The Nitroxide Antioxidant Tempol Is Cerebroprotective against Focal Cerebral Ischemia in Spontaneously Hypertensive Rats

Outcome after traumatic brain injury (TBI) is worsened by hemorrhagic shock (HS), but the optimal resuscitation approach is unclear. In particular, treatment of TBI patients with colloids remains controversial. We hypothesized that resuscitation with the colloids polynitroxylated albumin (PNA) or Hextend (HEX) is equal or superior to resuscitation with the crystalloids hypertonic (3%) saline (HTS) or lactated Ringer's solution (LR) after TBI plus HS in mice. C57=BL6 mice (n ¼ 30) underwent controlled cortical impact (CCI) and 90 min of volumecontrolled HS (2 mL=100 g). The mice were randomized to resuscitation with LR, HEX, HTS, or PNA, followed by 30 min of test fluid administration targeting a mean arterial pressure (MAP) of >50 mm Hg. Shed blood was re-infused to target a MAP >70 mm Hg. At 7 days post-insult, hippocampal neuron counts were assessed in hematoxylin and eosin-stained sections to quantify neuronal damage. Prehospital MAP was higher, and prehospital and total fluid requirements were lower in the PNA and HEX groups ( p < 0.05 versus HTS or LR). Also, 7-day survival was highest in the PNA group, but was not significantly different than the other groups. Ipsilateral hippocampal CA1 and CA3 neuron loss did not differ between groups. We conclude that the colloids PNA and HEX exhibited more favorable effects on acute resuscitation parameters than HTS or LR, and did not increase hippocampal neuronal death in this model.

Section: Exo Et Almentioning

confidence: 99%

Resuscitation of Traumatic Brain Injury and Hemorrhagic Shock with Polynitroxylated Albumin, Hextend, Hypertonic Saline, and Lactated Ringer's: Effects on Acute Hemodynamics, Survival, and Neuronal Death in Mice

Exo

Shellington

Bayır

et al. 2009

“…As such, nitroxides can serve as protective agents both intra-and extracellularly. These molecules have recently been shown to benefit rats with focal brain ischemia (Beaulieu et al, 1998;Leker et al, 2002;Rak et al, 2000) or closed head injury (Beit-Yannai et al, 1996;Zhang et al, 1998), and gerbils with global brain ischemia (Cuzzocrea et al, 2000).…”

Section: Introductionmentioning

confidence: 98%

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

Kwon

Chao²,

Malloy³

et al. 2003

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.

“…Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) is a nitroxide antioxidant that has been used as a radioprotective agent for ionizing radiation (Mitchell et al, 1991) as well as for neuroprotection in brain ischemia (Kato et al, 2003;Cuzzocrea et al, 2000;Leker et al, 2002;Rak et al, 2000) or trauma (Beit-Yannai et al, 1996;Kwon et al, 2003;Zhang et al, 1998). In contrast to other antioxidants, tempol scavenges multiple types of ROS and can permeate cells to act intracellularly because it has a low molecular weight and can cross the blood-brain barrier (Mitchell et al, 1990).…”

Section: Introductionmentioning

confidence: 98%

Tempol, a Nitroxide Antioxidant, Improves Locomotor and Histological Outcomes after Spinal Cord Contusion in Rats

Hillard

Peng

Zhang

et al. 2004

We have determined whether the nitroxide antioxidant, tempol, can oppose tissue loss and improve recovery of locomotor function following contusion injury of the spinal cord. Contusion injury was produced in rats at the level of T10 with a weight-drop device and locomotor recovery was determined with the 21-point Basso, Beattie and Bresnahan (BBB) scale. Locomotor function recovered progressively during the 6-week postinjury observation period and was significantly greater in tempol-treated (275 mg/kg i.p., 20 min postinjury) compared to vehicle-treated rats (final BBB scores: 9.1 versus 6.4). Similarly enhanced locomotor recovery was observed with doses of tempol in the range of 138-550, but not 69 mg/kg, and with injection at 48 h postinjury indicating a therapeutic time-window of at least several days. The extent of recovery correlated with measurements of sparing of spinal cord white matter in a region several millimeters in length extending rostrally from the contusion epicenter. In contrast, loss of gray matter was unaffected by tempol treatment. Since tempol acts by scavenging reactive oxygen species (ROS) such as superoxide and hydroxyl radicals, the improved locomotor recovery and spared spinal cord tissue following contusion injury provides evidence of a direct role of ROS-mediated neurodegeneration in spinal cord injury.