A new model of cerebral microthrombosis in rats and the neuroprotective effect of a rho-kinase inhibitor

Y. Toshima, S. I. Satoh, I. Ikegaki, T. Asano, W. Dalton Dietrich

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

Background and Purpose - The aim of this study was to develop a new model of stroke based on endothelial damage and thrombotic occlusion in a perforating artery, leading to small cerebral infarcts and neurological deficits in rats. Moreover, the neuroprotective efficacy of fasudil, a rho-kinase inhibitor, was investigated in this model. Methods - Fifty-six male Sprague-Dawley rats were used in the present study. Rats were anesthetized with sodium pentobarbital, and 100 μg of sodium laurate was injected into the left internal carotid artery on days 1 and 3. The thrombus induction and consequent of ischemic brain damage were examined by histopathological analyses and neurological deficit scoring in a posture reflex test. To investigate the neuroprotective effects of fasudil, 1 or 10 mg/kg was administered intraperitoneally 5 minutes after the first injection of sodium laurate and once daily thereafter on the following 2 days. Results - One hour after the injection of sodium laurate, microscopic examination of phosphotungstic acid hematoxylinstained sections (n=5) revealed that microthrombi containing fibrin strands obstructed the perforating arteries in the ipsilateral hemisphere. Under a transmission electron microscope (n=6), endothelial cells appeared exfoliated and the vascular lumen was obstructed by a thrombus composed of degranulated platelets, fibrin, leukocytes, and erythrocytes. No evidence of endothelial cell damage or thrombus could be found in the ipsilateral side of the pial artery (middle cerebral artery). Twenty-four hours after the second injection of sodium laurate (day 4), 13 of 15 rats (86.6%) showed mild to severe neurological deficits. Multiple small cerebral infarcts were observed in the hippocampus, cortex, and thalamus. Treatment with fasudil (1 and 10 mg/kg, n=15 each) resulted in a significant improvement in neurological deficits. Fasudil also significantly reduced the area of cerebral infarction. Conclusions - We present a new model of stroke in rats, in which the perforating arteries are selectively occluded by microthrombi. This model is useful to investigate the pathophysiology and treatment of small cerebral infarction, which is caused by perforating arterial occlusive diseases such as lacunar infarcts. Fasudil may be beneficial in the treatment of acute ischemic stroke.

Original languageEnglish (US)
Pages (from-to)2245-2250
Number of pages6
JournalStroke
Volume31
Issue number9
StatePublished - 2000
Externally publishedYes

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lauric acid
rho-Associated Kinases
Neuroprotective Agents
Arteries
Thrombosis
Stroke
Cerebral Infarction
Fibrin
Injections
Endothelial Cells
Phosphotungstic Acid
Lacunar Stroke
Arterial Occlusive Diseases
Middle Cerebral Artery
Internal Carotid Artery
Pentobarbital
Posture
Thalamus
Blood Vessels
Sprague Dawley Rats

Keywords

  • Cerebral infarction
  • Cerebral thrombosis
  • Protein kinases
  • Rats

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Neuroscience(all)

Cite this

A new model of cerebral microthrombosis in rats and the neuroprotective effect of a rho-kinase inhibitor. / Toshima, Y.; Satoh, S. I.; Ikegaki, I.; Asano, T.; Dalton Dietrich, W.

In: Stroke, Vol. 31, No. 9, 2000, p. 2245-2250.

Research output: Contribution to journalArticle

Toshima, Y. ; Satoh, S. I. ; Ikegaki, I. ; Asano, T. ; Dalton Dietrich, W. / A new model of cerebral microthrombosis in rats and the neuroprotective effect of a rho-kinase inhibitor. In: Stroke. 2000 ; Vol. 31, No. 9. pp. 2245-2250.
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AU - Satoh, S. I.

AU - Ikegaki, I.

AU - Asano, T.

AU - Dalton Dietrich, W.

PY - 2000

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N2 - Background and Purpose - The aim of this study was to develop a new model of stroke based on endothelial damage and thrombotic occlusion in a perforating artery, leading to small cerebral infarcts and neurological deficits in rats. Moreover, the neuroprotective efficacy of fasudil, a rho-kinase inhibitor, was investigated in this model. Methods - Fifty-six male Sprague-Dawley rats were used in the present study. Rats were anesthetized with sodium pentobarbital, and 100 μg of sodium laurate was injected into the left internal carotid artery on days 1 and 3. The thrombus induction and consequent of ischemic brain damage were examined by histopathological analyses and neurological deficit scoring in a posture reflex test. To investigate the neuroprotective effects of fasudil, 1 or 10 mg/kg was administered intraperitoneally 5 minutes after the first injection of sodium laurate and once daily thereafter on the following 2 days. Results - One hour after the injection of sodium laurate, microscopic examination of phosphotungstic acid hematoxylinstained sections (n=5) revealed that microthrombi containing fibrin strands obstructed the perforating arteries in the ipsilateral hemisphere. Under a transmission electron microscope (n=6), endothelial cells appeared exfoliated and the vascular lumen was obstructed by a thrombus composed of degranulated platelets, fibrin, leukocytes, and erythrocytes. No evidence of endothelial cell damage or thrombus could be found in the ipsilateral side of the pial artery (middle cerebral artery). Twenty-four hours after the second injection of sodium laurate (day 4), 13 of 15 rats (86.6%) showed mild to severe neurological deficits. Multiple small cerebral infarcts were observed in the hippocampus, cortex, and thalamus. Treatment with fasudil (1 and 10 mg/kg, n=15 each) resulted in a significant improvement in neurological deficits. Fasudil also significantly reduced the area of cerebral infarction. Conclusions - We present a new model of stroke in rats, in which the perforating arteries are selectively occluded by microthrombi. This model is useful to investigate the pathophysiology and treatment of small cerebral infarction, which is caused by perforating arterial occlusive diseases such as lacunar infarcts. Fasudil may be beneficial in the treatment of acute ischemic stroke.

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