Category Archives: Amyotrophic lateral sclerosis (ALS) -Lou Gehrig’s disease

Cannabinoid receptor signalling in neurodegenerative diseases: a potential role for membrane fluidity disturbance

Posted on by
Reply

Abstract

“Type-1 cannabinoid receptor (CB1) is the most abundant G-protein-coupled receptor (GPCR) in the brain. CB1 and its endogenous agonists, the so-called ‘endocannabinoids (eCBs)’, belong to an ancient neurosignalling system that plays important functions in neurodegenerative and neuroinflammatory disorders like Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and multiple sclerosis. For this reason, research on the therapeutic potential of drugs modulating the endogenous tone of eCBs is very intense. Several GPCRs reside within subdomains of the plasma membranes that contain high concentrations of cholesterol: the lipid rafts. Here, the hypothesis that changes in membrane fluidity alter function of the endocannabinoid system, as well as progression of particular neurodegenerative diseases, is described. To this end, the impact of membrane cholesterol on membrane properties and hence on neurodegenerative diseases, as well as on CB1 signalling in vitro and on CB1-dependent neurotransmission within the striatum, is discussed. Overall, present evidence points to the membrane environment as a critical regulator of signal transduction triggered by CB1, and calls for further studies aimed at better clarifying the contribution of membrane lipids to eCBs signalling. The results of these investigations might be exploited also for the development of novel therapeutics able to combat disorders associated with abnormal activity of CB1.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165948/

Cannabinoids as Therapeutic Agents for Ablating Neuroinflammatory Disease

Posted on by
Reply

“Cannabinoids have been reported to alter the activities of immune cells in vitro and in vivo. These compounds may serve as ideal agents for adjunct treatment of pathological processes that have a neuroinflammatory component. As highly lipophilic molecules, they readily access the brain. Furthermore, they have relatively low toxicity and can be engineered to selectively target cannabinoid receptors. To date, two cannabinoid receptors have been identified, characterized and designated CB1 and CB2. CB1 appears to be constitutively expressed within the CNS while CB2 apparently is induced during inflammation. The inducible nature of CB2 extends to microglia, the resident macrophages of the brain that play a critical role during early stages of inflammation in that compartment. Thus, the cannabinoid-cannabinoid receptor system may prove therapeutically manageable in ablating neuropathogenic disorders such as Alzheimer’s disease, multiple sclerosis, amyotrophic.”

“The marijuana plant, Cannabis sativa, has been consumed therapeutically and recreationally for centuries because of its medicinal and psychotropic attributes. Cannabis contains a complex array of substances, including a group of terpenoid-like, highly lipophilic compounds referred to as cannabinoids. To date, over 60 cannabinoids have been identified from the marijuana plant. Cannabinoids account for the majority of the effects attributed to marijuana that users experience, including euphoria, impaired perception and memory, and mild sedation. While cannabinoids have been used to abolish loss of appetite and to ablate nausea and pain in patients suffering from severe medical disorders, these compounds also possess immune modulatory properties that may prove detrimental to human health. However, accumulating evidence suggests that cannabinoids also may serve as therapeutic agents in neuropathogenic diseases, pathologically hallmarked by elicitation of pro-inflammatory factors by cells of the central nervous system (CNS) and infiltrated peripheral immunocytes. Cannabinoids have the potential to be ideal therapeutic candidates in abolishing inflammatory neuropathies in that they can readily penetrate the blood brain barrier (BBB) to access the brain, have low levels of toxicity, and can specifically exert their effects through cannabinoid receptors. The major cannabinoid receptor type that appears to be targeted in neuroinflammation is cannabinoid receptor 2 (CB2). This receptor has been identified in select cells of the CNS, can be induced on demand during early inflammatory events, and has been shown to attenuate pro-inflammatory cytokine production by microglia, the resident macrophages of the brain that play a central role in many neuropathological processes.”

