Contributions of cyclooxygenase-2 to neuroplasticity and neuropathology of the central nervous system

Hewett, Sandra J.; Bell, Stanley C.; Hewett, James A.

doi:10.1016/j.pharmthera.2005.04.011

Cited by 78 publications

(79 citation statements)

References 367 publications

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“…Induction of COX-2 activity and production of downstream prostaglandins is associated in a wide range of neurological disease models with neuronal injury [9,18]. Previous studies in organotypic excitotocity models have identified paradoxical neuroprotective effects of PGE 2 and PGD 2 receptors that have been confirmed in vivo in models of ischemia.…”

Section: Discussionmentioning

confidence: 99%

“…However, in pathologic conditions caused by either excitotoxicity or inflammation, COX-2 expression and activity are increased in neurons and glial cells, and can promote either primary or secondary neuronal injury, respectively. Thus increased COX-2 activity and prostaglandin production are hallmarks of a wide range neurological disease models, including acute excitotoxic events such as cerebral ischemia, traumatic brain or spinal cord injury, as well as paradigms of chronic neurodegeneration that model human amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD; reviewed in [9,18]) and aging [2]. In humans, increased COX-2 and prostaglandin production have been Correspondence should be addressed to: K. Andreasson, Stanford University Dept of Neurology and Neurological Sciences, 1201 Welch Road, MSLS P250, Stanford, CA 94305, E-mail: kandreas@stanford.edu.…”

Section: Introductionmentioning

confidence: 99%

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Divergent effects of prostaglandin receptor signaling on neuronal survival

Wang

Liang

et al. 2007

Neuroscience Letters

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Induction of cyclooxygenase-2 (COX-2) with production of prostaglandins occurs in a wide spectrum of acute and chronic neurodegenerative diseases and is associated with neuronal death. Inhibition of the COX-2 pathway and downstream production of prostaglandins protects neurons in rodent models of cerebral ischemia and neurodegeneration. Recent studies investigating the functions of selected prostaglandin receptor pathways in mediating COX-2 neurotoxicity have demonstrated both toxic and paradoxically neuroprotective effects of several receptors in models of excitotoxicity. In this study, we investigate the functions of additional prostaglandin receptors not previously characterized in organotypic models of glutamate excitotoxicity. We find that PGD 2 , PGI 2 , and PGF 2α receptors protect motor neurons in an organotypic spinal cord model of amyotrophic lateral sclerosis (ALS). In addition, PGI 2 and TXA 2 receptors rescue CA1 neurons in an organotypic hippocampal model of N-methyl D-aspartate excitotoxicity. However, in a model of inflammation induced by lipopolysaccharide, prostaglandin receptors previously found to be protective in excitotoxicity now cause CA1 neuronal death. Taken together, these studies identify novel eicosanoid receptor signaling pathways that mediate neuronal protection in excitotoxic paradigms; these data also support the emerging hypothesis that the toxic/protective effects of eicosanoid signaling on neuronal viability diverge significantly depending on whether excitotoxicity or inflammation predominates as the underlying toxic stimulus.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Divergent effects of prostaglandin receptor signaling on neuronal survival

Wang

Liang

et al. 2007

Neuroscience Letters

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“…Cyclooxygenase activation and prostaglandin receptor signaling elicits significant injury in models of cerebral ischemia and related models of spinal cord and brain trauma, and also contributes to neurodegeneration in models of Parkinson disease, amyotrophic lateral sclerosis, and Alzheimer disease (reviewed in ref. 5). Thus, pathological induction of cyclooxygenase/prostaglandin signaling is deleterious in a wide range of acute and chronic neurological diseases.…”

Section: Introductionmentioning

confidence: 99%

Signaling via the prostaglandin E2 receptor EP4 exerts neuronal and vascular protection in a mouse model of cerebral ischemia

