Category Archives: Alzheimer’s Disease (AD)

The development of cannabinoid CBII receptor agonists for the treatment of central neuropathies.

Posted on by
Reply

“Cannabinoids have been used in the treatment of nausea and emesis, anorexia and cachexia, tremor and pain associated with multiple sclerosis. These treatments are limited by the psychoactive side-effects of CBI activation. Recently CBII has been described within the CNS, both in microglia and neuronal progenitor cells (NPCs), but with few exceptions, not by neurons within the CNS.

This has suggested that CBII agonists could have potential to treat various conditions without psycho-activity.

This article reviews the potential for CBII agonists as treatments for neurological conditions, with a focus on microglia and NPCs as drug targets. We first discuss the role of microglia in the healthy brain, and then the role of microglia in chronic neuroinflammatory disorders, including Alzheimer’s disease and Parkinson’s disease, as well as in neuroinflammation following acute brain injury such as stroke and global hypoxia. As activation of CBII receptor on microglia results in suppression of the proliferation and activation of microglia, there is potential for the anti-inflammatory properties of CBII agonist to treat neuropathologies that involve heightened microglia activity. In addition, activating CBII receptors may result in an increase in proliferation and affect migration of NPCs.Therefore, it is possible that CBII agonists may assist in the treatment of neuropathologies by increasing neurogenesis…”

http://www.ncbi.nlm.nih.gov/pubmed/20236042

Activation of the CB(2) receptor system reverses amyloid-induced memory deficiency.

Posted on by
Reply

“Cannabinoid type 2 (CB(2)) agonists are neuroprotective and appear to play modulatory roles in neurodegenerative processes in Alzheimer’s disease. We have studied the effect of 1-((3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl) carbonyl) piperidine (MDA7)-a novel selective CB(2) agonist that lacks psychoactivity-on ameliorating the neuroinflammatory process, synaptic dysfunction, and cognitive impairment 

 Our findings suggest that MDA7 is an innovative therapeutic approach for the treatment of Alzheimer’s disease.”

http://www.ncbi.nlm.nih.gov/pubmed/22795792

The activation of cannabinoid CB2 receptors stimulates in situ and in vitro beta-amyloid removal by human macrophages.

Posted on by
Reply

“The endocannabinoid system is a promising therapeutic target in a wide variety of diseases. However, the non-desirable psychotropic effects of natural and synthetic cannabinoids have largely counteracted their clinical usefulness. These effects are mostly mediated by cannabinoid receptors of the CB(1) type, that exhibit a wide distribution in neuronal elements of the CNS. Thus, the presence of other elements of this system in the CNS, such as CB(2) receptors, may open new possibilities for the development of cannabinoid-based therapies. These receptors are almost absent from the CNS in normal conditions but are up-regulated in glial cells under chronic neuroinflammatory stimuli, as has been described in Alzheimer’s disease. To understand the functional role of these receptors, we tested their role in the process of beta-amyloid removal, that is currently considered as one of the most promising experimental approaches for the treatment of this disease.

Our results show that a CB(2) agonist (JWH-015) is capable of inducing the removal of native beta-amyloid removal from human frozen tissue sections as well as of synthetic pathogenic peptide by a human macrophage cell line (THP-1). Remarkably, this effect was achieved at low doses and was specific for this type of cells, as U373MG astrocytoma cells did not respond to the treatment. The effect was CB(2)-mediated, at least partially, as the selective CB(2) antagonist SR144528 prevented the JWH-015-induced plaque removal in situ.

 These data corroborate the possible therapeutic interest of CB(2) cannabinoid specific chemicals in the treatment of Alzheimer’s disease.”

http://www.ncbi.nlm.nih.gov/pubmed/19505450

The role of the immune system in clearance of Abeta from the brain.

Posted on by
Reply

“In Alzheimer’s disease (AD), there is abnormal accumulation of Abeta and tau proteins in the brain. There is an associated immunological response, but it is still unclear whether this is beneficial or harmful. Inflammation in AD, specifically in the form of microglial activation, has, for many years, been considered to contribute to disease progression. However, two types of evidence suggest that it may be appropriate to revise this view: first, the disappointing results of prospective clinical trials of anti-inflammatory agents and, second, the observation that microglia can clear plaques in AD following Abeta immunization. Although Abeta immunization alters AD pathology, there is limited evidence so far of benefit to cognitive function. Immunization against microorganisms is almost always used as a method of disease prevention rather than to treat a disease process that has already started. In animal models, immunotherapy at an early age can protect against Abeta accumulation and it will be interesting to see if this can usefully be applied to humans to prevent AD.”

http://www.ncbi.nlm.nih.gov/pubmed/18363937

CB(2) receptor and amyloid pathology in frontal cortex of Alzheimer’s disease patients.

Posted on by
Reply

“The cannabinoid system seems to play an important role in various neurodegenerative diseases including Alzheimer’s disease (AD). The relationship of cannabinoid receptors (CB(1)R and CB(2)R) to cognitive function and neuropathological markers in AD remains unclear. In the present study, postmortem cortical brain tissues (Brodmann area 10) from a cohort of neuropathologically confirmed AD patients and age-matched controls were used to measure CB(1)R and CB(2)R by immunoblotting. Correlational analyses were performed for the neurochemical and cognitive data. CB(1)R expression was significantly decreased in AD. Levels of CB(1)R correlated with hypophagia, but not with any AD molecular marker or cognitive status (Mini Mental State Examination score). The level of CB(2)R was significantly higher (40%) in AD. Increases in the expression of the glial marker glial fibrillar acidic protein were also found. CB(2)R expression did not correlate with cognitive status. Interestingly, expression levels of CB(2)R correlated with two relevant AD molecular markers, Aβ(42) levels and senile plaque score.

