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Rho-Kinase Inhibition Improves the Outcome of Focal Subcortical White Matter Lesions

Sanem A. Aykan
Hongyu Xie
Yi Zheng
David Y. Chung
Sreekanth Kura
James Han Lai
Taylan D. Erdogan
Andreia Morais
Isra Tamim
Damla Yagmur
Hidehiro Ishikawa
Ken Arai
M. Abbas Yaseen
David A. Boas
Sava Sakadzic
Cenk Ayata

Sanem A. Aykan

Sanem A. Aykan

https://orcid.org/0000-0001-7335-5556

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.).

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Hongyu Xie

Hongyu Xie

https://orcid.org/0000-0001-6386-8083

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.).

Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai, China (H.X.).

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Yi Zheng

Yi Zheng

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.).

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David Y. Chung

David Y. Chung

https://orcid.org/0000-0002-7149-5851

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.).

Stroke Service, Department of Neurology (C.A., D.Y.C.), Massachusetts General Hospital, Charlestown, MA.

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Sreekanth Kura

Sreekanth Kura

Neurophotonics Center, Department of Biomedical Engineering, Boston University, MA (S.K., D.A.B.).

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James Han Lai

James Han Lai

https://orcid.org/0000-0002-8414-0398

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.).

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Taylan D. Erdogan

Taylan D. Erdogan

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.).

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Andreia Morais

Andreia Morais

https://orcid.org/0000-0002-9351-2552

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.).

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Isra Tamim

Isra Tamim

https://orcid.org/0000-0002-4098-1160

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.).

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Damla Yagmur

Damla Yagmur

https://orcid.org/0000-0001-7729-1983

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Hidehiro Ishikawa

Hidehiro Ishikawa

https://orcid.org/0000-0002-3077-7262

Neuroprotection Research Laboratory, Department of Radiology and Neurology (H.I., K.A.), Massachusetts General Hospital, Harvard Medical School, Charlestown.

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Ken Arai

Ken Arai

Neuroprotection Research Laboratory, Department of Radiology and Neurology (H.I., K.A.), Massachusetts General Hospital, Harvard Medical School, Charlestown.

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M. Abbas Yaseen

M. Abbas Yaseen

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology (D.A.B., M.A.Y., S.S.), Massachusetts General Hospital, Charlestown, MA.

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David A. Boas

David A. Boas

https://orcid.org/0000-0002-6709-7711

Neurophotonics Center, Department of Biomedical Engineering, Boston University, MA (S.K., D.A.B.).

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology (D.A.B., M.A.Y., S.S.), Massachusetts General Hospital, Charlestown, MA.

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Sava Sakadzic

Sava Sakadzic

https://orcid.org/0000-0001-6318-1193

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology (D.A.B., M.A.Y., S.S.), Massachusetts General Hospital, Charlestown, MA.

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and

Cenk Ayata

Cenk Ayata

Correspondence to: Cenk Ayata, MD, PhD, Massachusetts General Hospital, 149 13th Street, 6403, Charlestown, MA 02129. Email

E-mail Address: [email protected]

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.).

Stroke Service, Department of Neurology (C.A., D.Y.C.), Massachusetts General Hospital, Charlestown, MA.

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Originally published3 Jun 2022https://doi.org/10.1161/STROKEAHA.121.037358Stroke. 2022;53:2369–2376

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.

Footnotes

Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.121.037358.

For Sources of Funding and Disclosures, see page 2375.

Correspondence to: Cenk Ayata, MD, PhD, Massachusetts General Hospital, 149 13th Street, 6403, Charlestown, MA 02129. Email [email protected]harvard.edu

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