Introduction
Cannabis sativa L. (Magnoliopsida; Cannabaceae) popularly known as hemp, marijuana, cannabis, weed, among other names is a species belonging to the Cannabaceae family [1-6]. All over the world,Cannabis sativa L. is an ancient and traditional plant in several cultures, which has been passing through generations, from antiquity to the present day. Although at the beginning of the 20th century it was established as an illegal drug, even with a reduced consumption, it was considered the most consumed recreational drug in the world. Its presence among humans is highlighted in religious rites, for food, psychoactive and especially medicinal use [7, 8].
The constituents of C. sativa are formed by nitrogen compounds, amino acids, hydrocarbons, terpenes, and sugars responsible for the toxicological and pharmacological effects [9]. However, it is widely known that the two main ingredients in Cannabis are Δ9 -tetrahidrocanabinol (THC) and Cannabidiol (CBD) [10], CBD being the most abundant phytocannabinoid that does not present psychoactive properties, which has shown benefits to human health, mainly due to its molecular interaction with the endocannabinoid system (ES) [11] .
After discovering cannabinoid receptors, mammals were shown to produce endogenous agonists for these receptors (the endocannabinoids), such as anandamide, also known as N-arachidonoylethanolamine (AEA) and 2-arachidonoyl-glycerol (2-AG) [6, 12]. Endocannabinoids are involved in food intake, analgesia, cancer, and addiction [13], but until the discovery of the ES, the receptor identified as “cannabinoid receptor 1 (CB1)” was a “receptor coupled to G” protein without a previously known ligand. The high affinity of THC for the CB1 receptor has increased knowledge about the ES [5]. However, the second cannabinoid receptor (CB2) has low psychoactive activity compared to the CB1 receptor [2-5, 14]. As for CBD, studies have shown that it develops an allosteric binding activity between CB1 and CB2 receptors and that it presents other potential therapeutic targets such as transient receptor potential vanilloid (TRPV), o peroxisome proliferator-actived receptor γ (PPARγ), o G protein-coupled receptor 55 (GPR55), receptors 5-hydroxytryptamine (5-HT), γ-Aminobutyric acid type A (GABAA) e transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8). While the CB2 receptor is mostly found in cells of the immune system, the CB2 receptor is highly common in the central nervous system (CNS), mainly in brain areas [15].
In this way, CBD has been identified as a potent anti-inflammatory and antioxidant that, interacting directly or indirectly with CB1 and CB2 receptors and other molecular targets, mediates neuroprotection. In this sense, it has been investigated as a potential therapy for neurodegenerative diseases [16], considering that throughout the world, due to the increase in people’s life expectancy, these diseases have been worrying because they gradually lead to functional loss of motor and /or cognitive and produce high economic and social impacts [16-19].
There are several suggestions about the pathogenesis of neurodegenerative diseases, including the idea that the entire brain begins to be invaded by abnormal protein aggregates that are the result of an abnormal conformation of the peptides β-amyloid, α-synuclein and tau [16, 18, 20, 21]. It is considered that Parkinson’s disease, a neurodegenerative disease that generally affects the elderly, presents aggregates of α-synuclein as a triggering factor for neurotoxicity and, consequently, neuronal death. In this process, microglia are activated leading to the production of pro-inflammatory cytokines and mediators of oxidative stress, resulting in the death of dopaminergic neurons in the white matter [22-25].
Also recognized as a neurodegenerative disease, multiple sclerosis affects around 2.8 million people worldwide, including children. It is a very prevalent chronic inflammatory disease of the CNS, with a complex and multifactorial etiology [26, 27]. In multiple sclerosis, there is no consensus that white matter lesions are of inflammatory or neurodegenerative origin, considering that in the early stages of the disease inflammation is rarely observed, thus suggesting that there is a direct involvement of lymphocytes in tissue damage or indirect involvement through the activation of microglia [27, 28]. CBD and THC formulas, in a 1:1 ratio, have been used to treat neuropathic pain and spasticity in multiple sclerosis considering, according to Russo and Guy [29] that beneficial therapeutic effects are increased when these phytocannabinoids are combined in a single product. In this sense, CBD has been seen as responsible for reducing the adverse effects of THC [16].
CBD has been indicated for pediatric epileptic disorders, refractory to medications, and its clinical use was authorized in 2018 by the Food and Drug Administration (FDA). It is known that epileptic disorders are triggered by an imbalance in the excitatory and inhibitory neurotransmission system [30]. On the other hand, epilepsy has currently been recognized as comorbidity in neurodegenerative diseases, consequently increasing longevity. Seeking to control epilepsy in the elderly, for example, would result in the reduction of cognitive deficits, the prevention of mortality from injuries arising from seizures and even from falls, which are frequent in this case [19]. Thus, alone or as an adjuvant, in the near future, CBD may extend its clinical use to secondary neurodegenerative disorders [16].
It is known that cannabis has promoted the modulation of several pathophysiological phenomena due to the interaction between the ES and different preparations, natural (phytocannabinoids) or synthetic (cannabinoids) [31-34]. Thus, this review aimed to provide an overview of the ES and a summary of the clinical and preclinical findings of the therapeutic use of cannabinoids in epilepsy, multiple sclerosis and Parkinson’s disease, pointing out the interactions between them and molecular targets. We sought to show the great potential for neuroprotection of CBD and its promise in primary neurodegenerative diseases and secondary to other CNS complications, such as epilepsy.