Liang

Lin²,

Woodling³

et al. 2011

J. Clin. Invest.

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Stroke is the third leading cause of death in the United States. Fewer than 5% of patients benefit from the only intervention approved to treat stroke. Thus, there is an enormous need to identify new therapeutic targets. The role of inducible cyclooxygenase (COX-2) activity in stroke and other neurologic diseases is complex, as both activation and sustained inhibition can engender cerebral injury. Whether COX-2 induces cerebroprotective or injurious effects is probably dependent on which downstream prostaglandin receptors are activated. Here, we investigated the function of the PGE 2 receptor EP4 in a mouse model of cerebral ischemia. Systemic administration of a selective EP4 agonist after ischemia reduced infarct volume and ameliorated long-term behavioral deficits. Expression of EP4 was robust in neurons and markedly induced in endothelial cells after ischemiareperfusion, suggesting that neuronal and/or endothelial EP4 signaling imparts cerebroprotection. Conditional genetic inactivation of neuronal EP4 worsened stroke outcome, consistent with an endogenous protective role of neuronal EP4 signaling in vivo. However, endothelial deletion of EP4 also worsened stroke injury and decreased cerebral reperfusion. Systemic administration of an EP4 agonist increased levels of activated eNOS in cerebral microvessels, an effect that was abolished with conditional deletion of endothelial EP4. Thus, our data support the concept of targeting protective prostaglandin receptors therapeutically after stroke. IntroductionStroke is the third leading cause of death after cardiovascular disease and cancer, and stroke survivors have a 30%-50% chance of losing functional independence (1). Treatment with recombinant tPA, a thrombolytic agent, is the only approved therapy for acute stroke; however, less than 5% of stroke patients benefit from this intervention (2), in large part because of the limited time window of administration and the risk of hemorrhagic transformation. Translational attempts to validate neuroprotective strategies in the early poststroke setting have been uniformly unsuccessful, even in cases of compelling preclinical animal data. Although many reasons have been raised for this lack of success, there is consensus that single agents targeting early short-lived components of the neurotoxic cascade may not be effective (3). Thus, there is a crucial need to identify new interventions that can be therapeutically implemented after stroke.The cyclooxygenases COX-1 and COX-2 catalyze the first committed step in the formation of prostaglandins PGE 2 , PGD 2 , PGF 2a , TXA 2 , and PGI 2 , which activate distinct classes of GPCRs (reviewed in ref. 4). Cyclooxygenase activation and prostaglandin receptor signaling elicits significant injury in models of cerebral ischemia and related models of spinal cord and brain trauma, and also contributes to neurodegeneration in models of Parkinson disease, amyotrophic lateral sclerosis, and Alzheimer disease (reviewed in ref. 5). Thus, pathological induction of cyclooxygenase/prostagla...

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“…In ad di ti on, se ve ral stu di es ha ve sug ges ted that PGE 2 in du ces cas pa se-de pendent apop to sis, ac ting vi a an EP2-li ke re cep tor, and a sig na ling me di a tor in vol ved in hip po cam pal ex cita tory glu ta mi ner gic synap tic trans mis si on in rat cul tu red cor ti cal ne u rons. 19,20 It has be en de mons tra ted that in do met ha cin, a cyclo oxy ge na se in hi bi tor of pros tag lan din synthesis, in hi bits de la yed ne u ro nal da ma ge and dec re ases bra in in farct vo lu me, es pe ci ally DNA da ma ge. In the sa me way, in do met ha cin pre vents de la yed ne u ro nal de ath.…”

Section: Discussionmentioning

confidence: 99%

Indomethacin Prevents Neuronal Apoptosis in Newborn Rats with Hypoxic-Ischemic Brain Injury

