Abstract
Decline in cognitive performance, an aspect of the normal aging process, is influenced by the endocannabinoid system (ECS). Cannabinoid receptor 1 (CB1) signaling diminishes with advancing age in specific brain regions that regulate learning and memory and abolishing CB1 receptor signaling accelerates cognitive aging in mice. We recently demonstrated that prolonged exposure to low dose (3 mg/kg/day) Δ9-tetrahydrocannabinol (THC) improved the cognitive performances in old mice on par with young untreated mice. Here we investigated the potential influence of cannabidiol (CBD) on this THC effect, because preclinical and clinical studies indicate that the combination of THC and CBD often exhibits an enhanced therapeutic effect compared to THC alone. We first tested the effectiveness of a lower dose (1 mg/kg/day) THC, and then the efficacy of the combination of THC and CBD in 1:1 ratio, same as in the clinically approved medicine Sativex®. Our findings reveal that a 1 mg/kg/day THC dose still effectively improved spatial learning in aged mice. However, a 1:1 combination of THC and CBD failed to do so. The presence of CBD induced temporal changes in THC metabolism ensuing in a transient elevation of blood THC levels. However, as CBD metabolizes, the inhibitory effect on THC metabolism was alleviated, causing a rapid clearance of THC. Thus, the beneficial effects of THC seemed to wane off more swiftly in the presence of CBD, due to these metabolic effects. The findings indicate that THC-treatment alone is more efficient to improve spatial learning in aged mice than the 1:1 combination of THC and CBD.
Highlights
Discreetly, the physiological aging process is associated with a decline in cognitive performance attributed to the volumetric changes in specific brain areas
A role of cannabinoid receptor 1 (CB1) signaling in the aging process has been suggested by genetic mouse models that show that the loss of CB1 receptors increased the mortality rate (Zimmer et al, 1999) and accelerated cognitive aging, accompanied by neuronal loss in the hippocampus and aging-like histological changes in the skin (Bilkei-Gorzo et al, 2005, 2012)
CB1 receptor expression decreases in various brain regions and undergo functional alterations in ligand-binding and G proteincoupling with advancing age (Berrendero et al, 1998; Feliszek et al, 2016)
Summary
The physiological aging process is associated with a decline in cognitive performance attributed to the volumetric changes in specific brain areas. All these changes rapidly aggravate under pathological conditions like Alzheimer’s disease (AD) (Harada et al, 2013). This cannabinoid is the major psychoactive ingredient in Cannabis sativa. Further studies from human postmortem brains reported a significant decrease in the expression of diacylglycerol lipase α (Daglα), the synthesizing enzyme of 2-AG, after a young age (Long et al, 2012). Both 2-AG and DAGLα protein levels decrease prominently in the hippocampus of aged mice (Piyanova et al, 2015)
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