BACKGROUND: Cyclopentenone prostaglandins have been identified as potential neurotoxic agents in the setting of hypoxia-ischemia. Cyclooxygenase-2 (COX-2), the upstream enzyme responsible for prostaglandin production is upregulated following hypoxic-ischemic brain injury. However, the temporal production and concentration of cyclopentenone prostaglandins has not been described following global brain ischemia. METHODS: Global brain ischemia was induced in rats by asphyxial cardiac arrest (ACA) followed by resuscitation. Rats were sacrificed between 24h and 7 days following resuscitation and their brains removed. Western blot, immunohistochemistry, and mass spectroscopy were performed. A cohort of rats was pretreated with the COX-2 inhibitor SC58125. RESULTS: COX-2 is induced in hippocampus at 24h following ACA. Multiple prostaglandins, including cyclopentenone prostaglandin species, are increased in hippocampus as 24h following ACA. Prostaglandin and cyclopentenone prostaglandin concentrations are returned to baseline at 3 and 7 days post-ischemia. The COX-2 inhibitor SC58125 completely abrogates the post-ischemic increase in prostaglandins and cyclopentenone prostaglandins. CONCLUSIONS: Prostaglandins, including cyclopentenone prostaglandins, are increased in ischemic brain, peak at 24h and can be attenuated by the COX-2 inhibitor SC58125. These data establish the presence of potentially neurotoxic cyclopentenone prostaglandins in post-ischemic brains, thus identifying a target and therapeutic window for neuroprotective therapies.
BACKGROUND:Cyclopentenone prostaglandins have been identified as potential neurotoxic agents in the setting of hypoxia-ischemia. Cyclooxygenase-2 (COX-2), the upstream enzyme responsible for prostaglandin production is upregulated following hypoxic-ischemic brain injury. However, the temporal production and concentration of cyclopentenone prostaglandins has not been described following global brain ischemia. METHODS: Global brain ischemia was induced in rats by asphyxial cardiac arrest (ACA) followed by resuscitation. Rats were sacrificed between 24h and 7 days following resuscitation and their brains removed. Western blot, immunohistochemistry, and mass spectroscopy were performed. A cohort of rats was pretreated with the COX-2 inhibitor SC58125. RESULTS:COX-2 is induced in hippocampus at 24h following ACA. Multiple prostaglandins, including cyclopentenone prostaglandin species, are increased in hippocampus as 24h following ACA. Prostaglandin and cyclopentenone prostaglandin concentrations are returned to baseline at 3 and 7 days post-ischemia. The COX-2 inhibitor SC58125 completely abrogates the post-ischemic increase in prostaglandins and cyclopentenone prostaglandins. CONCLUSIONS:Prostaglandins, including cyclopentenone prostaglandins, are increased in ischemic brain, peak at 24h and can be attenuated by the COX-2 inhibitor SC58125. These data establish the presence of potentially neurotoxiccyclopentenone prostaglandins in post-ischemic brains, thus identifying a target and therapeutic window for neuroprotective therapies.
Authors: C Iadecola; K Niwa; S Nogawa; X Zhao; M Nagayama; E Araki; S Morham; M E Ross Journal: Proc Natl Acad Sci U S A Date: 2001-01-30 Impact factor: 11.205
Authors: S Takei; S Hasegawa-Ishii; A Uekawa; Y Chiba; H Umegaki; M Hosokawa; D F Woodward; K Watanabe; A Shimada Journal: Neuroscience Date: 2012-05-17 Impact factor: 3.590
Authors: L Chastine Bell-Parikh; Tomomi Ide; John A Lawson; Peter McNamara; Muredach Reilly; Garret A FitzGerald Journal: J Clin Invest Date: 2003-09 Impact factor: 14.808
Authors: M Nakayama; K Uchimura; R L Zhu; T Nagayama; M E Rose; R A Stetler; P C Isakson; J Chen; S H Graham Journal: Proc Natl Acad Sci U S A Date: 1998-09-01 Impact factor: 11.205
Authors: Anna-Liisa Levonen; Aimee Landar; Anup Ramachandran; Erin K Ceaser; Dale A Dickinson; Giuseppe Zanoni; Jason D Morrow; Victor M Darley-Usmar Journal: Biochem J Date: 2004-03-01 Impact factor: 3.857
Authors: Ericka L Fink; Henry Alexander; Christina D Marco; C Edward Dixon; Patrick M Kochanek; Larry W Jenkins; Yichen Lai; Holly A Donovan; Robert W Hickey; Robert S Clark Journal: Pediatr Crit Care Med Date: 2004-03 Impact factor: 3.624
Authors: Hao Liu; Jie Chen; Wenjin Li; Marie E Rose; Sunita N Shinde; Manimalha Balasubramani; Guy T Uechi; Bülent Mutus; Steven H Graham; Robert W Hickey Journal: FEBS J Date: 2015-03-27 Impact factor: 5.542
Authors: Jing Ji; Sophie Baart; Anna S Vikulina; Robert Sb Clark; Tamil S Anthonymuthu; Vladimir A Tyurin; Lina Du; Claudette M St Croix; Yulia Y Tyurina; Jesse Lewis; Erin M Skoda; Anthony E Kline; Patrick M Kochanek; Peter Wipf; Valerian E Kagan; Hülya Bayır Journal: J Cereb Blood Flow Metab Date: 2014-11-19 Impact factor: 6.200
Authors: Maria E Figueiredo-Pereira; Patricia Rockwell; Thomas Schmidt-Glenewinkel; Peter Serrano Journal: Front Mol Neurosci Date: 2015-01-13 Impact factor: 5.639
Authors: Charles H Wallace; Giovanni Oliveros; Peter A Serrano; Patricia Rockwell; Lei Xie; Maria Figueiredo-Pereira Journal: Life Sci Alliance Date: 2022-09-27
Authors: H Liu; W Li; M E Rose; R W Hickey; J Chen; G T Uechi; M Balasubramani; B W Day; K V Patel; S H Graham Journal: Cell Death Dis Date: 2015-11-05 Impact factor: 8.469