Human Group IIA Secretory Phospholipase A2Induces Neuronal Cell Death via Apoptosis
| Autor: | Satoshi Hata, Kazushige Tanaka, Keiichi Ueda, Toshiyuki Sakaeda, Tatsurou Yagami, Takefumi Gemba, Nobuo Takasu, Yozo Hori, Kenji Asakura, Takayuki Kuroda |
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| Rok vydání: | 2002 |
| Předmět: |
Male
Programmed cell death Cell Survival Apoptosis Arachidonic Acids In Vitro Techniques Biology Pharmacology Group II Phospholipases A2 Neuroprotection Phospholipases A Rats Sprague-Dawley chemistry.chemical_compound medicine Animals Humans Cyclooxygenase Inhibitors Enzyme Inhibitors Rats Wistar Neurons Cyclooxygenase 2 Inhibitors Prostaglandin D2 Neurodegeneration Neurotoxicity Brain Membrane Proteins Cerebral Infarction medicine.disease Rats Isoenzymes Phospholipases A2 medicine.anatomical_structure chemistry Cyclooxygenase 2 Prostaglandin-Endoperoxide Synthases Cerebral cortex Immunology Eicosanoids Molecular Medicine Arachidonic acid |
| Zdroj: | Molecular Pharmacology. 61:114-126 |
| ISSN: | 1521-0111 0026-895X |
| DOI: | 10.1124/mol.61.1.114 |
| Popis: | Expression of group IIA secretory phospholipase A2 (sPLA2-IIA) is documented in the cerebral cortex (CTX) after ischemia, suggesting that sPLA2-IIA is associated with neurodegeneration. However, how sPLA2-IIA is involved in the neurodegeneration remains obscure. To clarify the pathologic role of sPLA2-IIA, we examined its neurotoxicity in rats that had the middle cerebral artery occluded and in primary cultures of cortical neurons. After occlusion, sPLA2 activity was increased in the CTX. An sPLA2 inhibitor, indoxam, significantly ameliorated not only the elevated activity of the sPLA2 but also the neurodegeneration in the CTX. The neuroprotective effect of indoxam was observed even when it was administered after occlusion. In primary cultures, sPLA2-IIA caused marked neuronal cell death. Morphologic and ultrastructural characteristics of neuronal cell death by sPLA2-IIA were apoptotic, as evidenced by condensed chromatin and fragmented DNA. Before apoptosis, sPLA2-IIA liberated arachidonic acid (AA) and generated prostaglandin D2 (PGD2), an AA metabolite, from neurons. Indoxam significantly suppressed not only AA release, but also PGD2 generation. Indoxam prevented neurons from sPLA2-IIA-induced neuronal cell death. The neuroprotective effect of indoxam was observed even when it was administered after sPLA2-IIA treatment. Furthermore, a cyclooxygenase-2 inhibitor significantly prevented neurons from sPLA2-IIA-induced PGD2 generation and neuronal cell death. In conclusion, sPLA2-IIA induces neuronal cell death via apoptosis, which might be associated with AA metabolites, especially PGD2. Furthermore, sPLA2 contributes to neurodegeneration in the ischemic brain, highlighting the therapeutic potential of sPLA2-IIA inhibitors for stroke. |
| Databáze: | OpenAIRE |
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