Taşkın¹,

Satar²,

Zorludemir³

et al. 2011

Turkiye Klinikleri J Med Sci

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A AB BS S T TR RA AC CT T O Ob b j je ec c t ti i v ve e: : Cyclo oxy ge na se path way and pros tag lan dins play an im por tant ro le in the pat ho ge ne sis and de la yed mec ha nisms of hypo xic-isc he mic bra in in jury. The aim of this study was to in ves ti ga te the ef fect of dif fe rent do ses of in do met ha cin, a non se lec ti ve cyclo oxy ge na se in hi bitor, on ne u ro nal apop to sis in rats with hypo xic-isc he mic bra in in jury. M Ma a t te e r ri i a al l a an nd d M Me et t h ho od ds s: : Seven-day-old rat pups with the Ri ce mo del of hypo xic-isc he mic ce reb ral in jury we re ran domly di vi ded in to fi ve gro ups. Gro up 1 (n= 15) pups we re gi ven physi o lo gic sa li ne, ne it her li ga ti on nor hypo xi a we re per for med. Gro up 2 (n= 15) pups we re tre a ted with physi o lo gic sa li ne af ter hypoxic-isc he mi a. Gro up 3 (n= 15) pups we re tre a ted with in do met ha cin at a do se of 2 mg/kg be fo re hypo xic isc he mi a. Gro up 4 (n= 15) pups we re tre a ted with thre e do ses of in do met ha cin at a dose of 2 mg/kg every 12 h af ter hypo xic-isc he mi a. Gro up 5 (n= 15) pups we re tre a ted with thre e do ses of in do met ha cin, at a do se of 4mg/kg every 12 h af ter hypo xic isc he mi a. Af ter 72 ho urs, the rats we re de ca pi ta ted and bra in he misp he res we re eva lu a ted by the TU NEL (Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling) sta i ning met hod. R Re e s su ul lt ts s: : In do met ha cin tre at ment, eit her be fo re or af ter hypo xi a, re sul ted in a sig ni fi cant re duc ti on in the num bers of apopto tic cells in the rat bra in when com pa red to tho se who we re tre a ted with physi o lo gic sa li ne af ter hypo xic-isc he mi a (P< 0.001). C Co on nc c l lu u s si i o on n: : Our re sults de mons tra ted that in do met ha cin ad mi nistra ti on, eit her be fo re or af ter hypo xic-isc he mi a, re du ces ne u ro nal apop to sis; and we pro po se that in do met ha cin may be a po ten ti al cho i ce of tre at ment for hypo xic-isc he mic bra in in jury.K Ke ey y W Wo or rd ds s: : Hypo xi a-isc he mi a, bra in; apop to sis; in do met ha cin Ö ÖZ ZE ET T A Am ma aç ç: : Sik lo ok si je naz yo la ğı ve pros tag lan din ler, hi pok sik-is ke mik be yin ha sa rı nın pa to gene zin de ve geç dö nem ki sü re cin de önem li rol oy na mak ta dır. Bu ça lış ma nın ama cı, bir non-se lektif sik lo ok si je naz in hi bi tö rü olan in do me ta zi ni fark lı doz lar da uy gu la rak hi pok sik-is ke mik be yin ha sar lı rat lar da nö ro nal apo pi to zis üze ri ne et ki le ri ni araş tır mak tır. G Ge e r re eç ç v ve e Y Yö ön n t te em m l le er r: : Le vi neRi ce me to du na gö re hi pok sik is ke mi oluş tu ru lan ye di gün lük rat yav ru la rı rast ge le beş gru ba ay rıl -dı. Grup 1'de ki (n: 15) yav ru la ra ne li gas yon ne de hi pok si uy gu lan ma dan sa de ce se rum fiz yo lo jik ve ril di. Grup 2'de ki (n: 15) yav ru la ra hi pok sik-is ke mik ha le ge ti ril dik ten son ra se rum fiz yo lo jik veril di. Grup 3'te ki (n: 15) yav...

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Contributions of cyclooxygenase-2 to neuroplasticity and neuropathology of the central nervous system

Cited by 78 publications

References 367 publications

Divergent effects of prostaglandin receptor signaling on neuronal survival

Divergent effects of prostaglandin receptor signaling on neuronal survival

Signaling via the prostaglandin E2 receptor EP4 exerts neuronal and vascular protection in a mouse model of cerebral ischemia

Indomethacin Prevents Neuronal Apoptosis in Newborn Rats with Hypoxic-Ischemic Brain Injury

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