Stem Cells as Potential Targets of Polyphenols in Multiple Sclerosis and Alzheimer’s Disease

Table 4

Factors involved in the pathogenesis of MS.

S. No.	Factors	Involvement in MS	References
1.	Genetics	(i) HLA-DRB115 is the most common genetic risk factor for MS.	[258, 259]
		(ii) GWAS have predicted GRIN2A, encoding NR2A subunit of NMDA-type glutamate receptors a possible candidate in MS.	[260, 261]
2.	Oxidative Stress	(i) ROS and RNS such as nitric oxide (NO) produced by macrophages and microglia in MS lesions lead to inflammation.	[262–264]
		(ii) In MS lesions, microglia has shown up-regulation of NOX1, NOX2, and NOX organizer 1 enzymes responsible for ROS generation.	[265]
		(iii) Iron accumulation in MS patients further amplified ROS and RNS-mediated injury through the generation of toxic reactants.	[266, 267]
		(iv) NRF2 mediated HMOX1 anti-oxidant enzyme levels are known to increase in MS lesions.	[268, 269]
		(v) Dimethyl fumarate (DMF) induces Nrf2 expression in neurons, thus contributing to attenuation of MS in patients.	[270]
3.	Mitochondrial Dysfunction	(i) Altered mitochondrial transport, mediated by translocation of HDAC1 from the nucleus to the axoplasm, thereby hindering kinesin motor protein functions, is evident in experimental autoimmune encephalomyelitis (EAE) lesions model of MS.	[263, 271]
		(ii) Resveratrol-mediated attenuation of neuronal damage in optic neuritis in EAE is brought about by activating SIRT1, thus promoting mitochondrial function.	[272, 273]
		(iii) Mitochondrial permeability transition (MPT), which is dependent on cyclophilin D (CyPD), results in equilibration of ionic gradients, loss of mitochondrial transmembrane potential and termination of oxidative phosphorylation followed by necrosis.	[274]
		(iv) Due to impaired mitochondrial function in MS hypoxia develops which causes nuclear translocation of HIF1α and its subsequent activation.	[275–277]
4.	Ion Channel Dysfunction	(i) Increased Na^+ concentration associates with MS pathology.	[278]
		(ii) Presence of voltage-gated Na^+ channel ()1.2, 1.6 and Na^+/Ca2^+ exchanger (NCX) subunits is evident in MS lesions.	[279]
		(iii) Altered expression or activation of voltage-gated K^+ () channels, which is evident in MS, is blocked by 4-aminopyridine (non-specific blocker of channels) in MS patients.	[280]
		(iv) Altered glutamate levels result in excessive neuronal signaling, thereby leading to Ca^2+ mediated excitotoxicity as evident in MS.	[281]
		(v) The glutamate-mediated axonal injury increases by a reduction in mitochondrial complex IV activity, thereby contributing to EAE pathology.	[282]
		(vi) Abnormal NMDA receptor function contributes to dysfunctional mitochondrial activity. Thus, inhibition of NMDA and AMPA receptors leads to improvement in EAE.	[283–285]
		(vii) Inhibition of calpains (Ca^2+- dependent proteases involved in degradation of axonal components) improved EAE pathology.	[286]
5.	Apoptosis	(i) Mice overexpressing the antiapoptotic Bcl-2 protein showed attenuated EAE severity and reduced axonal loss.	[287]
		(ii) Cytokine TRAIL can induce caspase-dependent apoptosis in neurons by binding to death receptors DR4 and DR5.	[288]
		(iii) Wallerian degeneration is involved in axon loss in MS patients. Expression of Wallerian degeneration slow () protein inhibits this process through decreased microglial and macrophage activation levels and increased expression of CD200 glycoprotein, which inactivates monocytes by binding to the CD200 receptor, thereby providing protection.	[289, 290]
6.	Environment	(i) Genes that encode proteins involved in the actions of vitamin D associate with the risk of developing MS. Polymorphisms in 1α-hydroxylase encoding gene CYP27B1 are coupled with an increased risk of developing MS.	[291]
		(ii) Infection with Epstein Barr virus (EBV) in association with infectious mononucleosis (IM) is linked with increased MS risk. Increased MS risk explicitly associates with higher IgG antibody titers to Epstein-Barr nuclear antigens (EBNA).	[292–294]
		(iii) An increased MS risk associated with the interaction between smoking and high anti-EBNA titers is observed.	[295]