Neuroprotective effects of nicotinamide after experimental spinal cord injury.

OBJECTIVE: To investigate the ability of nicotinamide to protect against secondary damage in spinal cord tissue after an experimental injury. Trauma to the spinal cord induces a cascade of cellular events that lead to progressive tissue injury over time. Nicotinamide has been shown to affect many elements of this cascade, including excitatory amino acid release, inflammation, apoptosis, and cellular energy balance. METHODS: Male Long-Evans (n = 12) rats received an excitotoxic spinal cord injury by intraspinal injection of quisqualic acid (QUIS), a glutamate receptor agonist. A second set of rats (n = 4) received intraspinal saline as a sham injury. Thirty minutes after injury, animals that had QUIS injections received an intraperitoneal injection of either saline (control, n = 4) or nicotinamide (500 mg/kg, n = 8). Seven days postinjury, the spinal cords were removed, and serial sections were cut, mounted on slides, and stained. By using light microscopy, the extent of tissue damage was assessed at the epicenter of injury as well as sections up to 450- microm rostral and 450- microm caudal to the epicenter. RESULTS: Only those animals receiving QUIS injections showed damaged tissue. There was no significant difference in the amount of damage at the epicenter of injury between the saline- and nicotinamide-treated animals. However, when comparing the total amounts of damage over the 975- microm length of cord examined, the rostro-caudal extent of injury was significantly reduced in the nicotinamide-treated animals compared with the saline-treated animals. CONCLUSIONS: Systemic nicotinamide serves to limit the rostro-caudal extent of cell death after experimental spinal cord injury.

A single dose of monoclonal anti-phencyclidine IgG offers long-term reductions in phencyclidine behavioral effects in rats.

These studies tested the hypothesis that a single dose of high-affinity anti-phencyclidine monoclonal antibody (anti-PCP mAb) provides long-term protection against behavioral effects of repeated PCP administration in rats. Rats were treated with saline, nonspecific bovine IgG (NS-IgG), or anti-PCP mAb (1.0 g/kg). The next morning, the rats were challenged with escalating i.v. doses of PCP (0.32, 0.56, and 1.0 mg/kg) at 90-min intervals. This regimen was repeated every 3 days for 2 weeks. In the saline and NS-IgG control groups, PCP yielded reproducible and linear dose-dependent effects that remained constant during the experiment. In contrast, the anti-PCP mAb treatment blocked PCP effects on day 1, and sustained significant (P < 0.05) reductions in drug effects for the entire 2-week experiment. Brain PCP concentrations (determined at study termination) were reduced by ~55%, whereas serum concentrations were increased over 4000% compared with controls. Thus, a single dose of antibody medication provided long-term reductions in drug effects and brain concentrations, beyond the expected capacity of the drug-antibody interaction. These data challenge current concepts about in vivo dose dependence and unimolecular interaction between antibody binding sites and small molecules and establish that neuroprotection by mAbs may have an unique mechanism of action.