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.