Table 4.

Implications of ECS in various pathological aspects of MS; ↓: decrease; ↑ = increase.

Mechanisms of MS Pathogenesis	The Endocannabinoid System and Its Implications in MS		Cannabinoid Receptor Ligands with Potential Benefits in Therapeutic Management of MS
	Target Components	Physiological Function	Disease Model and Species	Compound	Biological Effect
spasticity → the mainly observed symptom in MS is associated with spasms, pain and sleep disturbance [176,177]	CB1R and CB2R	CB1R inhibits synaptic transmission → main target for control of spasticity [204]	chronic relapsing EAE	Δ9-THC methanandamide (analogue of AEA) (CB1R agonists) WIN 55,212-2 (CB1R/CB2R agonist) JWH-133 (CB2-R agonist)	amelioration of some motor symptoms such as limb spasticity, tremor and paralysis [203]
inflamamation→ recruitment of leukocytes from the blood into the CNS adhesion to endothelial cells (added space) cerebrospinal fluid: increased glutamate level, differential expression of glutamate receptors [232] increased glutamate level → neurodegeneration due to excitotoxicity [210,216]	CB1R and CB2R	CB2R have immunomodulatory properties [209]	EAE induced C57BL/6 mice immunized with MOG35–55 + pertussis toxin	WIN 55,212-2 SR 141716A (CB1R antagonist) SR144528 (CB2R antagonist)	CB1R antagonist → no influence on the protective effect → key role in the protective effect of WIN55212-2 [212] stimulation → attenuated EAE progression potential target to inhibit leukocyte trafficking in EAE [209]
	CB1R	activation of cannabinoid receptors inhibits the release of glutamate presynaptically [217]	Rat hippocampal neurons culture	AEA Memantine Δ9-THC	(added space) antiglutamatergic effects by ↓ of Mg2+ concentration →↓ excitation level in the entire network of neurons in the culture glutamatergic excitatory postsynaptic currents elicited by direct stimulation of the presynaptic neuron [217]
			EAE induced C57BL/6 mice—i.p. administration for 3 consecutive days	CBD	(added space) Low dose of CBD → ↓ inflammation → axonal damage ↓ spinal activation of glia inhibition of T-cell migration in the spinal cord [220] High dose of CBD → ↓microglial activity↓ ↓cell infiltration and demyelination ↓axonal damage ↓levels of IL-6 [221]
	CB1R and CB2R	involvement in treating of neurodegenerative diseases driven by chronic neuro-inflammation	EAE-induced C57BL/6 mice immunized with MOG35–55 + pertussis toxin	Δ9-THC + CBD	Δ9-THC + CBD→attenuates the development of EAE [157]
	CB1R	immunosuppressive effects on astrocytes	In vitro method TMEV-infected astrocytes	AEA	dose-dependent potentiating of IL-6 [219] inhibition of astrocytes activation →the production of IL-6 [231] inhibition IL-1β, IL-6, IL-12 and IL-23 release in myeloid dendritic cells inhibition of microglial activation [161]
			Mouse model TMEV-induced demyelinating disease	PEA	↓ expression of IL-1, TNF-α↓ microglial activation in the spinal cord of mice [228]
				UCM707 WIN 55,212-2 JWH-015 ACEA	↓ microglial activation inhibition of MHC class II antigen expression ↓ of spinal cord infiltrating CD4T cells– ↓ the production of IL-1β, IL-6 and TNF-α [229,230]