Effects of treatment with U-74006F on neurological outcome following experimental spinal cord injury

Abstract

The compound U-74006F is one of a series of 21-aminosteroids that lack glucocorticoid or mineralocorticoid activity. These potent inhibitors of lipid peroxidation have been specifically developed for the acute treatment of central nervous system trauma and ischemia. This study evaluated the dose-response characteristics and capability of U-74006F to promote functional recovery in cats subjected to compression trauma of the upper lumbar (L-2) spinal cord. Thirty minutes following injury, randomized and investigator-blinded treatment was initiated with the intravenous administration of either vehicle (citrate-buffered saline) or one of eight doses of U-74006F. Initial doses of U-74006F ranged from 0.01 to 30 mg/kg. Subsequent doses consisted of intravenous bolus injections followed by a continuous 42-hour intravenous infusion. Over the 48-hour treatment period, cats received total U-74006F doses ranging from 0.048 to 160 mg/kg. The animals were evaluated weekly for neurological recovery based upon an 11-point behavioral scale. With the exception of two cats in one group, the animals receiving accumulated doses of U-74006F (ranging from 1.6 to 160.0 mg/kg/48 hrs) exhibited nearly 75% of normal neurological function by 4 weeks after injury. Lower total doses of 0.16 and 0.48 mg/kg/48 hrs were associated with approximately 50% return of normal function, which was not significantly better than the recovery in the vehicle-treated control group. The lowest total dose tested (0.048 mg/kg/48 hrs) gave results indistinguishable from those in vehicle-treated cats, which had recovered only 20% of their preinjury neurological function by 4 weeks. These findings demonstrate that over a 100-fold range of doses, U-74006F has a remarkable capacity to promote functional recovery in spinal cord-injured cats.

Oxidative stress in spinal cord injury and antioxidant-based intervention

“…2 The dose-response characteristics and capability of U-74006F to promote functional recovery in cats subjected to compression trauma of the upper lumbar (L-2) spinal cord have also been evaluated. 58 Results showed that over a 100-fold range of doses, U-74006F has a remarkable capacity to promote functional recovery in spinal cord injured cats. The mechanism of protective action of U-74006F against SCI is believed to involve an inhibition of oxygen radical-mediated lipid peroxidation.…”

Increased production of reactive oxygen species contributes to motor neuron death in a compression mouse model of spinal cord injury

“…5,6 Inhibition and scavenging of ROS production have been demonstrated to increase functional recovery following traumatic CNS injuries, thereby suggesting that enhanced ROS production contributes to SCI-mediated neuronal cell damage and neurological dysfunction. 7,8 Neurons are the most oxidative stress-susceptible cell type in the CNS. Both necrosis and apoptotic neuronal cell death have been detected in mouse and rat models following traumatic brain injury and/or SCI.…”

Antioxidant Therapies for Acute Spinal Cord Injury

“…This led to the discovery and development of more potent steroidal LP inhibitors, the 21-aminosteroids or "lazaroids," which lack the glucocorticoid receptor-mediated side effects that limit the clinical use of high-dose MP. One of these, tirilazad (also known as U-74006F), was selected for development based on its beneficial effects in animal SCI models [60,94,95].…”