NIM811 Treatment for Pediatric Spinal Cord Injury

Human infants are not exempt from spinal cord injury (SCI), but ontogenetic differences in the biochemical, neuroanatomical, and behavioral sequelae of SCI have not been thoroughly evaluated. This paucity of investigation is likely due to the relatively low number of pediatric patients, relative to adults. Early models of pediatric SCI revealed that the extent of neuron death is greater following injury to the infant spinal cord compared to the adult, but also suggested that behavioral recovery was more complete in the younger animals. However, virtually nothing is known about ontogenetic differences in the extent of glial cell death, and injury to the developing spinal cord can cause unique behavioral alterations that are not observed after injury to the mature spinal cord. The proposed experiments will test the hypotheses that ( 1) the extent of oligodendroglia! death and proliferation in the spinal cord will be greater with younger age at the time of injury, (2) recovery of locomotor function will be more complete with younger age at the time of injury, (3) spinal cord demyelination and remyelination will be more extensive with younger age at the time of injury, and (2) posttreatment with the non-immunosuppressive cyclosporin A derivative, NIM811, will have therapeutic value in the treatment of pediatric SCI. On postnatal day 10, 20, or 30, rats will receive a spinal cord compression, followed by an injection of NIM811 (40 mg/kg, ip) or vehicle 1 hr later. Drug or vehicle will be re-adrninistered at 24 hr and 48 hr post-injury. Normal controls will be included for comparison. Specific Aim 1: Some rats from each experimental group will be injected twice daily with 50 mg/kg (ip) 5-bromo-2-deoxyuridine I[BrdU) throughout the experiment to enable identification of newborn cells. These rats will be euthanized on post-operative day 2, 4, 8, or 16, and the spinal cords will be processed for flw:>rescence immunocytochemistry. Unbiased stereology will reveal age-, drug-, and time-dependent differences in the number of oligodendroglia in the ventrolateral funiculus of the spinal cord, as well as the percentage of newborn cells. Specific Aim 2: Hindlimb locomoltor function will be assessed for 4 weeks in the remaining rats, and then the spinal cords will be processed for age- and drug-dependent differences in the amount of tissue at the lesion etpicenter, or the amount of myelination (myelin index). The results of the proposed experiments will break new ground by revealing ontogenetic differences in the progression of oligodendroglia! death and proliferation following injury to the developing spinal cord, locomotor recovery, and spinal cord myelination. Importantly, the results will indicate whether NIM811 has therapeutic potential in the treatment of pediatric SCI.