Prostaglandin FP receptor inhibitor reduces ischemic brain damage and neurotoxicity

Neurobiology of Disease

Takayuki Maruyama¹  Sang Kwan Moon²  Sylvain Doré³  Yun Tai Kim⁴  Shuh Narumiya⁵ 

[1] Neurologic Disease, Hospital of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea;;Department of Cardiovascular &Department of Pharmacology, Kyoto University, Kyoto, Japan;Korea Food Research Institute, Seongnam, Republic of Korea;Pharmacological Research Laboratories, Ono Pharmaceutical Co. Ltd, Mishima-gun, Osaka, Japan;

关键词: Cerebral ischemia;    Inflammation;    Receptor;    Stroke;    Oxygen glucose deprivation;   

DOI  :  

来源: DOAJ

【 摘 要 】

Bioactive lipids such as the prostaglandins have been reported to have various cytoprotective or toxic properties in acute and chronic neurological conditions. The roles of PGF2α and its receptor (FP) are not clear in the pathogenesis of ischemic brain injury. Considering that this G-protein coupled receptor has been linked to intracellular calcium regulation, we hypothesized that its blockade would be protective. We used FP antagonist (AL-8810) and FP receptor knockout (FP−/−) mice in in vivo and in vitro stroke models. Mice that were treated with AL-8810 had 35.7±6.3% less neurologic dysfunction and 36.4±6.0% smaller infarct volumes than did vehicle-treated mice after 48 h of permanent middle cerebral artery occlusion (pMCAO); FP−/− mice also had improved outcomes after pMCAO. Blockade of the FP receptor also protected against oxygen-glucose deprivation (OGD)-induced cell death and reactive oxygen species formation in slice cultures. Finally, we found that an FP receptor agonist dose dependently increased intracellular Ca2+ levels in cultured neurons and established that FP-related Ca2+ signaling is related to ryanodine receptor signaling. These results indicate that the FP receptor is involved in cerebral ischemia-induced damage and could promote development of drugs for treatment of stroke and acute neurodegenerative disorders.

【 授权许可】

Unknown