Low-Dose Activated Protein C Suppresses the Development of Cerebral Infarction and Neurological Deficits in Mice. Issue 4 (13th October 2020)

• Record Type: Journal Article
• Authors: Yamato, Keiko; Nakajo, Yukako; Yamamoto-Imoto, Hitomi; Kokame, Koichi; Miyata, Toshiyuki; Takahashi, Jun C; Kataoka, Hiroharu; Yanamoto, Hiroji
• Is Part Of: Neurosurgery open. Volume 1:Issue 4(2020)
• Publication Date: 2020-10-13
• Subjects: Activated protein C -- Acute ischemic stroke -- Endothelial cells -- Animal model -- Neuroprotection -- Serine protease -- Preclinical study; Nervous system -- Surgery -- Periodicals; 617.48
• DOI: 10.1093/neuopn/okaa014
• Languages: English
• ISSNs: 2633-0873

Abstract

Abstract: BACKGROUND: A large prospective study previously reported that a higher plasma level of protein C (PC) was associated with a lower incidence of ischemic stroke. OBJECTIVE: To investigate the neuroprotective properties of activated PC (APC) against acute ischemic stroke using the 3-vessel occlusion model. METHODS: Male C57BL/6J mice received APC (human APC) at 0.25, 0.5, or 1.0 (low dose) or 2.0, 4.0, or 8.0 mg/kg (high dose). Edaravone (Eda) (1.0, 3.0, or 10 mg/kg, a neuroprotectant approved for use in Japan), albumin (2.0 mg/kg), heparin (100 or 600 U/kg), or saline was used as the control. The drug or control was administered intravenously twice in the initial 24 h or 5 times in 3 d, starting 5 min after the induction of ischemia. RESULTS: Low-dose APC significantly reduced lesion volumes, not affecting the depth of ischemia. High-dose APC did not significantly reduce lesion volumes, causing hemorrhagic transformation in some cases. In the chronic phase, lesion volumes were significantly suppressed in the APC or Eda group, and only the APC group showed a significant attenuation of neurological deficits. The protease-activated receptor (PAR)-1 antagonist SCH79797, administered during preischemia, completely abolished APC-induced neuroprotection. The overshoot-like abrupt recovery in regional cerebral blood flow observed in the control in the initial reperfusion phase was significantly suppressed by the APC treatment, indicating that the cerebral autoregulation system, consisting of endothelial cells and blood-brain barrier functions, was preserved. CONCLUSION: Low-dose APC, potentially via the PAR-1-dependent anti-inflammatory cascade, protects the brain against ischemic stroke without increasing the risk of hemorrhagic transformation or death.