Endocannabinoid signalling in Alzheimer's disease

Maroof, Nazia; Pardon, Marie‐Christine; Kendall, David A.

doi:10.1042/bst20130140

Cited by 27 publications

(14 citation statements)

References 51 publications

(67 reference statements)

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“…It has been suggested that the ECS may be hypofunctional, and/or dysfunctional in neurodegenerative diseases, suggesting circumstance-dependent protective or potentially damaging effects (reviewed in [192,193]) and consistent with its largely adaptive role in mammalian physiology.…”

Section: Cbd Receptor Targets In Neurodegenerationmentioning

confidence: 92%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

449

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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Section: Cbd Receptor Targets In Neurodegenerationmentioning

confidence: 92%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

449

323

View full text Add to dashboard Cite

show abstract

“…The levels of extracellular eCBs and the ensuing activation of CB1 and CB2 receptors is a reflection of the balance between their production and inactivation. In vivo and in vitro models of inflammation have shown that exogenous and endogenous CBs have immunomodulatory properties that may mediate some of their beneficial effects in diverse pathological states (Arévalo-Martín et al, 2008;Maroof et al, 2013). Microglia express a functional eCB signaling system (eCBSS) and the activation of CB receptors modulates microglia behaviors such as migration, proliferation, cytokines and free radicals release, or phagocytosis (Stella, 2009).…”

Section: Introductionmentioning

confidence: 99%

Endocannabinoids drive the acquisition of an alternative phenotype in microglia

Mecha¹,

Feliú²,

Carrillo‐Salinas³

et al. 2015

Brain, Behavior, and Immunity

182

152

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“…In general, both dysregulation and endogenous protection are active in numerous neurodegenerative pathologies, both acute (e.g., stroke [6], brain trauma [7], spinal injury [8]) and chronic progressive disorders (e.g., Alzheimer’s disease [9], Parkinson’s disease [10], Huntington’s chorea [11,12], amyotrophic lateral sclerosis [13,14] and others [2]). Such responses have also been seen in autosomal-dominant spinocerebellar ataxias (SCAs; [15–17]), a group of inherited neurodegenerative disorders that mainly affect the cerebellum and its afferent/efferent structures, in which motor discoordination (“ataxia”) is the key symptom [18–21].…”

Section: Introductionmentioning

confidence: 99%

Altered striatal endocannabinoid signaling in a transgenic mouse model of spinocerebellar ataxia type-3

et al. 2017

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Spinocerebellar ataxia type-3 (SCA-3) is the most prevalent autosomal dominant inherited ataxia. We recently found that the endocannabinoid system is altered in the post-mortem cerebellum of SCA-3 patients, and similar results were also found in the cerebellar and brainstem nuclei of a SCA-3 transgenic mouse model. Given that the neuropathology of SCA-3 is not restricted to these two brain regions but rather, it is also evident in other structures (e.g., the basal ganglia), we studied the possible changes to endocannabinoid signaling in the striatum of these transgenic mice. SCA-3 mutant mice suffer defects in motor coordination, balance and they have an abnormal gait, reflecting a cerebellar/brainstem neuropathology. However, they also show dystonia-like behavior (limb clasping) that may be related to the malfunction/deterioration of specific neurons in the striatum. Indeed, we found a loss of striatal projecting neurons in SCA-3 mutant mice, accompanied by a reduction in glial glutamate transporters that could potentially aggravate excitotoxic damage. In terms of endocannabinoid signaling, no changes in CB2 receptors were evident, yet an important reduction in CB1 receptors was detected by qPCR and immunostaining. The reduction in CB1 receptors was presumed to occur in striatal afferent and efferent neurons, also potentially aggravating excitotoxicity. We also measured the endocannabinoid lipids in the striatum and despite a marked increase in the FAAH enzyme in this area, no overall changes in these lipids were found. Collectively, these studies confirm that the striatal endocannabinoid system is altered in SCA-3 mutant mice, adding to the equivalent changes found in other strongly affected CNS structures in this type of ataxia (i.e.: the cerebellum and brainstem). These data open the way to search for drugs that might correct these changes.

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Endocannabinoid signalling in Alzheimer's disease

Cited by 27 publications

References 51 publications

Molecular Targets of Cannabidiol in Neurological Disorders

Molecular Targets of Cannabidiol in Neurological Disorders

Endocannabinoids drive the acquisition of an alternative phenotype in microglia

Altered striatal endocannabinoid signaling in a transgenic mouse model of spinocerebellar ataxia type-3

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