Mitigation of Sensory and Motor Deficits by Acrolein Scavenger Phenelzine in a Rat Model of Spinal Cord Contusive Injury

Currently there are no effective therapies available for the excruciating neuropathic pain that develops after spinal cord injuries (SCI). As such, a great deal of effort is being put into the investigation of novel therapeutic targets that can alleviate this pain. One such target is acrolein, a highly reactive aldehyde produced as a byproduct of oxidative stress and inflammation that is capable of activating the transient receptor potential ankyrin 1 (TRPA1) cation channel, known to be involved in the transmission and propagation of chronic neuropathic pain. One anti-acrolein agent, hydralazine, has already been shown to reduce neuropathic pain behaviors and offer neuroprotection after SCI. This study investigates another acrolein scavenger, phenelzine, for its possible role of alleviating sensory hypersensitivity through acrolein suppression. The results show that phenelzine is indeed capable of attenuating neuropathic pain behaviors in acute, delayed, and chronic administration schedules after injury in a rat model of SCI. In addition, upon the comparison of hydralazine to phenelzine, both acrolein scavengers displayed a dose-dependent response in the reduction of acrolein in vivo. Finally, phenelzine proved capable of providing locomotor function recovery and neuroprotection of spinal cord tissue when administered immediately after injury for 2 weeks. These results indicate that phenelzine may be an effective treatment for neuropathic pain after SCI and likely a viable alternative to hydralazine. We have shown that phenelzine can attenuate neuropathic pain behavior in acute, delayed, and chronic administration in post-SCI rats. This was accompanied by a dose-dependent reduction in an acrolein metabolite in urine and an acrolein adduct in spinal cord tissue, and the suppression of TRPA1 over-expression in central and peripheral locations post-trauma. Acrolein scavenging might be a novel therapeutic strategy to reduce post-SCI neuropathic pain.