Cannabinoid-profiled agents improve cell survival via reduction of oxidative stress and inflammation, and Nrf2 activation in a toxic model combining hyperglycemia+Aβ 1-42 peptide in rat hippocampal neurons

Neurochemistry International “Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder linked to various converging toxic mechanisms. Evidence suggests that hyperglycemia induces oxidative stress, mitochondrial dysfunction, inflammation and excitotoxicity, all of which play important roles in the onset and progression of AD pathogenesis.

The endocannabinoid system (ECS) orchestrates major physiological responses, including neuronal plasticity, neuroprotection, and redox homeostasis, to name a few. The multi-targeted effectiveness of the ECS emerges as a potential approach to treat AD.

Here we characterized the protective properties of the endocannabinoids arachidonylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), the synthetic cannabinoids CP 55-940 and WIN 55,212-2, and the fatty acid amide hydrolase (FAAH) inhibitor URB597, on a combined hyperglycemia+oligomeric amyloid β peptide (Aβ1-42) neurotoxic model in primary hippocampal neurons which exhibit several AD features.

All agents tested preserved cell viability and stimulated mitochondrial membrane potential, while reducing all the evaluated toxic endpoints in a differential manner, with URB597 showing the highest efficacy. The neuroprotective efficacy of all cannabinoid agents, except for URB597, led to partial recruitment of specific antioxidant activity and Nrf2 pathway regulation.

Our results support the neuroprotective potential of these agents at low concentrations against the damaging effects of GLU+Aβ1-42, affording new potential modalities for the design of AD therapies.”

https://pubmed.ncbi.nlm.nih.gov/32781098/

“All cannabinoid agents prevented the GLU + Aβ1-42 toxicity in a differential manner. All cannabinoid agents recruited Nrf2 signaling to protect cells.”

https://www.sciencedirect.com/science/article/abs/pii/S0197018620302084?via%3Dihub

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