Metallothionein treatment attenuates microglial activation and expression of neurotoxic quinolinic acid following traumatic brain injury.
The kynurenine pathway has been implicated as a major component of the neuroinflammatory response to brain injury and neurodegeneration. We found that the neurotoxic kynurenine pathway intermediate quinolinic acid (QUIN) is rapidly expressed, within 24 h, by reactive microglia following traumatic injury to the rodent neocortex. Furthermore, administration of the astrocytic protein metallothionein attenuated this neuroinflammatory response by reducing microglial activation (by approximately 30%) and QUIN expression. The suppressive effect of MT was confirmed upon cultured cortical microglia, with 1 mug/ml MT almost completely blocking interferon-gamma induced activation of microglia and QUIN expression. These results demonstrate the neuroimmunomodulatory properties of MT, which may have therapeutic applications for the treatment of traumatic brain injury.
Chung
R S
RS
NeuroRepair Group, Menzies Research Institute, University of Tasmania, Private Bag 58, Hobart, TAS, 7001, Australia. rschung@utas.edu.au
Leung
Y K
YK
Butler
C W
CW
Chen
Y
Y
Eaton
E D
ED
Pankhurst
M W
MW
West
A K
AK
Guillemin
G J
GJ
D000704:Analysis of Variance; D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005293:Ferritins / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D005786:Gene Expression Regulation / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D008668:Metallothionein / Q000494:pharmacology*; D017628:Microglia / Q000737:chemistry / Q000187:drug effects*; D019579:Neocortex / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000473:pathology; D017378:Quinolinic Acid / Q000032:analysis / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D017077:Culture Media, Conditioned; D005904:Glial Fibrillary Acidic Protein; D007371:Interferon-gamma; D005293:Ferritins; D008668:Metallothionein; D017378:Quinolinic Acid