Effect of indomethacin and a free radical scavenger on cerebral blood flow and edema after cerebral artery occlusion in cats.

Johshita, Hiroo; Asano, Takao; Hanamura, Tetsu; Takakura, Kintomo

doi:10.1161/01.str.20.6.788

Cited by 39 publications

(9 citation statements)

References 51 publications

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“…Consequently, these studies have led to contradictory findings. Some investigators found that COX inhibition ameliorates ischemic injury, whereas others reported no effect or worsening of the damage (Cole et al, 1993;Johshita et al, 1989;Petersen, 1989). The results of the present study, in concert with recent data in COX-2-null mice (Iadecola et al, 2001), help reconcile these conflicting observations.…”

Section: Cox-1 and Ischemic Injury 1439supporting

confidence: 58%

Increased Susceptibility to Ischemic Brain Injury in Cyclooxygenase-1–Deficient Mice

Iadecola

Sugimoto

Niwa

et al. 2001

J Cereb Blood Flow Metab

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Cyclooxygenase-1 (COX-1), a rate-limiting enzyme in the synthesis of prostanoids, is involved in selected vasodilatatory responses of the cerebral circulation. Cyclooxygenase-1-null mice were used to determine whether COX-1 influences cerebral ischemic damage. The middle cerebral artery was occluded in COX-1 -/- and +/+ mice (n = 9/group), and lesion volume was determined in thionin-stained sections 24 or 96 hours later. Middle cerebral artery occlusion produced larger infarcts in COX-1 -/- mice, both at 24 (35 +/- 17%; P < 0.05) and 96 hours (41 +/- 16%; P < 0.05) after ischemia. The enlargement was not due to increased susceptibility to glutamate excitotoxicity, because microinjection of N-methyl-D-aspartate or kainate in the parietal cortex produced comparable lesions in COX-1 +/+ and -/- mice ( P > 0.05; n = 8/group). To examine the contribution of hemodynamic factors to the enlargement of the infarct, cerebral blood flow was monitored by laser-Doppler flowmetry in the ischemic territory (n = 6/group). Although the reduction in cerebral blood flow was comparable in the ischemic core ( P > 0.05), at the periphery of the ischemic territory the reduction was greater in COX-1 -/- mice (-58 +/- 4%) than in COX-1 +/+ mice (-34 +/- 5%; P < 0.05). It is concluded that mice lacking COX-1 are more susceptible to focal cerebral ischemia, an effect that can be attributed to a more severe cerebral blood flow reduction in vulnerable regions at the periphery of the ischemic territory. Thus, the vascular effects of COX-1 may contribute to maintain cerebral blood flow in the postischemic brain and, as such, play a protective role in ischemic brain injury.

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Section: Cox-1 and Ischemic Injury 1439supporting

confidence: 58%

Increased Susceptibility to Ischemic Brain Injury in Cyclooxygenase-1–Deficient Mice

Iadecola

Sugimoto

Niwa

et al. 2001

J Cereb Blood Flow Metab

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“…In addition, previous studies have reported the effect of nonselective COX inhibitors, e.g., indomethacin and ibuprofen, on cerebral ischemic damage. The results of these investigations have been contradictory; some report protection and others show no effect or worsening (Harris et al, 1982;Johshita et al, 1989;Cole et al, 1993). These conflicting observations are likely to result from the fact that the effects of COX-2 inhibition were confounded by effects of COX-1 inhibition, an enzyme involved in normal cellular function.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, indomethacin, one of the agents studied most extensively, has profound effects on cerebral blood flow and vascular reactivity (for review, see Busija and Heistad, 1984). Because indomethacin was administered before or shortly after induction of ischemia (Harris et al, 1982;Johshita et al, 1989), it is likely that the attendant cerebrovascular effects of this agent influenced the outcome of cerebral ischemia.…”

