The therapeutic potential of the endocannabinoid system for Alzheimer's disease

Neuroscience Research Australia, Randwick, NSW, Australia.
Expert Opinion on Therapeutic Targets (Impact Factor: 5.14). 03/2012; 16(4):407-20. DOI: 10.1517/14728222.2012.671812
Source: PubMed


INTRODUCTION: Dementia currently affects over 35 million people worldwide. The most common form of dementia is Alzheimer's disease (AD). Currently, treatments for AD do not stop or reverse the progression of the disease and they are accompanied by side effects. AREAS COVERED: The main features of AD pathology, treatment options currently available, the endocannabinoid system and its functionality in general and its role in AD pathology in detail will be outlined. A particular focus will be on the therapeutic potential of the phytocannabinoid cannabidiol. EXPERT OPINION: Based on the complex pathology of AD, a preventative, multimodal drug approach targeting a combination of pathological AD symptoms appears ideal. Importantly, cannabinoids show anti-inflammatory, neuroprotective and antioxidant properties and have immunosuppressive effects. Thus, the cannabinoid system should be a prime target for AD therapy. The cannabinoid receptor 2 appears to be a promising candidate but its role in AD has to be investigated cautiously. Furthermore, the phytocannabinoid cannabidiol is of particular interest as it lacks the psychoactive and cognition-impairing properties of other cannabinoids. In conclusion, future research should focus on the evaluation of the effects of manipulations to the endocannabinoid system in established animal models for AD, combined with early-phase studies in humans.

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Available from: Tim Karl
    • "On the other hand, the increase in 2-AG and the upregulation of microglial CB 2 receptors may protect against β-amyloid-induced neuroinflammation and neuronal injury (Benito et al. 2003;Ramírez et al. 2005). A neuroprotective therapy for AD based on compounds that act on the eCB system may be effective in reducing classic neurotoxic events, such as excessive glutamatergic transmission, prolonged calcium influx, oxidative stress, and inflammation (Gowran et al. 2011;Karl et al. 2012), although it may also cause more specific effects on the processing, aggregation, and clearance of β-amyloid protein (Tol on et al. 2009;Martín-Moreno et al. 2012;Scuderi et al. 2014). One example of a drug which acts classically through CB 1 and CB 2 receptors and also through mechanisms independent of CB receptors is Δ 9 -THC (Gowran et al. 2011). "
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    ABSTRACT: This review focuses on the role of the endocannabinoid signaling system in controlling neuronal survival, an extremely important issue to be considered when developing new therapies for neurodegenerative disorders. First, we will describe the cellular and molecular mechanisms, and the signaling pathways, underlying these neuroprotective properties, including the control of glutamate homeostasis, calcium influx, the toxicity of reactive oxygen species, glial activation and other inflammatory events; and the induction of autophagy. We will then concentrate on the preclinical studies and the few clinical trials that have been carried out targeting endocannabinoid signaling in three important chronic progressive neurodegenerative disorders (Parkinson's disease, Huntington's chorea, and Alzheimer's disease), as well as in other less well-studied disorders. We will end by offering some ideas and proposals for future research that should be carried out to optimize endocannabinoid-based treatments for these disorders. Such studies will strengthen the possibility that these therapies will be investigated in the clinical scenario and licensed for their use in specific disorders.
    No preview · Article · Sep 2015 · Handbook of experimental pharmacology
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    • "However, augmentation of eCB signaling could reduce excitotoxicity , oxidative stress, and neuroinflammation and thus could alleviate symptoms of AD [5]. Previous reviews have highlighted the beneficial effects of cannabinoids in AD treatment [5] [6] [7] [8] [9] [10], but none of them have focused on the molecular mechanisms through which eCBs exert their beneficial effects. Thus, the present review will extensively cover recent findings on the dysregulation of eCB signaling and the molecular mechanisms involved in beneficial effects of cannabinoids in AD. "
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    ABSTRACT: Alzheimer's disease (AD) is the most common form of progressive neurodegenerative disease characterized by cognitive impairment and mental disorders. The actual cause and cascade of events in the progression of this pathology is not fully determined. AD is multifaceted in nature and is linked to different multiple mechanisms in the brain. This aspect is related to the lack of efficacious therapies that could slow down or hinder the disease onset/progression. The ideal treatment for AD should be able to modulate the disease through multiple mechanisms rather than targeting a single dysregulated pathway. Recently, the endocannabinoid system emerged as novel potential therapeutic target to treat AD. In fact, exogenous and endogenous cannabinoids seem to be able to modulate multiple processes in AD, although the mechanisms that are involved are not fully elucidated. This review provides an update of this area. In this review, we recapitulate the role of endocannabinoid signaling in AD and the probable mechanisms through which modulators of the endocannabinoid system provide their effects, thus highlighting how this target might provide more advantages over other therapeutic targets.
    Full-text · Article · Aug 2014 · Journal of Alzheimer's disease: JAD
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    • "The memory restoring properties of CBD were linked to a reduction in microglial activation and pro-inflammatory cytokines (i.e., decreased IL-6) [28]. Current research suggests existing interventions may be administered too late in the disease process when the damage caused by AD pathology is already too severe [17] [29] [30]. Thus, in the current study, we evaluated for the very first time the effectiveness of long-term oral CBD treatment to prevent the development of cognitive deficits and AD-relevant brain pathophysiology in an established transgenic mouse model of familial AD [31]. "
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    ABSTRACT: Impairments in cognitive ability and widespread pathophysiological changes caused by neurotoxicity, neuroinflammation, oxidative damage, and altered cholesterol homeostasis are associated with Alzheimer's disease (AD). Cannabidiol (CBD) has been shown to reverse cognitive deficits of AD transgenic mice and to exert neuroprotective, anti-oxidative, and anti-inflammatory properties in vitro and in vivo. Here we evaluate the preventative properties of long-term CBD treatment in male AβPPSwe/PS1ΔE9 (AβPP × PS1) mice, a transgenic model of AD. Control and AD transgenic mice were treated orally from 2.5 months of age with CBD (20 mg/kg) daily for 8 months. Mice were then assessed in the social preference test, elevated plus maze, and fear conditioning paradigms, before cortical and hippocampal tissues were analyzed for amyloid load, oxidative damage, cholesterol, phytosterols, and inflammation. We found that AβPP × PS1 mice developed a social recognition deficit, which was prevented by CBD treatment. CBD had no impact on anxiety or associative learning. The prevention of the social recognition deficit was not associated with any changes in amyloid load or oxidative damage. However, the study revealed a subtle impact of CBD on neuroinflammation, cholesterol, and dietary phytosterol retention, which deserves further investigation. This study is the first to demonstrate CBD's ability to prevent the development of a social recognition deficit in AD transgenic mice. Our findings provide the first evidence that CBD may have potential as a preventative treatment for AD with a particular relevance for symptoms of social withdrawal and facial recognition.
    Full-text · Article · Jul 2014 · Journal of Alzheimer's disease: JAD
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