“In the present review the immune modulatory properties of cannabinoids, including their relation to interaction with cannabinoid receptors as linked to inflammatory neuropathies will be discussed. Included in this review will be an overview of the signal transduction cascades associated with cannabinoid receptors, and the effects of cannabinoid receptor signaling on immune cell function and immunity, and more importantly in the CNS. These discussions will lay the groundwork for the critical element of this review, in which we explore the potential of cannabinoid receptors to serve as therapeutic targets to attenuate the elicitation of pro-inflammatory mediators during neuropathogenic diseases and disorders such as Alzheimer’s disease (AD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), HIV Encephalitis (HIVE), Closed Head Injury (CHI) and Granulomatous Amebic Encephalitis (GAE).”

“It is apparent that therapeutic intervention at an early stage of neuroinflammation is critical. The recognition that microglia express CB2 and that its activation results in ablation of untoward immune responses indicates that this receptor may serve as an ideal therapeutic target. Cannabinoids, as highly lipophilic compounds, can readily penetrate the BBB and access the brain. Furthermore, these compounds can be designed to have low toxicity, minimal psychotropic properties, and to selectively target cells that express the CB2, particularly microglia that serve as endogenous immune cells of the CNS and that play a prominent role in neuroinflammatory processes.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750822/

Cannabinoid receptors and endocannabinoids: role in neuroinflammatory and neurodegenerative disorders.

Posted on by
Reply

Abstract

“The G-protein coupled receptors for Δ⁹-tetrahydrocannabinol, the major psychoactive principle of marijuana, are known as cannabinoid receptors of type 1 (CB₁) and 2 (CB₂) and play important functions in degenerative and inflammatory disorders of the central nervous system. Whilst CB₁ receptors are mostly expressed in neurons, where they regulate neurotransmitter release and synaptic strength, CB₂ receptors are found mostly in glial cells and microglia, which become activated and over-express these receptors during disorders such as Alzheimer’s disease, multiple sclerosis, amyotropic lateral sclerosis, Parkinson’s disease, and Huntington’s chorea. The neuromodulatory actions at CB₁ receptors by endogenous agonists (‘endocannabinoids’), of which anandamide and 2-arachidonoylglycerol are the two most studied representatives, allows them to counteract the neurochemical unbalances arising during these disorders. In contrast, the immunomodulatory effects of these lipophilic mediators at CB₂ receptors regulate the activity and function of glia and microglia. Indeed, the level of expression of CB₁ and CB₂ receptors or of enzymes controlling endocannabinoid levels, and hence the concentrations of endocannabinoids, undergo time- and brain region-specific changes during neurodegenerative and neuroinflammatory disorders, with the initial attempt to counteract excitotoxicity and inflammation. Here we discuss this plasticity of the endocannabinoid system during the aforementioned central nervous system disorders, as well as its dysregulation, both of which have opened the way to the use of either direct and indirect activators or blockers of CB₁ and CB₂ receptors for the treatment of the symptoms or progression of these diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/20632970

Therapeutic aspects of cannabis and cannabinoids

Posted on by
2

The British Journal of Psychiatry

“HISTORY OF THERAPEUTIC USE

The first formal report of cannabis as a medicine appeared in China nearly 5000 years ago when it was recommended for malaria, constipation, rheumatic pains and childbirth and, mixed with wine, as a surgical analgesic. There are subsequent records of its use throughout Asia, the Middle East, Southern Africa and South America. Accounts by Pliny, Dioscorides and Galen remained influential in European medicine for 16 centuries.”

“It was not until the 19th century that cannabis became a mainstream medicine in Britain. W. B. O’Shaughnessy, an Irish scientist and physician, observed its use in India as an analgesic, anticonvulsant, anti-spasmodic, anti-emetic and hypnotic. After toxicity experiments on goats and dogs, he gave it to patients and was impressed with its muscle-relaxant, anticonvulsant and analgesic properties, and recorded its use-fulness as an anti-emetic.”

