Emerging potential of cannabidiol in reversing proteinopathies

Highlights

• Proteinopathy is the common hallmarks of many age-related neurodegenerative disorders.

• Activation of proteostasis can reverse proteinopathies and halt neurodegenerations.

• Cannabidiol can boost proteostasis through diverse signaling pathways of proteostasis.

• Cannabidiol reduces oxidative stress and neuroinflammation of brain.

• Cannabidiol modulates protein clearance system and also inhibits Ca²⁺ induced protein misfolding.

Abstract

The aberrant accumulation of disease-specific protein aggregates accompanying cognitive decline is a pathological hallmark of age-associated neurological disorders, also termed as proteinopathies, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and multiple sclerosis. Along with oxidative stress and neuroinflammation, disruption in protein homeostasis (proteostasis), a network that constitutes protein surveillance system, plays a pivotal role in the pathobiology of these dementia disorders. Cannabidiol (CBD), a non-psychotropic phytocannabinoid of Cannabis sativa, is known for its pleiotropic neuropharmacological effects on the central nervous system, including the ability to abate oxidative stress, neuroinflammation, and protein misfolding. Over the past years, compelling evidence has documented disease-modifying role of CBD in various preclinical and clinical models of neurological disorders, suggesting the potential therapeutic implications of CBD in these disorders. Because of its putative role in the proteostasis network in particular, CBD could be a potent modulator for reversing not only age-associated neurodegeneration but also other protein misfolding disorders. However, the current understanding is insufficient to underpin this proposition. In this review, we discuss the potentiality of CBD as a pharmacological modulator of the proteostasis network, highlighting its neuroprotective and aggregates clearing roles in the neurodegenerative disorders. We anticipate that the current effort will advance our knowledge on the implication of CBD in proteostasis network, opening up a new therapeutic window for aging proteinopathies.

Introduction

Disruption in proteostasis network and protein misfolding are two major drivers in the pathobiology of age-associated neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). NDDs are generally characterized by the presence of protein aggregates either in the nucleus or cytoplasm (Menzies et al., 2015; Sarkar, 2013), and the region-specific neuronal death with a consequence of motor and cognitive deficits (Lumkwana et al., 2017; Skovronsky et al., 2006). A line of evidence supports the concept that NDDs are proteinopathies, where they share fundamental features of protein aggregate, for example, tau and amyloid-β in AD, α-synuclein in PD, huntingtin (Htt) in HD, etc. (Boland et al., 2018; Golde et al., 2013; Marsh, 2019). Proteostasis network constitutes the protein surveillance system that regulates all aspects of the cellular proteome, from protein synthesis to clearance of misfolded proteins. (Soares et al., 2019). Evidence from the recent studies correlates the higher incidence of NDD with the progressive failure of the proteostasis network, which results in proteotoxic stress that reduces both repair and/or clearance of misfolded protein; and thus contributes to pathological aging (Labbadia and Morimoto, 2015; López-Otín et al., 2013; Martínez et al., 2017; Morimoto and Cuervo, 2014). The proteostasis network is impaired by oxidative stress (OS), which is a pathological condition arising from excess production of reactive oxygen species (ROS) due to starvation, exposure to antibiotics (Morano et al., 2012), inflammation (Ravishankar et al., 2015), disease-associated mutations, polymorphisms, energetic deficits and aging (Ferrington and Gregerson, 2012; Luo et al., 2017; Powers et al., 2009; Reichmann et al., 2018), where it plays vulnerable roles in disrupting proteostasis by causing oxidative damage and neuroinflammation, leading to cell death (Korovila et al., 2017; Powers et al., 2009).

Accumulating evidence suggests that endocannabinoid systems regulate the functionality of redox homeostasis in different cell types (Ambrożewicz et al., 2018; Lipina and Hundal, 2016), thus maintain an equilibrium state between the redox system and pro-oxidant state (Gomes et al., 2018; Llanos-González et al., 2020). The endocannabinoid systems, consisting of cannabinoid receptors (CB1 and CB2), are either activated or antagonized by endocannabinoids and phytocannabinoids (Paloczi et al., 2018). Phytocannabinoids, such as cannabidiol (CBD), cannabivarin, delta-9-tetrahydrocannabinol (THC), cannabidivarin, and cannabigerol, have been widely studied for their involvement in endocannabinoid systems (Linge et al., 2016). CBD is one of the fascinating non-psychoactive phytocannabinoids with well-known anti-oxidant and anti-inflammatory properties (Giacoppo and Mazzon, 2016; Huestis et al., 2019).

CBD has shown to provide neuroprotection (Campos et al., 2016) and thus become a therapeutic option in neurodegenerative disorders like AD, PD, HD, ALS, and MS, where treatment slows down disease progression (Iuvone et al., 2009). Remarkedly, disease-modifying mechanisms of CBD are attributed to its antioxidant, anti-inflammatory, and neuroprotective potentials; the precise mechanisms, however, remain unclear, specifically in the regulation of proteostasis network (HAMPSON et al., 2000). In this review, an attempt has been made to link CBD-mediated pharmacological effects with the proteostasis network, providing a more extensive area for future research on CBD pharmacology in the management of neurodegenerative disorders.