Sanem A Aykan1, Hongyu Xie1,2, Yi Zheng1, David Y Chung1,3, Sreekanth Kura4, James Han Lai1, Taylan D Erdogan1, Andreia Morais1, Isra Tamim1, Damla Yagmur, Hidehiro Ishikawa5, Ken Arai5, M Abbas Yaseen6, David A Boas4,6, Sava Sakadzic6, Cenk Ayata1,3. 1. Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Charlestown (S.A.A., H.X., Y.Z., D.Y.C., J.H.L., T.D.E., A.M., I.T., D.Y., C.A.). 2. Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai, China (H.X.). 3. Stroke Service, Department of Neurology (C.A., D.Y.C.), Massachusetts General Hospital, Charlestown, MA. 4. Neurophotonics Center, Department of Biomedical Engineering, Boston University, MA (S.K., D.A.B.). 5. Neuroprotection Research Laboratory, Department of Radiology and Neurology (H.I., K.A.), Massachusetts General Hospital, Harvard Medical School, Charlestown. 6. Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology (D.A.B., M.A.Y., S.S.), Massachusetts General Hospital, Charlestown, MA.
Abstract
BACKGROUND: Subcortical white matter lesions are exceedingly common in cerebral small vessel disease and lead to significant cumulative disability without an available treatment. Here, we tested a rho-kinase inhibitor on functional recovery after focal white matter injury. METHODS: A focal corpus callosum lesion was induced by stereotactic injection of N5-(1-iminoethyl)-L-ornithine in mice. Fasudil (10 mg/kg) or vehicle was administered daily for 2 weeks, starting one day after lesion induction. Resting-state functional connectivity and grid walk performance were studied longitudinally, and lesion volumes were determined at one month. RESULTS: Resting-state interhemispheric functional connectivity significantly recovered between days 1 and 14 in the fasudil group (P<0.001), despite worse initial connectivity loss than vehicle before treatment onset. Grid walk test revealed an increased number of foot faults in the vehicle group compared with baseline, which persisted for at least 4 weeks. In contrast, the fasudil arm did not show an increase in foot faults and had smaller lesions at 4 weeks. Immunohistochemical examination of reactive astrocytosis, synaptic density, and mature oligodendrocytes did not reveal a significant difference between treatment arms. CONCLUSIONS: These data show that delayed fasudil posttreatment improves functional outcomes after a focal subcortical white matter lesion in mice. Future work will aim to elucidate the mechanisms.
BACKGROUND: Subcortical white matter lesions are exceedingly common in cerebral small vessel disease and lead to significant cumulative disability without an available treatment. Here, we tested a rho-kinase inhibitor on functional recovery after focal white matter injury. METHODS: A focal corpus callosum lesion was induced by stereotactic injection of N5-(1-iminoethyl)-L-ornithine in mice. Fasudil (10 mg/kg) or vehicle was administered daily for 2 weeks, starting one day after lesion induction. Resting-state functional connectivity and grid walk performance were studied longitudinally, and lesion volumes were determined at one month. RESULTS: Resting-state interhemispheric functional connectivity significantly recovered between days 1 and 14 in the fasudil group (P<0.001), despite worse initial connectivity loss than vehicle before treatment onset. Grid walk test revealed an increased number of foot faults in the vehicle group compared with baseline, which persisted for at least 4 weeks. In contrast, the fasudil arm did not show an increase in foot faults and had smaller lesions at 4 weeks. Immunohistochemical examination of reactive astrocytosis, synaptic density, and mature oligodendrocytes did not reveal a significant difference between treatment arms. CONCLUSIONS: These data show that delayed fasudil posttreatment improves functional outcomes after a focal subcortical white matter lesion in mice. Future work will aim to elucidate the mechanisms.
Authors: H Bito; T Furuyashiki; H Ishihara; Y Shibasaki; K Ohashi; K Mizuno; M Maekawa; T Ishizaki; S Narumiya Journal: Neuron Date: 2000-05 Impact factor: 17.173
Authors: Francesco Blasi; Ying Wei; Mustafa Balkaya; Saara Tikka; Joseph B Mandeville; Christian Waeber; Cenk Ayata; Michael A Moskowitz Journal: Stroke Date: 2014-04-10 Impact factor: 7.914
Authors: Jeong Hyun Lee; Yi Zheng; Daniel von Bornstadt; Ying Wei; Aygul Balcioglu; Ali Daneshmand; Nilufer Yalcin; Esther Yu; Fanny Herisson; Yahya B Atalay; Maya Hwewon Kim; Yong-Joo Ahn; Mustafa Balkaya; Paul Sweetnam; Olivier Schueller; Masha V Poyurovsky; Hyung-Hwan Kim; Eng H Lo; Karen L Furie; Cenk Ayata Journal: Ann Clin Transl Neurol Date: 2014-01-01 Impact factor: 4.511