Cannabis Therapeutics and the Future of Neurology

Ethan B. Russo  (October 2018)

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Recent reviews (Aso and Ferrer, 2014; Ahmed et al., 2015) have nicely summarized the pathophysiology of AD: a neurodegenerative disease with senile plaques formed of fibrillar β-amyloid (Aβ) from cleavage of the Aβ precursor protein (APP) by β- and γ-secretases and by presence of neurofibrillary tangles composed of hyper-phosphorylated and nitrated tau protein. The latter precedes Aβ deposition in sporadic cases. Once the process begins, deterioration is inexorable. Additional pathology includes functional mitochondrial defects, increased reactive oxygen species (ROS) and reactive nitrogen species (RNS), and failure of enzymes involved in energy production that, in turn, produces nerve cell exhaustion. Eventually, synapses and dendritic branching fail, with consequent progressive neuronal wastage. Dementia and cognitive decline develop, and no treatment arrests the process. Intervention must begin at an early preclinical stage to have any hope of success. Endocannabinoid function modulates the primary pathological processes of AD during the silent phase of neurodegeneration: protein misfolding, neuroinflammation, excitotoxicity, mitochondrial dysfunction and oxidative stress. CB2 levels increase in AD especially in microglia around senile plaques, and its stimulation stimulates Aβ removal by macrophages.

Cannabidiol Reverses Deficits in Hippocampal LTP in a Model of Alzheimer’s Disease

Blathnaid Hughes (March 2018)

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Here we demonstrate for the first time that cannabidiol (CBD) acts to protect synaptic plasticity in an in vitro model of Alzheimer’s disease (AD). The non-psycho active component of Cannabis sativa, CBD has previously been shown to protect against the neurotoxic effects of beta amyloid peptide (Aβ) in cell culture and cognitive behavioural models of neurodegeneration.

Innovative Therapeutic Potential of Cannabinoid Receptors as Targets in Alzheimer’s disease and Less Well-Known Diseases.

JA Paez, NE Campillo  (February 2018)

The endocannabinoid system has been implicated in a wide diversity of biological processes, in both the central and peripheral nervous systems, including memory, learning, neuronal development, stress and emotions, food intake, energy regulation, peripheral metabolism, and the regulation of hormonal balance through the endocrine system. In this context, this article will review the current knowledge of the therapeutic potential of cannabinoid receptor as a target in Alzheimer’s disease and other less well-known diseases that include, among others, multiple sclerosis, bone metabolism, and Fragile X syndrome. The therapeutic applications will be addressed through the study of cannabinoid agonists acting as single drugs and multi-target drugs highlighting the CB2 receptor agonist.

Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer’s disease and levodopa-induced dyskinesia

GemmaNavarroDasielBorroto-EscuelaEdgarAngelatsÍñigoEtayoIreneReyes-ResinaMartaPulido-SalgadoAna I.Rodríguez-PérezEnric I.CanelaJosepSauraJosé LuisLanciegoJosé LuisLabandeira-GarcíaCarlos A.SauraKjellFuxeRafaelFranco  (January 2018)

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Endocannabinoids are important regulators of neurotransmission and, acting on activated microglia, they are postulated as neuroprotective agents. Endocannabinoid action is mediated by CB1 and CB2 receptors, which may form heteromeric complexes (CB1-CB2Hets) with unknown function in microglia. We aimed at establishing the expression and signaling properties of cannabinoid receptors in resting and LPS/IFN-γ-activated microglia. In activated microglia mRNA transcripts increased (2 fold for CB1 and circa 20 fold for CB2), whereas receptor levels were similar for CB1 and markedly upregulated for CB2; CB1-CB2Hets were also upregulated.

The therapeutic potential of the phytocannabinoid cannabidiol for Alzheimer’s disease

Tim Karl, Brett Garner, David Cheng  (April 2017)

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Alzheimer’s disease (AD) is the most common neurodegenerative disorder, characterized by progressive loss of cognition. Over 35 million individuals currently have AD worldwide. Unfortunately, current therapies are limited to very modest symptomatic relief. The brains of AD patients are characterized by the deposition of amyloid-β and hyperphosphorylated forms of tau protein. AD brains also show neurodegeneration and high levels of oxidative stress and inflammation. The phytocannabinoid cannabidiol (CBD) possesses neuroprotective, antioxidant and anti-inflammatory properties and reduces amyloid-β production and tau hyperphosphorylation in vitro. CBD has also been shown to be effective in vivo making the phytocannabinoid an interesting candidate for novel therapeutic interventions in AD, especially as it lacks psychoactive or cognition-impairing properties.

In vivo Evidence for Therapeutic Properties of Cannabidiol (CBD) for Alzheimer’s Disease

Georgia Watt and Tim Karl  (February 2017)

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Here, we summarize the current status quo of in vivo effects of CBD in established pharmacological and transgenic animal models for AD. The studies demonstrate the ability of CBD to reduce reactive gliosis and the neuroinflammatory response as well as to promote neurogenesis. Importantly, CBD also reverses and prevents the development of cognitive deficits in AD rodent models. Interestingly, combination therapies of CBD and Δ9-tetrahydrocannabinol (THC), the main active ingredient of cannabis sativa, show that CBD can antagonize the psychoactive effects associated with THC and possibly mediate greater therapeutic benefits than either phytocannabinoid alone.

Endocannabinoids and Neurodegenerative Disorders: Parkinson’s Disease, Huntington’s Chorea, Alzheimer’s Disease, and Others

Javier Fernández-Ruiz, Julián Romero, José A. Ramos  (2015)

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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.