Cannabidiol for neurodegenerative disorders: A comprehensive review

Abstract

Despite the significant advances in neurology, the cure for neurodegenerative conditions remains a formidable task to date. Among various factors arising from the complex etiology of neurodegenerative diseases, neuroinflammation and oxidative stress play a major role in pathogenesis. To this end, some phytocannabinoids isolated from Cannabis sativa (widely known as marijuana) have attracted significant attention as potential neurotherapeutics. The profound effect of ∆⁹-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, has led to the discovery of the endocannabinoid system as a molecular target in the central nervous system (CNS). Cannabidiol (CBD), the major non-psychoactive component of cannabis, has recently emerged as a potential prototype for neuroprotective drug development due to its antioxidant and anti-inflammatory properties and its well-tolerated pharmacological behavior. This review briefly discusses the role of inflammation and oxidative stress in neurodegeneration and demonstrates the neuroprotective effect of cannabidiol, highlighting its general mechanism of action and disease-specific pathways in Parkinson's disease (PD) and Alzheimer's disease (AD). Furthermore, we have summarized the preclinical and clinical findings on the therapeutic promise of CBD in PD and AD, shed light on the importance of determining its therapeutic window, and provide insights into identifying promising new research directions.

Keywords: Alzheimer’s disease; Parkinson’s disease; cannabidiol; neurodegenerative diseases; neuroinflammation; oxidative stress.

FIGURE 1

(A) Chemical structure of CBD, THC, anandamide (AEA), and 2-arachidonoylglycerol (2AG). (B) CBD indirectly activates CB1 receptor and TRPV1 by inhibiting FAAH and thereby promoting the accumulation of AEA at synapse which may play a role in inhibiting glutamate-based excitotoxicity.

FIGURE 2

(A) Inflammatory components in Alzheimer’s disease (left): initially, microglia act as neuroprotectants that can sense and migrate to the Aβ aggregates. The Aβ aggregates interact with different cell surface receptors (TLR and RAGE) of microglia which induce activation of some transcription factors such as NF-kB and AP-1 and produce reactive species (ROS and NO) and cytokines (microglial activation). However, under sustained inflammation, activated microglia exhibit compromised Aβ clearance ability due to impaired ApoE/LRP uptake, while the production of ROS and inflammatory mediators remains unaltered which directly causes apoptosis/necrosis in neurons. Activated microglia can also activate astrocytes by releasing cytokines which in return can further activate the microglia. In addition, ATP released from neuronal death activates microglia via the purinergic receptors (PR), and collectively, a feed-forward loop is established. (B) Parkinson’s disease (right): intracellular deposition of α-synuclein known as Lewy bodies caused stress in dopaminergic neurons, while the oligomeric α-synuclein in the extracellular space causes activation of glia cells (microglia and astrocytes) in a similar manner to amplify the neuroinflammation and oxidative stress causing the death of dopaminergic neurons. Adapted with permission from (Glass et al., 2010).

FIGURE 3

Different molecular targets of CBD in the brain.

FIGURE 4

Amyloid β pathogenesis of AD. APP protein is processed by secretase enzymes to produce Aβ peptides. Aggregated Aβ causes microglial activation to produce ROS and inflammatory cytokines which further activate astrocytes. ROS binds to NF-κB sites in the promoters of APP in neurons to activate transcription of the Aβ peptide. Aβ plaques enhance glutamate release from neurons and astrocytes. Prolonged activation of extrasynaptic NMDA receptors by excess glutamate leads to intense transient Ca²⁺ influx which alters some signaling pathways and causes neuronal death (excitotoxicity). Aβ also inhibits the activity of acetylcholine esterase and lowers the expression of nicotinic acetylcholine receptor (nAchR). In addition, Aβ accumulation promotes endocytosis of NMDA receptors at synapses which suppresses synaptic transmission and alters synaptic plasticity.

FIGURE 5

Molecular pathways of contributing neuroprotective role of CBD.