Axonal dysfunction in internal capsule is closely associated with early motor deficits after intracerebral hemorrhage in mice.
Previously we showed that expansion of intracerebral hemorrhage (ICH) into the internal capsule greatly aggravated neurological symptoms in mice. Here we examined ICH-associated events in the internal capsule with relation to neurological dysfunction. Corticospinal axons labeled by biotinylated dextran amine exhibited fragmented appearance after ICH induced by local injection of collagenase into the internal capsule. Fragmentation of axonal structures was confirmed by neurofilament-H immunostaining, which was evident from 6h after induction of ICH. We also observed accumulation of amyloid precursor protein, which indicated compromised axonal transport, from 3h after induction of ICH. The early defect in axonal transport was accompanied by a robust decline in motor performance. Local application of an axonal transport inhibitor colchicine to the internal capsule induced a prompt decline in motor performance, suggesting that compromised axonal transport is closely associated with early neurological dysfunction in ICH. Arrest of axonal transport and fragmentation of axonal structures were also induced by local injection of thrombin, but not by thrombin receptor activator peptide-6, a protease-activated receptor-1 agonist. These results suggest that receptor-independent actions of thrombin mediate disruption of structure and function of axons by hemorrhage expansion into the internal capsule, which leads to severe neurological dysfunction.
Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
Masanori
M
Hijioka
Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
Junpei
J
Anan
Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
Hideaki
H
Matsushita
Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
Hayato
H
Ishibashi
Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
Yuki
Y
Kurauchi
Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto 862-8555, Japan; Program for Leading Graduate Schools "HIGO (Health Life Science: Interdisciplinary and Glocal Oriented) Program", Kumamoto University, Kumamoto 862-0973, Japan.
Akinori
A
Hisatsune
Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
Takahiro
T
Seki
Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan. Electronic address: hkatsuki@gpo.kumamoto-u.ac.jp.
Hiroshi
H
Katsuki
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects; D001369:Axons / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000503:physiopathology*; D003078:Colchicine / Q000494:pharmacology; D017364:Collagenases; D020772:Internal Capsule / Q000503:physiopathology*; D008297:Male; D008810:Mice, Inbred C57BL; D000068079:Motor Disorders / Q000503:physiopathology*; D013917:Thrombin / Q000494:pharmacology
D016564:Amyloid beta-Protein Precursor; D013917:Thrombin; D017364:Collagenases; D003078:Colchicine
Axonal injury; Axonal transport; Corticospinal tract; Hemorrhagic stroke; Motor dysfunction; Thrombin