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

Abstract

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.

Antioxidant Therapies for Acute Spinal Cord Injury

“…Accumulating evidence strongly suggests that the most important reactive oxygen species in acute SCI is probably PN [30,34]. Consistent with this view, several compounds that scavenge either PN, including uric acid [98] and the PN decomposition catalyst 5, 10, 15, 20-tetrakis (4-sulfanatophenyl) porphyrin iron III cloride (FeTSPP) [99], or that scavenger PN-derived free radicals such as tempol, a catalytic scavenger of PN-derived •NO 2 and •CO 3 [62,[100][101][102] have been reported to have neuroprotective and/or neurological recovery-promoting effects in SCI models. A major mechanism of the protective effect of tempol appears to be preservation of spinal cord mitochondrial function from post-traumatic PN-mediated impairment [101] .…”

Current status of acute spinal cord injury pathophysiology and emerging therapies: promise on the horizon

“…164 Peroxynitrite has been directly associated with the induction of apoptosis in neurons in rat SCI. 8 Highlighting the importance of ROS in SCI pathology is the demonstrated neuroprotective effects of antioxidant compounds such as tempol 73 and selective inhibition of peroxynitrite-mediated reactions by uric acid. 144 The modest neuroprotective effects of the now standard methylprednisolone treatment following SCI are also believed to be due, at least in part, to the inhibition of lipid peroxidation.…”

Antioxidant therapies in traumatic brain and spinal cord injury

“…Additionally, tempol decreased post-traumatic brain edema and improved neurological recovery in the rat contusion head injury model [113]. Similarly, in SCI models tempol protected against post-traumatic PN-induced mitochondrial impairment, cytoskeletal degradation [114], white matter loss and loss of locomotor function [115]. Although, therapeutic window analyses experiments revealed a short 1 h treatment window for tempol to achieve mitochondrial protective effects [114], others reported a therapeutic treatment-window of several days for tempol-induced locomotor recovery [115].…”