TY - JOUR
T1 - The dual role of prostaglandin E2 in excitotoxicity and preconditioning-induced neuroprotection
AU - Gendron, Tania F.
AU - Brunette, Eric
AU - Tauskela, Joseph S.
AU - Morley, Paul
N1 - Funding Information:
T. Gendron was supported by a Focus on Stroke Doctoral Research Award. We acknowledge financial support from the Heart and Stroke Foundation of Ontario (#T-4916), the Canadian Stroke Network and the National Research Council Canada.
PY - 2005/7/4
Y1 - 2005/7/4
N2 - Cyclooxygenase-2 is harmful in models of cerebral ischemia yet plays a protective role in preconditioning-induced ischemic tolerance in the heart. This study examined the mechanisms underlying cyclooxygenase-2-mediated neurotoxicity and preconditioning-induced neuroprotection in an in vitro model of cerebral ischemia. Inhibition of cyclooxygenase-2 protects cortical neuronal cultures from death induced by oxygen-glucose deprivation and reduces oxygen-glucose deprivation-induced increases in intracellular Ca2+ ([Ca2+]i). In the present study, we determined if prostaglandin E2 (PGE2) is responsible for this cyclooxygenase-2-mediated effect. Rat cortical cultures expressed mRNA for the prostanoid EP1-EP4 receptors. PGE2 reversed the attenuation in [Ca2+]i and the protection offered by cyclooxygenase-2 inhibition during oxygen-glucose deprivation. These effects likely occur via activation of the prostanoid EP1 receptor since blocking this receptor during oxygen-glucose deprivation reduced [Ca 2+]i and neurotoxicity. Next, we considered if the moderate activation of this pathway, by preconditioning cultures with sub-lethal oxygen-glucose deprivation, influenced the development of tolerance to an otherwise lethal oxygen-glucose deprivation insult, 48 h later. Inhibition of cyclooxygenase-2 during oxygen-glucose deprivation-preconditioning abolished preconditioning-induced protection. Furthermore, cultures were rendered tolerant to oxygen-glucose deprivation by the transient exposure to exogenous PGE 2 24 h prior to the insult, indicating that this product of the cyclooxygenase-2 pathway is sufficient to induce ischemic tolerance. This study shows that cyclooxygenase-2 and PGE2 are involved in both oxygen-glucose deprivation-induced neurotoxicity and preconditioning-induced neuroprotection. While neurotoxic in the context of lethal oxygen-glucose deprivation, the moderate activation of this signalling pathway confers ischemic tolerance.
AB - Cyclooxygenase-2 is harmful in models of cerebral ischemia yet plays a protective role in preconditioning-induced ischemic tolerance in the heart. This study examined the mechanisms underlying cyclooxygenase-2-mediated neurotoxicity and preconditioning-induced neuroprotection in an in vitro model of cerebral ischemia. Inhibition of cyclooxygenase-2 protects cortical neuronal cultures from death induced by oxygen-glucose deprivation and reduces oxygen-glucose deprivation-induced increases in intracellular Ca2+ ([Ca2+]i). In the present study, we determined if prostaglandin E2 (PGE2) is responsible for this cyclooxygenase-2-mediated effect. Rat cortical cultures expressed mRNA for the prostanoid EP1-EP4 receptors. PGE2 reversed the attenuation in [Ca2+]i and the protection offered by cyclooxygenase-2 inhibition during oxygen-glucose deprivation. These effects likely occur via activation of the prostanoid EP1 receptor since blocking this receptor during oxygen-glucose deprivation reduced [Ca 2+]i and neurotoxicity. Next, we considered if the moderate activation of this pathway, by preconditioning cultures with sub-lethal oxygen-glucose deprivation, influenced the development of tolerance to an otherwise lethal oxygen-glucose deprivation insult, 48 h later. Inhibition of cyclooxygenase-2 during oxygen-glucose deprivation-preconditioning abolished preconditioning-induced protection. Furthermore, cultures were rendered tolerant to oxygen-glucose deprivation by the transient exposure to exogenous PGE 2 24 h prior to the insult, indicating that this product of the cyclooxygenase-2 pathway is sufficient to induce ischemic tolerance. This study shows that cyclooxygenase-2 and PGE2 are involved in both oxygen-glucose deprivation-induced neurotoxicity and preconditioning-induced neuroprotection. While neurotoxic in the context of lethal oxygen-glucose deprivation, the moderate activation of this signalling pathway confers ischemic tolerance.
KW - Ca
KW - Cyclooxygenase-2
KW - Oxygen-glucose deprivation
KW - Preconditioning
KW - Primary cortical cultures
KW - Prostaglandin E
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U2 - 10.1016/j.ejphar.2005.05.031
DO - 10.1016/j.ejphar.2005.05.031
M3 - Article
C2 - 15964567
AN - SCOPUS:21344452607
SN - 0014-2999
VL - 517
SP - 17
EP - 27
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-2
ER -