title: Experimental model of small subcortical infarcts in mice with long-lasting functional disabilities.
abstract: Small subcortical infarcts account for 25% of all ischemic strokes. Although once considered to be a small vessel disease with a favorable outcome, recent studies have reported relatively poor long-term prognoses following small subcortical infarcts. Limited pre-clinical modeling has hampered understanding of the etiology and development of treatments for this disease. Therefore, we attempted to develop a new experimental model of small subcortical infarcts in mice to investigate pathophysiological changes in the corticospinal tract and assess long-term behavioral performance. The vasoconstrictor peptide, endothlin-1 (ET-1), in combination with the nitric oxide synthase inhibitor, N(G)-nitro-l-arginine methyl ester (l-NAME), were injected into the internal capsule of mice. Histological and behavioral tests were performed 0-8 weeks after the injection. The ET-1/l-NAME injection resulted in severe neurological deficits that continued for up to 8 weeks. The loss of axons and myelin surrounded by reactive gliosis was identified in the region of the injection, in which the vasoconstriction of microvessels was also observed. Moreover, a tract-tracing study revealed an interruption in axonal flow at the internal capsule. The present model of small subcortical infarcts is unique and novel due to the reproduction of neurological deficits that continue for a long period, up to 8 weeks, as well as the use of mice as experimental animals. The reproducibility, simplicity, and easy adoptability make the present model highly appealing for use in further pre-clinical studies on small subcortical infarcts.
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Miyagi, Japan; Department of Anatomy and Anthropology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan. Electronic address: h.uchida0206@gmail.com.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Uchida
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Miyagi, Japan. Electronic address: sakata@nsg.med.tohoku.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sakata
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Miyagi, Japan. Electronic address: fujimur@nsg.med.tohoku.ac.jp.
authors.forename: Miki
authors.initials: M
authors.lastname: Fujimura
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Miyagi, Japan. Electronic address: niizuma@nsg.med.tohoku.ac.jp.
authors.forename: Kuniyasu
authors.initials: K
authors.lastname: Niizuma
authors.affiliation: Department of Anatomy and Anthropology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan. Electronic address: y-kushida@med.tohoku.ac.jp.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kushida
authors.affiliation: Department of Anatomy and Anthropology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan; Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan. Electronic address: mdezawa@med.tohoku.ac.jp.
authors.forename: Mari
authors.initials: M
authors.lastname: Dezawa
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Miyagi, Japan. Electronic address: tomi@nsg.med.tohoku.ac.jp.
authors.forename: Teiji
authors.initials: T
authors.lastname: Tominaga
mesh_terms: D000818:Animals; D002544:Cerebral Infarction / Q000139:chemically induced* / Q000503:physiopathology*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000633:toxicity; D020772:Internal Capsule / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology*; D020521:Stroke / Q000139:chemically induced* / Q000503:physiopathology*; D013997:Time Factors
chemical_list: D019332:Endothelin-1; D019331:NG-Nitroarginine Methyl Ester
keywords: Animal models; Behavior (rodent); Brain ischemia; Small subcortical infarcts; White matter disease