Effects of cannabidiol interactions with Wnt/β-catenin pathway and PPARγ on oxidative stress and neuroinflammation in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease, in which the primary etiology remains unknown. AD presents amyloid beta (Aβ) protein aggregation and neurofibrillary plaque deposits. AD shows oxidative stress and chronic inflammation. In AD, canonical Wingless-Int (Wnt)/β-catenin pathway is downregulated, whereas peroxisome proliferator-activated receptor γ (PPARγ) is increased. Downregulation of Wnt/β-catenin, through activation of glycogen synthase kinase-3β (GSK-3β) by Aβ, and inactivation of phosphatidylinositol 3-kinase/Akt signaling involve oxidative stress in AD. Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid from Cannabis sativa plant. In PC12 cells, Aβ-induced tau protein hyperphosphorylation is inhibited by CBD. This inhibition is associated with a downregulation of p-GSK-3β, an inhibitor of Wnt pathway. CBD may also increase Wnt/β-catenin by stimulation of PPARγ, inhibition of Aβ and ubiquitination of amyloid precursor protein. CBD attenuates oxidative stress and diminishes mitochondrial dysfunction and reactive oxygen species generation. CBD suppresses, through activation of PPARγ, pro-inflammatory signaling and may be a potential new candidate for AD therapy.

Antioxidative and Anti-Inflammatory Properties of Cannabidiol

“…Lys48-linked polyubiquitin of the ligand-binding domain of PPARγ is responsible for proteosomal degradation of p65 [83]. In this way, PPARγ participates in the modulation of inflammation by inducing ubiquitination proteosomal degradation of p65, which causes inhibition of pro-inflammatory gene expression, such as cyclooxygenase (COX2) and some pro-inflammatory mediators such as TNF-α, IL-1β, and IL-6, as well as inhibition of NFκB-mediated inflammatory signaling [84]. For this reason, PPARγ agonists can play an anti-inflammatory role by inhibiting the NFκB-mediated transcription of downstream genes [84].…”

“…In addition, direct CBD activity is enhanced by the action of AEA and 2-AG, which are also PPARγ agonists and whose levels are elevated by CBD [92]. It has been found that stimulation of PPARα and reduction of oxidative stress by CBD prevents amyloid β-induced neuronal death by increasing the levels of Wnt/β-catenin [84]. However, there are no data on the interaction between CBD and other PPAR subtypes (PPARα, β, δ).…”

Is cannabidiol a drug acting on unconventional targets to control drug‐resistant epilepsy?

“…CBD decreases oxidative stress, mitochondrial dysfunction and reactive oxygen species generation, effects associated with reduced neuroinflammation. 97 CBD also augments microglial phagocytosis by the modification of TRPV channel activity. 98 It induces anti-inflammatory effects by decreasing the plasma levels of prostaglandin E2, the production of free radicals, and the activity of COX-1/COX-2.…”

“…Experimental evidence supports that CBD represents a novel strategy to reduce oxidative stress, excitotoxicity, and neuroinflammation in neurodegenerative disorders. CBD decreases oxidative stress, mitochondrial dysfunction and reactive oxygen species generation, effects associated with reduced neuroinflammation . CBD also augments microglial phagocytosis by the modification of TRPV channel activity .…”

Alzheimer’s Disease Neuroprotection: Associated Receptors

“…Peroxisome proliferatoractivated γ receptor is up-regulated in AD due to existing neuroinflammation and PPARγ agonists can be used in AD and shows anti-inflammatory effects, as well as improve learning and memory. Thus, PPARγ might be a significant new therapeutic target in AD treatment [52]. In addition, emerging evidence suggests that PPARγ effectively regulates microglia activation under physiological and pathological conditions, facilitating Aβ microglial phagocytosis [53].…”