Cannabidiol regulates CB1‐pSTAT3 signaling for neurite outgrowth, prolongs lifespan, and improves health span in Caenorhabditis elegans of Aβ pathology models

Abstract

Cannabidiol (CBD), a phytocannabinoid from the Cannabis sativa plant, exhibits a broad spectrum of potential therapeutic properties for neurodegenerative diseases.An accumulation of amyloid-β (Aβ) protein is one of the most important neuropathology in neurodegenerative diseases like Alzheimer's disease (AD). Data on the effect of CBD on the amelioration of Aβ-induced neurite degeneration and its consequences of life and health spans is sparse. This study aimed to investigate the effects of CBD on neurite outgrowth in cells and lifespan and health span in Caenorhabditis elegans (C. elegans). In human SH-SY5Y neuronal cells, CBD prevented neurite lesion induced by Aβ 1-42 and increased the expression of fatty acid amide hydrolase (FAAH) and cannabinoid receptor 1 (CB1R). Furthermore, CBD both protected the reduction of dendritic spine density and rescued the activity of synaptic Ca 2+ / calmodulin-dependent protein kinase II (CaMKII) from Aβ 1-42 toxicity in primary hippocampal neurons. In C. elegans, we used the transgenic CL2355 strain of C. elegans, which expresses the human Aβ peptide throughout the nervous system and found that CBD treatment extended lifespan and improved health span. The neuroprotective effect of CBD was further explored by observing the dopaminergic neurons using transgenic dat-1: GFP strains using the confocal microscope. This study shows that CBD prevents the neurite degeneration induced by Aβ, by a mechanism involving CB1R activation, and extends lifespan and improves health span in Aβoverexpressing worms. Our findings support the potential therapeutic approach of CBD for the treatment of AD patients.

Cannabinoids and Neurogenesis: The Promised Solution for Neurodegeneration?

“…Neuronal culture exposed to Aβ reacts with a shortening in neurite length, but this can be reversed after treatment with CBD (20 mg/kg) and the effect is CB1-dependent., Moreover, CBD protects AEA from deactivation, reducing the amount of fatty acid amide hydrolase (FAAH), the enzyme responsible for AEA degradation. The same protective mechanism is suggested as explanation of neurogenesis rescue also in genetic AD mouse models [ 103 , 104 ]. In this way, an increased amount of AEA can interact with CB1 and its downstream signal, involving the PI3K/AKT pathway and signal transducer and activator of transcription 3 (STAT3) subsequently, mediate neurite outgrowth.…”

“…Treatment with CBD increased the expression of synaptophysin and synapsin I, both expressed on synapsis, indicating a role in inducing synapsis formation or in potentiating the already existent ones. Furthermore, the activation of tropomyosin receptor kinase A (TrkA) receptors was found [ 104 ]. TrkA is the main target of nerve growth factor (NGF) and both seem to regulate also apoptosis in neurons.…”

Modeling Alzheimer’s Disease in Caenorhabditis elegans

“…Cannabidiol increased longevity and prevented Aβ-induced neurite degeneration in a pan-neuronal Aβ expression model in C. elegans through a mechanism involving cannabinoid receptor 1 activation [ 158 ].…”

ACEA Attenuates Oxidative Stress by Promoting Mitophagy via CB1R/Nrf1/PINK1 Pathway after Subarachnoid Hemorrhage in Rats

“…Cannabinoid receptor 1 (CB1R), a G-protein-coupled receptor, was reported to be a potential therapeutic target for many central nervous system diseases, such as ischemic stroke, epilepsy, and Parkinson's and Alzheimer's disease [ 29 , 40 – 42 ]. CB1R is widely expressed in different organs, especially in the central nervous system (e.g., cerebral cortex, hippocampus, striatum, and cerebellum) [ 43 ].…”

“…ACEA, a highly selective CB1R agonist, was reported to provide a neuroprotective effect for ischemic stroke, Parkinson's disease, Alzheimer's disease, and epilepsy [ 29 , 41 , 42 , 44 ]. However, there is no published research attempted to treat SAH using ACEA.…”