From Cannabis sativa to Cannabidiol: Promising Therapeutic Candidate for the Treatment of Neurodegenerative Diseases

Abstract

Cannabis sativa, commonly known as marijuana, contains a pool of secondary plant metabolites with therapeutic effects. Besides Δ9-tetrahydrocannabinol that is the principal psychoactive constituent of Cannabis, cannabidiol (CBD) is the most abundant nonpsychoactive phytocannabinoid and may represent a prototype for anti-inflammatory drug development for human pathologies where both the inflammation and oxidative stress (OS) play an important role to their etiology and progression. To this regard, Alzheimer's disease (AD), Parkinson's disease (PD), the most common neurodegenerative disorders, are characterized by extensive oxidative damage to different biological substrates that can cause cell death by different pathways. Most cases of neurodegenerative diseases have a complex etiology with a variety of factors contributing to the progression of the neurodegenerative processes; therefore, promising treatment strategies should simultaneously target multiple substrates in order to stop and/or slow down the neurodegeneration. In this context, CBD, which interacts with the eCB system, but has also cannabinoid receptor-independent mechanism, might be a good candidate as a prototype for anti-oxidant drug development for the major neurodegenerative disorders, such as PD and AD. This review summarizes the multiple molecular pathways that underlie the positive effects of CBD, which may have a considerable impact on the progression of the major neurodegenerative disorders.

Keywords: Alzheimer's disease; Cannabis sativa; Parkinson's disease; cannabidiol; oxidative stress; phytocannabinoids.

Figure 1

Effect of cannabidiol (CBD) in Parkinson's disease and Alzheimer' disease (AD). CBD antagonizes the action of cannabinoid receptors (CB1, CB2) acting as a reverse agonist and negative allosteric modulator of both receptors. CBD also inhibits fatty acid amide hydrolase (FAAH), resulting in increased levels of endocannabinoids (ECs). ECs activate the anti-oxidant and anti-inflammatory effects that are partially mediated by the actions of the CBD of transient receptor potential cation channel subfamily V member 1 (TRPV1) [1]. CBD binds the peroxisome proliferator-activated receptors (PPARs), antagonizes the action of nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), and reduces the expression of proinflammatory enzymes such as inducible nitric oxide synthases (iNOS), cyclooxygenase-2 (COX-2), and proinflammatory cytokines [2]. Activation of PPARγ by modulating the expression of proinflammatory mediators such as nitric oxide (NO), tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6), iNOS, and COX-2 [3]. The CBD downregulates the β- and γ-secretase genes leading to a reduction in amyloid-β (Aβ) production [4]. CBD is able to reduce the oxidative stress (OS) through the attenuation of mitochondrial dysregulation and reactive oxygen species (ROS) generation or by the decrease of the expression of several ROS generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase isoforms [5]. The stimulation of transient receptor potential vanilloid-1 (TRPV1) by CBD can activate phosphoinositide 3-kinases/protein kinase B (PI3K/Akt) signaling, which in turn inhibits glycogen synthase kinase 3 β (GSK-3β) by phosphorylation of Ser9, thus reducing tau phosphorylation [6]. CBD reduces the activity of p-GSK-3β, the active phosphorylated form of GSK3-β, and causes an increase in the Wnt/β-catenin pathway. The activation of this pathway can protect against OS and Aβ neurotoxicity in AD [7].