MK 801 and dexamethasone reduce both tumor necrosis factor levels and infarct volume after focal cerebral ischemia in the rat brain Rosalia Bertorelli a, *, Marina Adami a , Elena Di Santo b , Pietro Ghezzi b a Schering-Plough Research Institute, San Raffaele Science Park, Via Olgettina, 58, 20132 Milan, Italy b Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea, 62, 20157 Milan, Italy Received 13 October 1997; received in revised form 6 February 1998; accepted 6 March 1998 Abstract Focal cerebral ischemia in rats produces elevated levels of tumor necrosis factor (TNF)a in the ischemic brain region. To better understand the modulation of TNF during brain ischemia processes we carried out studies in a model of permanent middle cerebral artery occlusion (MCAo) in the rat. In non-treated ischemic animals, the maximum expression of TNF was observed at 12 h (246.1 ± 33 U/g) in the ischemic cortex and declined reaching near zero levels 24 h after MCAo. Given 10 min after MCAo, MK 801 (3 mg/kg, i.p.), a non-competitive NMDA receptor antagonist, exerted significant neuroprotection as measured by 47% reduction of total volume of infarction (P  0.01 vs. ischemic-control). At the high dose of 3 mg/kg i.p., dexamethasone (DEX), which is known to reduce brain edema, decreased infarct size by 50% (P  0.01 vs. ischemic-control). Both MK 801 and DEX reduced TNF production in the ipsilateral cortex of ischemic animals by 61 and 73%, respectively (P  0.01 vs. ischemic- control). The data indicate that TNF levels increase after brain infarction, whereas they are reduced by neuroprotective agents, such as MK 801 and DEX, which act on different cellular levels.  1998 Elsevier Science Ireland Ltd. Keywords: Middle cerebral artery occlusion; Neuroprotection; Cytokines; Glutamate; Corticosteroids Cytokines are implicated in acute and chronic inflamma- tory reactions both in peripheral tissues and in the central nervous system (CNS). Overexpression of cytokines is observed in the brain of patients suffering from viral infec- tion, i.e. AIDS dementia complex, demyelinating disease, such as multiple sclerosis, or acute brain injury, such as stroke or head trauma, suggesting that cytokine imbalance could play an important role in the development of these pathologies [17]. Tumor necrosis factor (TNF) is a pleio- tropic cytokine with several biological functions, and it has been widely studied for its role in human diseases. Recently, it has been reported that focal cerebral ischemia in rats [4,13] produces elevated levels of either TNFa mRNA or the protein itself in ischemic regions. The present study was designed to determine whether, under the condition of distal middle cerebral artery occlu- sion (MCAo) in Sprague–Dawley rats, there is an increase of TNF levels in brain ischemic cortex. Furthermore, we tested the non-competitive NMDA antagonist, MK 801, to verify whether its neuroprotective action was associated with inhibition of TNF production. There is evidence of MK 801 effectiveness in focal models of cerebral ischemia [12], while it is not known whether this drug could affect TNF production induced by stroke. For comparison, we studied the effect of dexamethasone (DEX), a potent inhi- bitor of TNF production [14] on both brain infarction size and cerebral TNF levels after MCAo. Procedures involving animals and their care were con- ducted in conformity with the institutional guidelines, in compliance with the European Economic Community Council Directive 86/609 (OJ L 358, 1, December 12, 1987). Male Sprague–Dawley rats, weighing 230–300 g (Charles River, Calco, Italy), were anesthetized with an intraperitoneal (i.p.) injection of chloral hydrate (400 mg/ Neuroscience Letters 246 (1998) 41–44 0304-3940/98/$19.00  1998 Elsevier Science Ireland Ltd. All rights reserved PII S0304-3940(98)00221-3 * Corresponding author. Tel.: +39 2 21219216; fax: +39 2 21219253; e-mail: bertorel.sch-pl@science-park.spr.it