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

ABSTRACT 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, Sep 26, 2015
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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.
    Journal of Alzheimer's disease: JAD 08/2014; 43(4). DOI:10.3233/JAD-141635 · 4.15 Impact Factor
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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.
    Journal of Alzheimer's disease: JAD 07/2014; 42(4). DOI:10.3233/JAD-140921 · 4.15 Impact Factor
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    • "This raises the possibility that many eCB and CB effects in the CNS may be attributable to varying levels of these diverse receptor-mediated pathways, which result in/from an interplay between these parallel endogenous systems. A great deal of research has unraveled the different biological mechanisms involved in the AEA and 2-AG metabolic pathways (Paradisi et al., 2006; Di Marzo, 2009; Petrosino & Di Marzo, 2010; Karl et al., 2012; Marco & Laviola, 2012; Pertwee, 2012). AEA is derived from the cleavage of N-arachidonoylphosphatidylethanolamine (NAPE), a precursor synthesised by the enzyme Nacyltransferase , which requires the presence of Ca 2+ and is regulated by cAMP (Cadas et al., 1996; Piomelli, 2003). "
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    ABSTRACT: Synaptic neuromodulation acts across different functional domains to regulate cognitive processing and behavior. Recent challenges are related to elucidating the molecular and cellular mechanisms through which neuromodulatory pathways act on multiple time scales to signal state-dependent contingencies at the synaptic level or to stabilise synaptic connections during behavior. Here, we present a framework with the synaptic neuromodulators endocannabinoids (eCBs) as key players in dynamic synaptic changes. Modulation of various molecular components of the eCB pathway yields interconnected functional activation states of eCB signaling (prior, tonic, and persistent), which may contribute to metaplastic control of synaptic and behavioral functions in health and disease. The emerging picture supports aberrant metaplasticity as a contributor to cognitive dysfunction associated with several pathological states in which eCB signaling, or other neuromodulatory pathways, are deregulated.
    European Journal of Neuroscience 04/2014; 39(7). DOI:10.1111/ejn.12501 · 3.18 Impact Factor
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