Long-term elevation of cyclooxygenase-2, but not lipoxygenase, in regions synaptically distant from spreading depression

Caggiano, Anthony O.; Breder, Christopher D.; Kraig, Richard P.

doi:10.1002/(sici)1096-9861(19961216)376:3<447::aid-cne7>3.0.co;2-2

Cited by 47 publications

(17 citation statements)

References 45 publications

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“…Furthermore, COX2 expression is induced in neurons by spreading depression, which resembles in many respects the anoxic depolarization that occurs in cerebral ischemia (43). The current data show that there is dramatic induction of COX2 protein expression in neurons after ischemia.…”

Section: Discussionsupporting

confidence: 63%

Cyclooxygenase-2 inhibition prevents delayed death of CA1 hippocampal neurons following global ischemia

Nakayama

Uchimura

Zhu

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

316

265

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The inducible isoform of the enzyme cyclooxygenase-2 (COX2) is an immediate early gene induced by synaptic activity in the brain. COX2 activity is an important mediator of inflammation, but it is not known whether COX2 activity is pathogenic in brain. To study the role of COX2 activity in ischemic injury in brain, expression of COX2 mRNA and protein and the effect of treatment with a COX2 inhibitor on neuronal survival in a rat model of global ischemia were determined. Expression of both COX2 mRNA and protein was increased after ischemia in CA1 hippocampal neurons before their death. There was increased survival of CA1 neurons in rats treated with the COX2-selective inhibitor SC58125 {1-[(4-methylsulfonyl) phenyl]-3-trifluoro-methyl-5-[(4-fluoro)phenyl] pyrazole} before or after global ischemia compared with vehicle controls. Furthermore, hippocampal prostaglandin E 2 concentrations 24 h after global ischemia were decreased in drug-treated animals compared with vehicle-treated controls. These results suggest that COX2 activity contributes to CA1 neuronal death after global ischemia.Cyclooxygenase (prostaglandin G͞H synthase) is the first committed step in the production of prostaglandins and thromboxanes. Two forms of the cyclooxygenase enzyme have been cloned. Cyclooxygenase-1 (COX1) is constitutively expressed in many tissues including platelets, gastrointestinal mucosa, and kidney (1-3). The inducible form, cyclooxygenase-2 (COX2), is primarily expressed in leukocytes and brain (4). Its expression is induced by cytokines and inhibited by glucocorticoids, and it is an important mediator of cell injury in inflammation (5-7). Transcription of COX2 mRNA does not require new protein synthesis; therefore, it is an immediate early gene (6). The rat brain COX2 is identical to the nonnervous system COX2 (8). Its mRNA expression is rapidly induced by synaptic activity but blocked by the N-methyl-Daspartate receptor antagonist MK801 (8). This finding suggests that COX2 transcription is induced by increased intraneuronal Ca 2ϩ . COX2 is found in dendrites of neurons that receive excitatory input (9). Thus, COX2 may produce rapid neuronal responses to synaptic activity.Neuronal excitation and increased intracellular calcium, two stimuli that induce expression of COX2, are also important in the pathophysiology of neuronal death in ischemia and a variety of neurodegenerative diseases (10, 11). In nonneural cells, COX2 activity mediates inflammatory injury (12); however, COX2 overexpression may prevent apoptosis in intestinal epithelium (13). What role COX2 expression and activity have in mediating injury after global ischemia in brain is unknown. To address this question, the expression of COX2 mRNA and protein was studied in rat brain after global ischemia, and the effect of treatment with a selective inhibitor of COX2 {SC58125; 1-[(4-methylsulfonyl)phenyl]-3-trifluoro-methyl-5-[(4-fluoro)phenyl] pyrazole} on hippocampal neuronal survival and prostaglandin E 2 (PGE 2 ) concentrations was determined. METHODSAnimal M...

