Mitigation of sensory and motor deficits by acrolein scavenger phenelzine in a rat model of spinal cord contusive injury

Abstract

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. Additionally, 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 two weeks. These results indicate that phenelzine may be an effective treatment for neuropathic pain after SCI and likely a viable alternative to hydralazine.

Dimercaprol is an acrolein scavenger that mitigates acrolein‐mediated PC‐12 cells toxicity and reduces acrolein in rat following spinal cord injury

“…; Chen et al . ). In the case of dimercaprol, the reported dosage employed for in vivo application to alleviate heavy metal‐induced tissue damage was 2.5–50 mg/kg (Wenzel and Beckloff ; Jindal et al .…”

“…; Chen et al . ). However, these compounds have potential inherent undesirable side effects when used in high concentrations (Khan ; Reece ), prompting the investigation of alternative pharmaceuticals, perhaps also FDA‐approved medications, that can be repurposed to scavenge acrolein with increased efficacy and reduced risk of side effects.…”

“…An extensive body of evidence exists suggesting the toxic nature of acrolein and its pathological role in a variety of disease processes, prompting the use of acrolein scavengers as a new therapeutic approach for alleviating symptoms and curtailing tissue damage in neuropathic disorders (Burcham et al 2000;Burcham and Pyke 2006;Liu-Snyder et al 2006;Hamann and Shi 2009;Leung et al 2011;Due et al 2014;Park et al 2014a,b;Chen et al 2016).…”

“…To date, the most common acrolein scavengers have been the U.S. Food and Drug Administration (FDA)-approved compounds containing a hydrazine group, such as hydralazine and phenelzine (Burcham et al 2000;Kaminskas et al 2004b;Liu-Snyder et al 2006;Hamann et al 2008b;Park et al 2014b;Chen et al 2016). However, these compounds have potential inherent undesirable side effects when used in high concentrations (Khan 1953;Reece 1981), prompting the investigation of alternative pharmaceuticals, perhaps also FDA-approved medications, that can be repurposed to scavenge acrolein with increased efficacy and reduced risk of side effects.…”

Nitroxidative Signaling Mechanisms in Pathological Pain

“…These products all share the ability to induce nociceptive hypersensitivity by directly activating TRPA1 [67–72]. Acrolein is elevated in the DRG and spinal cord after SCI, and blockade with hydralazine or phenelzine partially attenuated allodynia [73,74]. Moreover, nociceptive hypersensitivity induced by CIPN was abolished in Trpa1 deficient mice, or with a TRPA1 antagonist [75].…”