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

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.

Thymoquinone, the active ingredient ofNigella sativaseeds, enhances survival and activity of antigen-specific CD8-positive T cellsin vitro

“…43 It has also been shown that addition of pharmacological antioxidants during T-cell activation in vitro can augment activation of extracellular signal-regulated kinase, coinciding with decreases in T-cell apoptosis. 44,45 In conclusion, the present results indicate that the activation phenotype, survival and function of antigenspecific T cells can be differentially modulated by TQ concentrations. At low concentration, TQ not only directly modulates the expression of CD62L on activated CD8 + T cells but also selectively promotes the survival and function of activated CD8 + T cells that express high levels of CD62L.…”

Oxidative Stress Increases Blood–Brain Barrier Permeability and Induces Alterations in Occludin during Hypoxia–Reoxygenation

“…), and the carbonate radical (CO 3 .À ) (Augusto et al, 2008). Tempol readily crosses the BBB (Zhelev et al, 2009), and has previously been shown to provide neuroprotection as a free radical scavenger in several models of brain injury and ischemia (Kwon et al, 2003;Deng-Bryant et al, 2008;Rak et al, 2000;Cuzzocrea et al, 2000).…”

The chemistry and biology of nitroxide compounds

“…Acute subdural hematoma can also result in local cerebral ischemia and O 2 • − mediated damage. Tempol administration resulted in a 42% decrease in infarct size and 2,3-dihydrobenzoic acid levels in rats following experimentally induced subdural hematoma [72]. Similar trials studying renal protection were performed by clamping the renal pedicle in rats and Tempol again had a protective effect on kidney function after reperfusion [73].…”