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