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Section: Discussionsupporting

confidence: 63%

Cyclooxygenase-2 inhibition prevents delayed death of CA1 hippocampal neurons following global ischemia

Nakayama

Uchimura

Zhu

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

316

265

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“…Increased neuronal cyclooxygenase (COX)-2 expression is also associated with neuropathology, including traumatic brain injury, 13) cerebral ischemia, 14,15) spreading depression, 16) and Alzheimer's disease. 17) Brain injuries stimulate cortical and subcortical COX-2 expression in neurons and glia.…”

Section: )mentioning

confidence: 99%

Indomethacin Ameliorates Trimethyltin-Induced Neuronal Damage <i>in Vivo</i> by Attenuating Oxidative Stress in the Dentate Gyrus of Mice

Huong

Nakamura

Kuramoto

et al. 2011

Biological & Pharmaceutical Bulletin

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The organotin trimethyltin chloride (TMT) selectively produces neuronal damage in both human and rodent central nervous systems by acting as a potent neurotoxin.1) TMT neurotoxicity is characterized by neuronal destruction in selective regions, such as the olfactory bulb, hippocampus, amygdaloidal nuclei, piriform/entorhinal cortex, and pyramidal cells in the neocortex. [2][3][4][5] Accumulating evidence suggests that the neuronal damage induced by TMT results from the generation of reactive oxygen species (ROS) and reactive nitrogen species.6,7) Our previous reports showed that TMT elevates the formation of 4-hydroxynonenal (4-HNE), 8) which is a major aldehydic product of lipid peroxidation and believed to be largely responsible for the cytopathological effects observed during oxidative stress. 9) TMT activates caspase 3 as an effector caspase for neuronal damage in the hippocampus, 10) olfactory bulb, and anterior olfactory nucleus 5) of mice in vivo, as well as in the neural progenitor cells derived from mouse embryonic neocortex in vitro. 11) As the initiator caspase for TMT-induced neuronal death, caspase-8 is activated at the earliest time window post-TMT treatment in cortical neurons in vitro.12) In addition to caspases, calpains are known to be activated in the dentate gyrus of mice by TMT 8) or in cultures of embryonic neural progenitor cells by it.11) Furthermore, pharmacological studies using inhibitors for caspases and calpain suggest that TMT neurotoxicity is due to activation of both caspase-8/caspase-3 and calpain in neuronal cells 12) and neural progenitor cells. 11)Increased neuronal cyclooxygenase (COX)-2 expression is also associated with neuropathology, including traumatic brain injury, 13) cerebral ischemia, 14,15) spreading depression, 16) and Alzheimer's disease. 17) Brain injuries stimulate cortical and subcortical COX-2 expression in neurons and glia. 18,19) In addition to that of COX-2, genetic inhibition of COX-1 also ameliorates neuronal damage induced by b-amyloid by reducing the inflammatory response in the murine brain.20) Pharmacological evidence for neuroprotection by COX inhibition comes from the considerable findings that the non-selective COX inhibitor indomethacin protects neurons against damage induced by traumatic injury in the rabbit spinal cord, 21) by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the mouse brain 22) or by ischemic injury in the forebrain. 23)A previous report demonstrated that exposure of astrocytes in primary culture to TMT produces prostaglandin E 2 release and formation of ROS, which effects are completely prevented by indomethacin, a common non-steroidal antiinflammatory drug (NSAID). 24) However, there has been no direct evidence for indomethacin-mediated neuroprotection in TMT neurotoxicity in vivo. Furthermore, the mechanisms underlying the preventive effect of COX inhibitors against neurodegeneration is not yet fully understood. Therefore, we assessed whether indomethacin could ameliorate neuronal degeneration in the dentate gyrus of mice foll...

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“…While basal COX2 appears to be regulated by normal glutamatergic synaptic activity in the adult brain, COX2 can be transiently induced by pathological exposure to glutamate agonists or blocked by NMDA receptor mediated inhibition (Yamagata et al, 1993;Chen et al, 1995;Kaufmann et al, 1996;Adams et al, 1996;Marcheselli and Bazan, 1996). Neuronal induction of COX2 occurs after traumatic brain injury (Graham et al, 1996a;Strauss et al, 1997Strauss et al, , 1998, spinal cord injury (Resnick et al, 1998), cerebral ischemia Graham et al, 1996b;Nogawa et al, 1997;Kong et al, 1997;Sanz et al, 1997;Walton et al, 1997), spreading depression (Caggiano et al, 1996), and seizures (Yamagata et al, 1993;Adams et al, 1996;Marcheselli and Bazan, 1996;Wallace et al, 1998). COX2 expression is also regulated by inflammatory cytokines both in the periphery and in the CNS (Seibert et al, 1994;Moore et al, 1997;Ott et al, 1994;Young and Ott, 1996).…”