“After these observations were published in 1842, medicinal use of cannabis expanded rapidly. It soon became available ‘over the counter’ in pharmacies and by 1854 it had found its way into the United States Dispensatory. The American market became flooded with dozens of cannabis-containing home remedies.”

“Cannabis was outlawed in 1928 by ratification of the 1925 Geneva Convention on the manufacture, sale and movement of dangerous drugs. Prescription remained possible until final prohibition under the 1971 Misuse of Drugs Act, against the advice of the Advisory Committee on Drug Dependence.”

“In the USA, medical use was effectively ruled out by the Marijuana Tax Act 1937. This ruling has been under almost constant legal challenge and many special dispensations were made between 1976 and 1992 for individuals to receive ‘compassionate reefers’. Although this loophole has been closed, a 1996 California state law permits cultivation or consumption of cannabis for medical purposes, if a doctor provides a written endorsement. Similar arrangements apply in Italy and Canberra, Australia.”

“Results and Conclusions Cannabis and some cannabinoids are effective anti-emetics and analgesics and reduce intra-ocular pressure. There is evidence of symptom relief and improved well-being in selected neurological conditions, AIDS and certain cancers. Cannabinoids may reduce anxiety and improve sleep. Anticonvulsant activity requires clarification. Other properties identified by basic research await evaluation. Standard treatments for many relevant disorders are unsatisfactory. Cannabis is safe in overdose but often produces unwanted effects, typically sedation, intoxication, clumsiness, dizziness, dry mouth, lowered blood pressure or increased heart rate. The discovery of specific receptors and natural ligands may lead to drug developments. Research is needed to optimise dose and route of administration, quantify therapeutic and adverse effects, and examine interactions.”

http://bjp.rcpsych.org/content/178/2/107.long

The therapeutic potential of novel cannabinoid receptors.

Posted on by
Reply

Cover image

“Cannabinoids produce a plethora of biological effects, including the modulation of neuronal activity through the activation of CB(1) receptors and of immune responses through the activation of CB(2) receptors. The selective targeting of either of these two receptor subtypes has clear therapeutic value. Recent evidence indicates that some of the cannabinomimetic effects previously thought to be produced through CB(1) and/or CB(2) receptors, be they on neuronal activity, on the vasculature tone or immune responses, still persist despite the pharmacological blockade or genetic ablation of CB(1) and/or CB(2) receptors. This suggests that additional cannabinoid and cannabinoid-like receptors exist. Here we will review this evidence in the context of their therapeutic value and discuss their true belonging to the endocannabinoid signaling system.”  http://www.ncbi.nlm.nih.gov/pubmed/19248809

“The therapeutic potential of novel cannabinoid receptors”  http://www.sciencedirect.com/science/article/pii/S0163725809000266

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

Posted on by
Reply

Abstract

“The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson’s and Huntington’s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB(1) receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB(1) receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB(2) receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients’ need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.”

Future Directions

“The length of this review, necessitated by the steady growth in the number of indications for the potential therapeutic use of cannabinoid-related medications, is a clear sign of the emerging importance of this field. This is further underlined by the quantity of articles in the public database dealing with the biology of cannabinoids, which numbered ∼200 to 300/year throughout the 1970s to reach an astonishing 5900 in 2004. The growing interest in the underlying science has been matched by a growth in the number of cannabinoid drugs in pharmaceutical development from two in 1995 to 27 in 2004, with the most actively pursued therapeutic targets being pain, obesity, and multiple sclerosis (Hensen, 2005). As in any rapidly growing area of research, not all the leads will turn out to be useful or even valid. Nevertheless, it is safe to predict that new therapeutic agents that affect the activity of the endocannaboinoid system will emerge and become members of our therapeutic armamentarium. The plant-derived cannabinoid preparation Sativex has already gained regulatory approval in Canada for the treatment of spasticity and pain associated with multiple sclerosis, and the CB1 receptor antagonist rimonabant has been approved in Europe and is awaiting Food and Drug Administration approval in the United States for the treatment of the metabolic syndrome. Undoubtedly, these will be followed by new and improved compounds aimed at the same or additional targets in the endocannabinoid system. However, it may be only after the widespread therapeutic use of such compounds that some important side effects will emerge. Although this occurrence would be undesirable from a health care perspective, such side effects may shed further light on the biological functions of endocannabinoids in health and disease.”

http://pharmrev.aspetjournals.org/content/58/3/389.long

The Endocannabinoid System and the Brain.