Section: Discussionmentioning

confidence: 99%

Cyclo-Oxygenase-2 Gene Expression in Neurons Contributes to Ischemic Brain Damage

et al. 1997

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Cyclo-oxygenase-2 (COX-2), a rate-limiting enzyme for prostanoid synthesis, is induced during inflammation and participates in inflammation-mediated cytotoxicity. Cerebral ischemia is followed by an inflammatory reaction that plays a role in the evolution of the tissue damage. We studied whether COX-2 is induced after cerebral ischemia and if so, whether such expression contributes to ischemic brain damage. The middle cerebral artery was occluded in rats, and the ischemic area was sampled for analysis 3-96 hr later. COX-2 mRNA was determined by the competitive reverse-transcription PCR. COX-2 mRNA was upregulated in the ischemic hemisphere, but not contralaterally, beginning 6 hr after ischemia. The upregulation reached a maximum at 12 hr, at which time a fivefold induction of the message occurred. Twenty-four hours after ischemia, the concentration of prostaglandin E 2 was elevated in the injured brain by 292 Ϯ 57% (n ϭ 6). COX-2 immunoreactivity was observed in neurons at the medial edge of the ischemic area. Administration of the COX-2 inhibitor NS-398 attenuated the elevation in prostaglandin E 2 in the postischemic brain and reduced the volume of the infarct by 29 Ϯ 6% ( p Ͻ 0.05). Thus, cerebral ischemia leads to upregulation of COX-2 message, protein, and reaction products in the injured hemisphere. The data implicate COX-2 in the mechanisms of delayed neuronal death at the infarct border and provide the rationale for neuroprotective strategies employing COX-2 inhibitors.

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“…In the case of the nizofenone administration, the cortical PO 2 level was higher than the preocclusion one, and the brain edema was not prevented. One of the causes of brain edema formation was reported to be the superoxide production induced by the excessive supply of O 2 after the start of reperfusion [17,18]. Accordingly, the effect of nizofenon on the cerebral blood flow may be inconvenient effect, at least on the edema.…”

Section: Discussionmentioning

confidence: 99%

Effect of Ozagrel on Locomotor and Motor Coordination after Transient Cerebral Ischemia in Experimental Animal Models

Ichikawa

Tazawa²,

Hamano³

et al. 1999

Pharmacology

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The effect of ozagrel, a selective thromboxane A₂ (TXA₂) synthetase inhibitor, on the obstruction after cerebral ischemia-reperfusion was studied in experimental animal models. The reduced spontaneously locomotor activity and the obstruction of motor coordination were improved by the administration of ozagrel in the conscious cerebral ischemia-reperfusion mouse model. Ozagrel suppressed the decrease in specific gravity of the brain tissue induced by the occlusion-reperfusion in the conscious cerebral ischemia-reperfusion SHR model, and recovered the postischemic decrease in cortical PO₂ after middle cerebral artery occlusion-reperfusion in cats. The level of TXB₂, a metabolite of TXA₂, in the brain increased after the cerebral ischemia-reperfusion, and ozagrel prevented this increase. Additionally, ozagrel also increased the level of 6-keto-PGF_1α, a metabolite of prostaglandin I₂ (PGI₂), in the brain tissue after cerebral ischemia-reperfusion, and the administration of PGI₂ improved the reduced spontaneous locomotor activity in the conscious cerebral ischemia-reperfusion mouse model. Our data suggest that ozagrel suppressed the obstruction following cerebral ischemia-reperfusion by preserving the cerebral blood flow via preventing the increase in TXA₂ and causing an increase in the PGI₂ level.

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Effect of indomethacin and a free radical scavenger on cerebral blood flow and edema after cerebral artery occlusion in cats.

Cited by 39 publications

References 51 publications

Increased Susceptibility to Ischemic Brain Injury in Cyclooxygenase-1–Deficient Mice

Increased Susceptibility to Ischemic Brain Injury in Cyclooxygenase-1–Deficient Mice

Cyclo-Oxygenase-2 Gene Expression in Neurons Contributes to Ischemic Brain Damage

Effect of Ozagrel on Locomotor and Motor Coordination after Transient Cerebral Ischemia in Experimental Animal Models

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