Natural Cannabinoids Improve Dopamine Neurotransmission and Tau and Amyloid Pathology in a Mouse Model of Tauopathy

Abstract

Abstract. Cannabinoids are neuroprotective in models of neurodegenerative dementias. Their effects are mostly mediated through CB1 and CB2 receptor-dependent modulation of excitotoxicity, inflammation, oxidative stress, and other processes. We tested the effects of Sativex ® , a mixture of 9 -tetrahydrocannabinol and cannabidiol, acting on both CB1 and CB2 receptors, in parkin-null, human tau overexpressing (PK −/− /Tau VLW ) mice, a model of complex frontotemporal dementia, parkinsonism, and lower motor neuron disease. The animals received Sativex ® , 4.63 mg/kg, ip, daily, for one month, at six months of age, at the onset of the clinical symptoms. We evaluated the effects of Sativex ® on behavior, dopamine neurotransmission, glial activation, redox state, mitochondrial activity, and deposition of abnormal proteins. PK −/− /Tau VLW mice developed the neurological deficits, but those treated with Sativex ® showed less abnormal behaviors related to stress, less auto and hetero-aggression, and less stereotypy. Sativex ® significantly reduced the intraneuronal, MAO-related free radicals produced during dopamine metabolism in the limbic system. Sativex ® also decreased gliosis in cortex and hippocampus, increased the ratio reduced/oxidized glutathione in the limbic system, reduced the levels of iNOS, and increased those of complex IV in the cerebral cortex. With regard to tau and amyloid pathology, Sativex ® reduced the deposition of both in the hippocampus and cerebral cortex of PK −/− /Tau VLW mice and increased autophagy. Sativex ® , even after a short administration in animals with present behavioral and pathological abnormalities, improves the phenotype, the oxidative stress, and the deposition of proteins in PK −/− /Tau VLW mice, a model of complex neurodegenerative disorders.

Involvement of inflammation in Alzheimer’s disease pathogenesis and therapeutic potential of anti-inflammatory agents

“…Activation of CB 2 receptor by the receptor agonists significantly decreased neuroinflammatory responses in the brains that received the injection of Ab (Fakhfouri et al 2012;Martin-Moreno et al 2011). Furthermore, similar anti-neuroinflammatory effects by cannabinoids were observed in APP transgenic and taupathy mice (Aso et al 2013;Casarejos et al 2013;MartinMoreno et al 2012). In addition to CB 2 receptors, CB 1 receptors appeared to downregulate neuroinflammation, as Aso et al showed that chronic treatment with the selective CB 1 receptor agonist, arachidonyl-2-chloroethylamide, reduced the astrocytic expression of the pro-inflammatory cytokine interferon-c in APP/PS1 transgenic mice (Aso et al 2012).…”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…Finally, a Sativex-like combination of ⌬ 9 -THC:CBD is neuroprotective in the malonate-lesioned rat inflammatory model of HD (865) and improves dopamine neurotransmission and tau and amyloid pathology in a mouse model of tauopathies (123).…”

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

“…An interesting formulation to be investigated at the clinical level is the recently licensed phytocannabinoid-based medicine Sativex (GWPharma), which, based on the activity of its 2 components, Δ 9 -THC and CBD, at different complementary targets identified as neuroprotective in AD, e.g. CB 1 R and CB 2 R, PPARs, could become a promising novel disease-modifying therapy for patients with AD, as has been recently demonstrated in a preclinical model of an AD-related disorder (frontotemporal dementia) [103].…”