1.5.2 Multiple sclerosis
Multiple sclerosis is a chronic, progressive, autoimmune disease caused by inflammation, demyelination, gliosis, and neurodegeneration [131]. It manifests itself clinically through sensory, motor, and psychological symptoms, and via neurological aspects. The most common signs are fatigue (40%), optic neuritis (22%), paresthesia (21%), diplopia (12%), vertigo (5%), and bladder dysfunction (5%). However, other symptoms include cognitive impairment, ataxic gait, spasticity, depression, and internuclear ophthalmoplegia. The region of the CNS that is affected will determine how multiple sclerosis manifests itself, as well as the frequency, severity, progression of the disease’s incapacitation, and the sequelae of the relapses [132]. In young adults between 20 and 40 years of age, it appears as the main cause of disability and has a higher incidence in women (2.3:1) [133].
Regarding the pathophysiology, self-reactive leukocytes cross the blood-brain barrier and form active plaques formed by perivascular and parenchymal infiltrates of macrophages, B lymphocytes, and T lymphocytes, which destroy the myelin sheath. The acute inflammatory phase is characterized by partial remyelination by oligodendrocytes in the affected axons [134]. Infiltration of T lymphocytes in the CNS accompanied by oligodendrocyte destruction and axonal damage marks the arrival of the progressive phase of the disease. After the demyelinating event, impulse transmission in the affected axons occurs at 5 to 10% of normal speed. In addition, demyelinated axons generate spontaneous electrical discharges known as Lhermitte’s sign [135].
Treatment aims to reduce the occurrence of new outbreaks, slow the progression of neurological damage, and delay the progressive phase of multiple sclerosis, mainly seeking to partially prevent axon destruction arising from the autoimmune inflammatory process. In this sense, CBD use in animal models and patients with multiple sclerosis has been reported (Table 2), with indications for spasticity, pain, relaxation, sleep, anxiety, and tremor [136]. Patients with multiple sclerosis have shown alterations in the expression of CB1 and CB2 receptors and, therefore, therapies with cannabis derivatives have been proposed [36, 126].
Table 2. Preclinical and clinical evidence using Cannabis derivatives in multiple sclerosis models and patients.
Nabiximols have been frequently prescribed as a spray solution for buccal spraying, consisting of THC:CBD (1:1) and trade names Sativex/Mevatyl when prepared synthetically [136-141]. An oral solution that can also be prescribed is dronabinol, being a synthetic enantiomer of THC, under the trade names Marinol/Syndros [142].
Recently, improvements in spasticity and pain linked to multiple sclerosis have been associated with the use of nabiximols. However, despite indicating to be a promising therapy, with good tolerability and safety, nabiximois and dronabinol were not able to significantly improve the symptoms of multiple sclerosis [113, 126, 143-146]. Thus, there is no consensus regarding the possible molecular and cellular mechanisms related to the treatment with these cannabinoids, mainly, how they act to reduce neuroinflammation.
With regard to better elucidating the interaction between THC + CBD and neuroinflammation in experimental autoimmune encephalomyelitis (EAE) models, the work by Al-Ghezi et al. [147] investigated the mechanism by which the THC + CBD combination (10 mg/kg each) suppressed neuroinflammation and showed that these effects were mediated by CB1 and CB2 receptors, since in mice deficient in CB1 and CB2 this effect was reversed, with no reduction in the inflammatory process. In addition, treated animals showed a decrease in the levels of CD4 + T cells infiltrated in the brain and pro-inflammatory molecules (IL-17, INF-γ, TNF-α, IL-1β, IL-6 and TBX21) and on the other hand , an increase in anti-inflammatory phenotype molecules such as FoxP3, STAT5b, IL-4, IL-10 and TGF-β. We also investigated epigenetic mechanisms through miRNA microarray analysis of brain-derived CD4 + T cells, transfection involving miR-21 and use of Mir21 - / - mice. It was suggested in this study that the combination of THC + CBD suppresses neuroinflammation and attenuates the clinical development of EAE and that this effect is associated with changes in the miRNA profile in cells that infiltrate the brain. In figure 3, a diagram showing interactions and effects of THC:CBD in multiple sclerosis.
Finally, in multiple sclerosis, among other mechanisms, interactions between cannabinoids and receptors need to be better explored, in particular, the pharmacological activation of the CB2 receptor since it has a strong involvement with neuroinflammation, remyelination and neuronal survival.
Fig. 3. Diagram of interactions and therapeutic effects of THC:CBD in multiple sclerosis