Tempol, a Novel Stable Nitroxide, Reduces Brain Damage and Free Radical Production, after Acute Subdural Hematoma in the Rat

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Abstract
Recent studies have shown that there is increased production of deleterious free radicals following acute subdural hematoma (ASDH). Scavenging them may therefore be of therapeutic benefit. Nitroxides are new, low molecular weight, cell permeable superoxide dismutase mimics. This study investigated the neuroprotective effect of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol) following ASDH in the rat. Twenty-one male Sprague-Dawley rats were used in two studies: (1) a volumetric study of ischemic brain damage (n = 10); and (2) a microdialysis study measuring free radical generation after ASDH (n = 11). Ten minutes after induction of hematoma, the animals received 10 mg/kg Tempol or vehicle intravenously. In the volumetric study, 4 h after treatment, the rats were perfused, the brain removed, cut into serial 12-microm coronal sections, and stained. Ischemic areas were measured in eight predetermined stereotactic planes. In the microdialysis study, free radical production was measured using the salicylate trapping technique by quantifying 2,3-dihydrobenzoic acid (2,3-DHBA) and 2,5-DHBA using HPLC. In the volumetric study, Tempol treatment significantly reduced infarct volumes; 100.2 +/- 15.7 mm3 in Tempol-treated animals compared with 171.5 +/- 13.6 mm3 in controls (42% reduction, p = 0.0005). The microdialysis study demonstrated an early twofold increase of free radical production at 30 min, and returning to the baseline levels in controls. However, in Tempol-treated animals, this early surge was attenuated, and all measured values remained around the baseline levels throughout the experiments. Tempol thus provides significant neuroprotective effect in a rat model of ASDH, related to attenuation of superoxide radical production. The use of these low molecular weight, cell-permeable agents, which readily cross the blood-brain barrier and enter cells, thus appears indicated for acute pathologies, ASDH.