Oral administration of metal chelator ameliorates motor dysfunction after a small hemorrhage near the internal capsule in rat.
Cerebral hemorrhage leads to local production of free iron, radicals, cytokines, etc. To investigate whether a decrease of iron-mediated radical production influences functional recovery after intracerebral hemorrhage (ICH), a modified ICH rat model with a small hemorrhage near the internal capsule (IC) accompanied with relatively severe motor dysfunction was first developed. Then clioquinol (CQ), an iron chelator that reduces hydroxyl radical production, was orally administrated. Injection of different doses of Type IV collagenase (1.4 mul 1-200 U/ml) into the left striatum near the IC in Wistar rats showed that injection of 7.5 U/ml collagenase resulted in a small hemorrhoidal lesion near the IC with relatively severe motor dysfunction (IC model). Retrograde labeling of neurons in the sensory-motor cortex and axons in the corticospinal tract using Fluoro-gold (FG) injection into the spinal cord (C3-C4) showed that few labeled neurons in the sensory-motor cortex were detected in the IC model, FG-labeled axons disappeared, and FG-including ED-1-positive cells appeared within 24 hr in the IC. Assessments of behavior and histologic analysis after oral administration of CQ in the IC model indicated that oral administration of CQ prevented a decrease of FG-labeled neurons, and resulted in better motor-function recovery. CQ inhibited hydrogen peroxide-induced cell toxicity in oligodendrocytes in vitro, but not in neurons. Our data suggests that CQ ameliorated motor dysfunction after a small hemorrhage near the IC by a mechanism that is related to reduction of chain-reactive hydroxyl radical production in oligodendrocytes.
Masuda
Tadashi
T
Department of Neurophysiology and Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Hida
Hideki
H
Kanda
Yoshie
Y
Aihara
Noritaka
N
Ohta
Kengo
K
Yamada
Kazuo
K
Nishino
Hitoo
H
D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002452:Cell Count; D002478:Cells, Cultured; D002543:Cerebral Hemorrhage / Q000150:complications / Q000473:pathology; D002614:Chelating Agents / Q000008:administration & dosage*; D007464:Clioquinol / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D007839:Functional Laterality; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020772:Internal Capsule / Q000473:pathology*; D020784:Matrix Metalloproteinase 8 / Q000008:administration & dosage*; D009043:Motor Activity / Q000187:drug effects; D016472:Motor Neuron Disease / Q000188:drug therapy* / Q000209:etiology; D009474:Neurons / Q000187:drug effects; D009836:Oligodendroglia / Q000187:drug effects; D011712:Pyramidal Tracts / Q000378:metabolism / Q000473:pathology; D051381:Rats; D013003:Somatosensory Cortex / Q000378:metabolism / Q000473:pathology; D013266:Stilbamidines / Q000378:metabolism
C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D002614:Chelating Agents; D013266:Stilbamidines; D007464:Clioquinol; D006861:Hydrogen Peroxide; D020784:Matrix Metalloproteinase 8