The Cycloxygenase-2 inhibitor SC58236 is neuroprotective in an in vivo model of focal ischemia in the rat

doi:10.1016/S0304-3940(01)01675-5

Neuroscience Letters

Volume 303, Issue 2, 4 May 2001, Pages 91-94

https://doi.org/10.1016/S0304-3940(01)01675-5 Get rights and content

Abstract

Focal ischemia was induced in the fronto-parietal region of rat brain, by injection of Rose Bengal, followed by light activation. Focal ischemia was accompanied by formation of PGD₂ peaking 60–90 min post irradiation and declining thereafter. Increased Cycloxygenase-2 (COX-2) expression was also observed. Control ischemic rats showed distinct morphological alterations with necrosis of neurons, glial cells and blood vessels, surrounded by a halo with pyknotic cells with cytoplasm swelling and vacuolization. Compound SC58236, a selective COX-2 inhibitor, dose-dependently prevented, ischemia-induced eicosanoid formation (area under the curve (AUC) of controls: 3.11±0.87; AUC of 20 mg/kg SC58236: 0.39±0.24), and caused significant reduction of damaged area (30.7 and 18.9% at SC58236 20 and 6.6 mg/kg), suggesting that selective inhibitors of COX-2 are neuroprotective.

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Acknowledgements

The Authors wish to thank Monsanto-Searle, St. Louis, MO and Searle Italia, Milan, for financial support. A generous supply of compound SC58236 by Dr P.C. Isakson is gratefully acknowledged. The authors would like to thank Ms Laura Nogueira for her skillful assistance. None of the authors hold an equity interest in any of the above entities.

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COX-2, a rate-limiting enzyme for the synthesis of prostaglandins, is known to be an important factor in acute and chronic neurodegenerative disorders such as stroke, Alzheimer's disease, and Parkinson's disease (Abdullah et al., 2006; Liang et al., 2007). Pharmacological inhibition of COX-2 reduced infarction size and the level of neuronal cell death (Govoni et al., 2001; Kunz et al., 2006; Takemiya et al., 2006). Moreover, COX-2 expression has been reported to involve P2 receptors (Brambilla et al., 2000; McLarnon, 2005; Xu et al., 2003), which act as purinergic receptors for adenosine 5′-triphosphate (ATP) (Ralevic and Burnstock, 1998).
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During the experiments, EEG was recorded continuously (24 h/day), as described previously (Gorter et al., 2001). For this study we have used the highly selective cox-2 inhibitor SC-58236 (SC) (Pfizer-Kalamazoo, MI, USA), as for this inhibitor, neuroprotective effects have been found in rats after a focally induced ischemic insult (Govoni et al., 2001). To assess the effects of the cox-2 inhibitor on epileptogenesis, a group of rats (n = 9) was treated with SC and SE was induced.
Status epilepticus (SE) leads to upregulation of pro-inflammatory proteins including cyclooxygenase-2 (cox-2) which could be implicated in the epileptogenic process and epileptic seizures. Recent studies show that cox-2 can regulate expression of P-glycoprotein (P-gp) during epileptogenesis and epilepsy. P-gp could cause pharmacoresistance by reducing brain entry of anti-epileptic drugs such as phenytoin (PHT). Here we have investigated the effects of cox-2 inhibition on epileptogenesis, spontaneous seizures and PHT treatment in a rat model for temporal lobe epilepsy (TLE).
A 3-day treatment with the cox-2 inhibitor SC-58236 (SC) was started 1 day before electrically induced SE. Chronic epileptic rats were treated with SC for 14 days, which was followed by a 7-day period of SC/PHT combination treatment. Seizure activity was monitored continuously using electroencephalography.
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Both SC treatment that started before SE and the 14-day treatment in chronic epileptic rats led to adverse effects in the TLE rat model. Despite a temporal reduction in seizure frequency with SC/PHT treatment, SC does not seem to be a suitable approach for anti-epileptogenic or anti-epileptic therapy.
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Cox-2 inhibition with SC58236 significantly reduced PGE2 production but, contrary to what we expected, did not appear to have any suppressing effect on microglia activation or hilar cell death. Various studies have shown that Cox-2 inhibition can reduce ischemia- or SE-induced neuronal degeneration when the treatment is started after the insult (Chen et al., 1995; Govoni et al., 2001; Kunz and Oliw, 2001; Kawaguchi et al., 2005; Jung et al., 2006) although aggravation of neurodegeneration has also been reported (Kim et al., 2008). When a Cox-2 inhibitor is applied before the SE, aggravation of seizure activity has been reported (Baik et al., 1999; Gobbo and O’Mara, 2004; Kim et al., 2008).
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The Cycloxygenase-2 inhibitor SC58236 is neuroprotective in an in vivo model of focal ischemia in the rat

Abstract

Section snippets

Acknowledgements

Neurosci. Lett.

Brain Res.

J. Biol. Chem.

J. Biol. Chem.

Neurosci. Lett.

Neuroscience

Prostaglandins Leukotrienes Essent. Fatty Acids

Brain Res.

Prostaglandins stimulate calcium-dependent glutamate release in astrocytes

Nature