Inhibition of axonal regrowth Neuroregeneration

1 inhibition of axonal regrowth

1.1 chondroitin sulfate proteoglycan
1.2 keratan sulfate proteoglycans
1.3 other inhibitory factors

inhibition of axonal regrowth

glial scar formation induced following damage nervous system. in central nervous system, glial scar formation inhibits nerve regeneration, leads loss of function. several families of molecules released promote , drive glial scar formation. instance, transforming growth factors b-1 , -2, interleukins, , cytokines play role in initiation of scar formation. accumulation of reactive astrocytes @ site of injury , regulation of molecules inhibitory neurite outgrowth contribute failure of neuroregeneration. up-regulated molecules alter composition of extracellular matrix in way has been shown inhibit neurite outgrowth extension. scar formation involves several cell types , families of molecules.

chondroitin sulfate proteoglycan

in response scar-inducing factors, discussed above, astrocytes regulate production of chondroitin sulfate proteoglycans. astrocytes predominant type of glial cell in central nervous system provide many functions including damage mitigation, repair, , glial scar formation. rhoa pathway involved. chondroitin sulfate proteoglycans (cspgs) have been shown regulated in central nervous system (cns) following injury. repeating disaccharides of glucuronic acid , galactosamine, glycosaminoglycans (cs-gags), covalently coupled protein core cspgs. cspgs have been shown inhibit regeneration in vitro , in vivo, role cspg core protein vs. cs-gags had not been studied until recently.

a recent study performed experiments determine cs-gags present in normal uninjured cortex, present following injury , resultant mature glial scar. difference in cs-gag types , amounts present between 2 used study inhibitory effects of cs-gag types regulated in glial scar on neurite extension. resulting analysis showed gag profiles of normal cortex , glial scar tissue different. glial scar tissue demonstrated regulation of chondroitin-4,6-sulfate, chondroitin-2-sulfate, , chondroitin-6-sulfate. on other hand, uninjured cortical tissue showed of cs-gag chondroitin-4-sulfate chondroitin , chondroitin-6-sulfate present.

using information, studies done quantify inhibitory effects of cspgs on neurite outgrowth. cspg samples test shown inhibitory neurite outgrowth. however, cs-e , aggrecan shown inhibitory large margin, contained 4,6-sulfated gag , 4-sulfated gag, respectively. average neurite length experiments using these samples 22 ± 40 µm , 24 ± 44 µm, respectively. compared other averages more ten times these values. study demonstrated major increase after injury spinal cord in 4-sulfated chondroitin. in study, authors demonstrate selective increases or decreases of 4-sulfation on astrocyte-derived chondroitin sulfate proteoglycans have growth promoting or growth inhibiting actions, respectively. taken together, these studies point 4-sulfation being critical modification of cspgs in glial scar.

the chondroitin sulfate proteoglycans phosphacan , neurocan have been shown play role in glial scar. phosphacan has been shown have decreased levels in glial scar when compared uninjured cortex. decrease beneficial nerve generation because phosphacan has been shown inhibit neurite extension other cspgs discussed already. alternatively, neurocan production regulated in astrocytes in glial scar when compared uninjured cortex , astrocytes in primary cell culture conditions. these elevated neurocan levels have been shown remain elevated 30 days after initial injury. implicates neurocan having prolonged role in chronic scar.

the inhibition of rho-kinase (rock) y-27632 has been shown activate reactive astrocytes , increase expression of cspgs. studies y-27632 have shown central nervous system injury sites treated y-27632 causes regulation of glial fibrillary acid protein , neurocan. in vitro cultures of astrocytes, same treatment showed increased expression of cspgs , resulting decrease in neurite outgrowth extension. inhibitory effect reduced digesting cspg components chondroitinase-abc.

ng2 type of chondroitin sulfate proteoglycan expressed oligodendrocyte precursor cells. oligodendrocyte precursor cells type of glial cell found in central nervous system play role in glial scar formation. these cell types can develop normal oligodendrocyte or glial fibrillary acidic protein positive astrocyte depending on environmental factors. ng2 found on surface of these cells , has been shown inhibit neurite outgrowth extension, well. these high molecular weight transmembrane molecules largest portion extending extracellular space.

following injury central nervous system, ng2 expressing oligodendrocyte precursor cells seen around site of injury within 48 hours of initial injury. number of ng2 expressing cells continues increase next 3 5 days , high levels of ng2 seen within seven–ten days of injury. in vitro studies have been done demonstrate effect ng2 levels play on neurite growth inhibition. notably, neurons not adhere substrates made solely of ng2, hints @ inhibitory effects on nerve regeneration. when grown on substrates containing both ng2 , adhesive molecules, neurite extension shown reduced 40-45% when compared neurite extension on substrates containing adhesive molecules. furthermore, cultures created striped surfaces alternated ng2 lanes lanes containing adhesive molecules. neurons , axons placed on these striped regions consistently stayed in lanes without ng2. clear, then, accumulation of ng2 expressing cells @ site of injury creates extracellular barrier inhibits axon regrowth glial scar area.

keratan sulfate proteoglycans

like chondroitin sulfate proteoglycans, keratan sulfate proteoglycan (kspg) production regulated in reactive astrocytes part of glial scar formation. kspgs have been shown inhibit neurite outgrowth extension, limiting nerve regeneration. keratan sulfate, called keratosulfate, formed repeating disaccharide galactose units , n-acetylglucosamines. 6-sulfated. sulfation crucial elongation of keratan sulfate chain. study done using n-acetylglucosamine 6-o-sulfotransferase-1 deficient mice. wild type mouse showed significant regulation of mrna expressing n-acetylglucosamine 6-o-sulfotransferase-1 @ site of cortical injury. however, in n-acetylglucosamine 6-o-sulfotransferase-1 deficient mice, expression of keratan sulfate decreased when compared wild type mice. similarly, glial scar formation reduced in n-acetylglucosamine 6-o-sulfotransferase-1 mice, , result, nerve regeneration less inhibited.

other inhibitory factors

proteins of oligodendritic or glial debris origin influence neuroregeneration:

nogo –the protein family nogo, particularly nogo-a, has been identified inhibitor of remyelination in cns, in autoimmune mediated demyelination, such found in experimental autoimmune encephalomyelitis (eae) , multiple sclerosis (ms). nogo functions via either amino-nogo terminus through unknown receptor, or nogo-66 terminus through ngr1, p75, troy or lingo1. antagonising inhibitor results in improved remyelination, involved in rhoa pathway.
ni-35 non-permissive growth factor myelin.
mag –myelin-associated glycoprotein acts via receptors ngr2, gt1b, ngr1, p75, troy , lingo1.
omgp –oligodendrocyte myelin glycoprotein
ephrin b3 functions through epha4 receptor , inhibits remyelination.
sema 4d(semaphorin 4d) functions through plexinb1 receptor , inhibits remyelination.
sema 3a (semaphorin 3a) present in scar forms in both central nervous system , peripheral nerve injuries , contributes outgrowth-inhibitory properties of these scars




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