These results may constitute the basis of CB(2)R-based therapies and/or diagnostic approaches.”

http://www.ncbi.nlm.nih.gov/pubmed/22763024

The Cannabinoid CB2 Receptor as a Target for Inflammation-Dependent Neurodegeneration

Posted on by
Reply

“THE CANNABINOID CB2 RECEPTOR AS A BIORATIONAL TARGET FOR THE TREATMENT OF NEURODEGENERATION. The presence of CB2 receptors in microglia in the human Alzheimer’s diseased brain suggests that CB2 may provide a novel target for a range of neuropathologies.

 The first approved cannabinoid drugs were analogues of Δ9-tetrahydrocannabinol (Δ9-THC). Dronabinol is a natural isomer of THC that is found in the cannabis plant, and Marinol™ contains synthetic dronabinol. Marinol, and another analogue nabilone (Cesamet™ ) are used to prevent nausea and vomiting after treatment with anti-cancer medicines. More recently, GW-100 (Sativex™) which combines nearly equal amounts of Δ9-THC and cannabidiol in a whole plant extract from cultivated cannabis, has been approved in Canada…

We conclude that the administration of CB2 agonists and antagonists may differentially alter microglia-dependent neuroinflammation. CB2 specific compounds have considerable therapeutic appeal over CB1 compounds, as the exclusive expression of CB2 on immune cells within the brain provides a highly specialised target, without the psychoactivity that plagues CB1 directed therapies.

In addition, CB2 activation appears to prevent or decrease microglial activation.

In a rodent model of Alzheimer’s disease microglial activation was completely prevented by administration of a selective CB2 agonist.”

http://www.ncbi.nlm.nih.gov/pubmed/18615177

Role of CB2 receptors in neuroprotective effects of cannabinoids.

Posted on by
Reply

“CB2 receptors, the so-called peripheral cannabinoid receptor type, were first described in the immune system, but they have been recently identified in the brain in healthy conditions and, in particular, after several types of cytotoxic stimuli. Specifically, CB2 receptors were identified in microglial cells, astrocytes and, to a lesser extent, in certain subpopulations of neurons.

Given the lack of psychoactivity demonstrated by selective CB2 receptor agonists, this receptor becomes an interesting target for the treatment of neurological diseases, in particular, the case of certain neurodegenerative disorders in which induction/up-regulation of CB2 receptors has been already demonstrated. These disorders include Alzheimer’s disease, Huntington’s chorea, amyotrophic lateral sclerosis and others. Interestingly, in experimental models of these disorders, the activation of CB2 receptors has been related to a delayed progression of neurodegenerative events, in particular, those related to the toxic influence of microglial cells on neuronal homeostasis.

 The present article will review the evidence supporting that CB2 receptors might represent a key element in the endogenous response against different types of cytotoxic events, and that this receptor type may be a clinically promising target for the control of brain damage in neurodegenerative disorders.”

 http://www.ncbi.nlm.nih.gov/pubmed/18291574

Cannabinoid CB2 receptors in human brain inflammation.

Posted on by
Reply

“CB2 receptors in neuroinflammatory conditions of the human brain.

“CB2 receptors have been found to be present in the CNS, thus offering new opportunities for the pharmacological use of cannabinoid agents. Furthermore, the fact that their expression is increased by inflammatory stimuli suggests that they may be involved in the pathogenesis and/or in the endogenous response to injury. Data obtained in vitro and in animal models show that CB2 receptors may be part of the general neuroprotective action of the ECS…

The anti-inflammatory effects triggered by the activation of the CB2 receptor make it an attractive target for the development of novel anti-inflammatory therapies.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219537/

Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation

Posted on by
Reply

“Activated microglial cells have been implicated in a number of neurodegenerative disorders, including Alzheimer’s disease (AD), multiple sclerosis (MS), and HIV dementia. Many data reveal that cannabinoids mediate suppression of inflammation in vitro and in vivo through stimulation of cannabinoid receptor 2 (CB2).

Taken together, these results provide mechanistic insight into beneficial effects provided by cannabinoid receptor CB2 modulation in neurodegenerative diseases, particularly AD.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1352348/

Does Smoking Marijuana Prevent Alzheimer’s Disease?

Posted on by
Reply

“Maintaining Memories with Marijuana. Research in my laboratory has demonstrated that stimulating the brain’s marijuana receptors may offer protection by reducing brain inflammation and by restoring neurogenesis. Thus, later in life, marijuana might actually help your brain, rather than harm it.

It takes very little marijuana to produce benefits in the older brain; my colleague in France, Dr. Yannick Marchalant, coined the motto “a puff is enough” because it appears as though only a single puff each day is necessary to produce significant benefit.

The challenge for pharmacologists in the future will be to isolate the beneficial effects of the marijuana plant from its psychoactive effects.”

http://www.theweedblog.com/does-smoking-marijuana-prevent-alzheimers-disease/