that many functional consequences of activating these receptors are altered in the absence of FMRP. These observations have led to the theory that exaggerated protein synthesis downstream of Gp1 mGluRs is a core pathogenic mechanism in FXS. This excess can be corrected by reducing signaling by Gp1 mGluRs, and numerous studies have shown that inhibition of mGluR5, in particular, can ameliorate multiple mutant phenotypes in animal models of FXS. Clinical trials based on this therapeutic strategy are currently under way. FXS is therefore poised to be the first neurobehavioral disorder in which corrective treatments have been developed from the bottom up: from gene identification to pathophysiology in animals to novel therapeutics in humans. The insights gained from FXS and other autism-related single-gene disorders may also assist in identifying molecular mechanisms and potential treatment approaches for idiopathic autism…

It is already clear that diverse molecular mechanisms can contribute to the synaptic abnormalities that underlie ASDs. In order to design appropriate therapeutic strategies for idiopathic autism, it will be critical to identify biomarkers that report the pathophysiological processes at work in the brains of the affected individuals.

Based on these findings, treatments that successfully target protein synthesis pathways in the single-gene disorders mentioned above, including mGluR5 modulators, may very well have broader therapeutic applications in idiopathic autism.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3100156/

 

Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials.

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“Effective therapeutic options for patients living with chronic pain are limited. The pain relieving effect of cannabinoids remains unclear. A systematic review of randomized controlled trials (RCTs) examining cannabinoids in the treatment of chronic non-cancer pain was conducted according to the PRISMA statement update on the QUORUM guidelines for reporting systematic reviews that evaluate health care interventions. Cannabinoids studied included smoked cannabis, oromucosal extracts of cannabis based medicine, nabilone, dronabinol and a novel THC analogue. Chronic non-cancer pain conditions included neuropathic pain, fibromyalgia, rheumatoid arthritis, and mixed chronic pain. Overall the quality of trials was excellent. Fifteen of the eighteen trials that met the inclusion criteria demonstrated a significant analgesic effect of cannabinoid as compared with placebo and several reported significant improvements in sleep. There were no serious adverse effects. Adverse effects most commonly reported were generally well tolerated, mild to moderate in severity and led to withdrawal from the studies in only a few cases. Overall there is evidence that cannabinoids are safe and modestly effective in neuropathic pain with preliminary evidence of efficacy in fibromyalgia and rheumatoid arthritis. The context of the need for additional treatments for chronic pain is reviewed. Further large studies of longer duration examining specific cannabinoids in homogeneous populations are required.

In conclusion this systematic review of 18 recent good quality randomized trials demonstrates that cannabinoids are a modestly effective and safe treatment option for chronic non-cancer (predominantly neuropathic) pain. Given the prevalence of chronic pain, its impact on function and the paucity of effective therapeutic interventions, additional treatment options are urgently needed. More large scale trials of longer duration reporting on pain and level of function are required.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243008/

Cannabinoid mechanisms of pain suppression.

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Abstract

“A large body of literature indicates that cannabinoids suppress behavioral responses to acute and persistent noxious stimulation in animals. This review examines neuroanatomical, behavioral, and neurophysiological evidence supporting a role for cannabinoids in suppressing pain at spinal, supraspinal, and peripheral levels. Localization studies employing receptor binding and quantitative autoradiography, immunocytochemistry, and in situ hybridization are reviewed to examine the distribution of cannabinoid receptors at these levels and provide a neuroanatomical framework with which to understand the roles of endogenous cannabinoids in sensory processing. Pharmacological and transgenic approaches that have been used to study cannabinoid antinociceptive mechanisms are described. These studies provide insight into the functional roles of cannabinoid CB1 (CB1R) and CB2 (CB2R) receptor subtypes in cannabinoid antinociceptive mechanisms, as revealed in animal models of acute and persistent pain. The role of endocannabinoids and related fatty acid amides that are implicated in endogenous mechanisms for pain suppression are discussed. Human studies evaluating therapeutic potential of cannabinoid pharmacotherapies in experimental and clinical pain syndromes are evaluated. The potential of exploiting cannabinoid antinociceptive mechanisms in novel pharmacotherapies for pain is discussed.”

http://www.ncbi.nlm.nih.gov/pubmed/16596786