Metallothionein-IIA promotes initial neurite elongation and postinjury reactive neurite growth and facilitates healing after focal cortical brain injury.
Metallothioneins (MTs) are small, cysteine-rich, metal binding proteins. Their function has often been considered as stress-related proteins capable of protecting cells from heavy metal toxicity and oxidative free radicals. However, recent interest has focused on the brain-specific MT-III isoform, which has neurite-inhibitory properties. To investigate the effect of another MT isoform, human MT-IIA, on neurite growth, we used rat cortical neuron cultures. MT-IIA promoted a significant increase in the rate of initial neurite elongation of individually plated neurons. We also investigated the effect of MT-IIA on the neuronal response to axonal transection in vitro. MT-IIA promoted reactive axonal growth after injury, and, by 18 hr after transection, MT-IIA had promoted axonal growth across the injury tract. Exogenous application of MT-IIA after cortical brain injury promoted wound healing, as observed by a significant decrease in cellular degradation at 4 d after injury. Furthermore, MT-IIA-treated rats exhibited numerous SMI-312-immunoreactive axonal processes within the injury tract. This was in contrast to vehicle-treated animals, in which few axonal sprouts were observed. By 7 d after injury, MT-IIA treatment resulted in a total closing over of the injury tract by microglia, astrocytes, and reactive axonal processes. However, although some reactive axonal processes were observed within the injury tract of vehicle-treated rats, the tract itself was almost never entirely enclosed. These results are discussed in relation to a possible physiological role of metallothioneins in the brain, as well as in a therapeutic context.
Chung
Roger S
RS
NeuroRepair Group, School of Medicine, University of Tasmania, Hobart, Tasmania 7001, Australia. Australia.rschung@postoffice.utas.edu.au
Vickers
James C
JC
Chuah
Meng Inn
MI
West
Adrian K
AK
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D001369:Axons / Q000187:drug effects / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000196:embryology / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008668:Metallothionein / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D016501:Neurites / Q000187:drug effects* / Q000502:physiology; D016900:Neurofilament Proteins / Q000096:biosynthesis; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D014945:Wound Healing / Q000187:drug effects
D016900:Neurofilament Proteins; C061195:neurofilament protein M; D008668:Metallothionein