Section: Introductionmentioning

confidence: 99%

Prolonged Cyclooxygenase-2 Induction in Neurons and Glia Following Traumatic Brain Injury in the Rat

Strauss

Barbe

Marshall

et al. 2000

Journal of Neurotrauma

110

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Cyclooxygenase-2 (COX2) is a primary inflammatory mediator that converts arachidonic acid into precursors of vasoactive prostaglandins, producing reactive oxygen species in the process. Under normal conditions COX2 is not detectable, except at low abundance in the brain. This study demonstrates a distinctive pattern of COX2 increases in the brain over time following traumatic brain injury (TBI). Quantitative lysate ribonuclease protection assays indicate acute and sustained increases in COX2 mRNA in two rat models of TBI. In the lateral fluid percussion model, COX2 mRNA is significantly elevated (>twofold, p < 0.05, Dunnett) at 1 day postinjury in the injured cortex and bilaterally in the hippocampus, compared to sham-injured controls. In the lateral cortical impact model (LCI), COX2 mRNA peaks around 6 h postinjury in the ipsilateral cerebral cortex (fivefold induction, p < 0.05, Dunnett) and in the ipsilateral and contralateral hippocampus (two-and sixfold induction, respectively, p < 0.05, Dunnett). Increases are sustained out to 3 days postinjury in the injured cortex in both models. Further analyses use the LCI model to evaluate COX2 induction. Immunoblot analyses confirm increased levels of COX2 protein in the cortex and hippocampus. Profound increases in COX2 protein are observed in the cortex at 1-3 days, that return to sham levels by 7 days postinjury (p < 0.05, Dunnett). The cellular pattern of COX2 induction following TBI has been characterized using immunohistochemistry. COX2-immunoreactivity (-ir) rises acutely (cell numbers and intensity) and remains elevated for several days following TBI. Increases in COX2-ir colocalize with neurons (MAP2-ir) and glia (GFAP-ir). Increases in COX2-ir are observed in cerebral cortex and hippocampus, ipsilateral and contralateral to injury as early as 2 h postinjury. Neurons in the ipsilateral parietal, perirhinal and piriform cortex become intensely COX2-ir from 2 h to at least 3 days postinjury. In agreement with the mRNA and immunoblot results, COX2-ir appears greatest in the contralateral hippocampus. Hippocampal COX2-ir progresses from the pyramidal cell layer of the CA1 and CA2 region at 2 h, to the CA3 pyramidal cells and dentate polymorphic and granule cell layers by 24 h postinjury. These increases are distinct from those observed following inflammatory challenge, and correspond to brain areas previously identified with the neurological and cognitive deficits associated with TBI. While COX2 induction following TBI may result in selective beneficial responses, chronic COX2 production may contribute to free radical mediated cellular damage, vascular dysfunction, and alterations in cellular metabolism. These may cause secondary injuries to the brain that promote neuropathology and worsen behavioral outcome.

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Long-term elevation of cyclooxygenase-2, but not lipoxygenase, in regions synaptically distant from spreading depression

Cited by 47 publications

References 45 publications

Cyclooxygenase-2 inhibition prevents delayed death of CA1 hippocampal neurons following global ischemia

Cyclooxygenase-2 inhibition prevents delayed death of CA1 hippocampal neurons following global ischemia

Indomethacin Ameliorates Trimethyltin-Induced Neuronal Damage <i>in Vivo</i> by Attenuating Oxidative Stress in the Dentate Gyrus of Mice

Prolonged Cyclooxygenase-2 Induction in Neurons and Glia Following Traumatic Brain Injury in the Rat

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