Posted on by
Reply

Abstract

“The psychoactive constituent in cannabis, Δ(9)-tetrahydrocannabinol (THC), was isolated in the mid-1960s, but the cannabinoid receptors, CB1 and CB2, and the major endogenous cannabinoids (anandamide and 2-arachidonoyl glycerol) were identified only 20 to 25 years later. The cannabinoid system affects both central nervous system (CNS) and peripheral processes. In this review, we have tried to summarize research-with an emphasis on recent publications-on the actions of the endocannabinoid system on anxiety, depression, neurogenesis, reward, cognition, learning, and memory. The effects are at times biphasic-lower doses causing effects opposite to those seen at high doses. Recently, numerous endocannabinoid-like compounds have been identified in the brain. Only a few have been investigated for their CNS activity, and future investigations on their action may throw light on a wide spectrum of brain functions. Expected final online publication date for the Annual Review of Psychology Volume 64 is November 30, 2012. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.”

http://www.ncbi.nlm.nih.gov/pubmed/22804774

THC From Cannabis Destroys Cancer Cells

Posted on by
1

“The study results strongly suggest that if taken regularly, cannabis oil may be able to induce remission in leukemia patients without the horrendous side effects typically associated with standard radio-chemical treatment options. Although this is only one such study, other similar studies have shown equally impressive results.

 Many of the active ingredients found in cannabis-derived drugs show exceptional promise in treating some of the greatest hurdles facing modern medical science. In addition to their aforementioned capacity for safely treating certain forms of deadly cancer, they also show great promise in alleviating autoimmune conditions such as rheumatoid arthritis, multiple sclerosis, and even inflammatory bowel disease. A growing number of experts also note their possible viability treating a range of neurological disorders including Alzheimer’s and Lou Gehrig’s disease.”

http://www.globalhealingcenter.com/natural-health/thc-from-cannabis-destroys-cancer-cells/

Marijuana in the management of amyotrophic lateral sclerosis

Posted on by
1

“Marijuana in the management of amyotrophic lateral sclerosis… Marijuana has been proposed as treatment for a widening spectrum of medical conditions. Marijuana is a substance with many properties that may be applicable to the management of amyotrophic lateral sclerosis (ALS). These include analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and sleep induction. In addition, marijuana has now been shown to have strong antioxidative and neuroprotective effects, which may prolong neuronal cell survival. In areas where it is legal to do so, marijuana should be considered in the pharmacological management of ALS…”

http://www.ncbi.nlm.nih.gov/pubmed/11467101

The endocannabinoid system in amyotrophic lateral sclerosis

Posted on by
Reply

“The endocannabinoid system in amyotrophic lateral sclerosis… Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative condition… there is significant evidence that several neurotoxic mechanisms including excitotoxicity, inflammation and oxidative stress, all contribute to disease pathogenesis… there is increasing evidence that cannabinoids and manipulation of the endocannabinoid system may have therapeutic value in ALS, in addition to other neurodegenerative conditions. Cannabinoids exert anti-glutamatergic and anti-inflammatory actions through activation of the CB(1) and CB(2) receptors… cannabinoid agents also exert anti-oxidant actions… the ability of cannabinoids to target multiple neurotoxic pathways in different cell populations increase their therapeutic potential in the treatment of ALS.”

http://www.ncbi.nlm.nih.gov/pubmed/18781981