An analog of phenelzine demonstrates effective acrolein scavenging and neuroprotection without monoamine oxidase inhibition in a rat SCI model

Oxidative stress is widely recognized as a critical factor in the functional deficits after spinal cord injury (SCI). Oxidative stress and lipid peroxidation-derived aldehydes such as acrolein are known to play a key role in SCI pathology and have therefore emerged as valuable therapeutic targets. This study introduces a novel phenelzine analogue (PhzA), designed to retain the acrolein scavenging capability of phenelzine (Phz) while removing its undesirable monoamine oxidase (MAO) inhibition effects through structure-based modification. Using a rat model of contusion SCI, we showed that PhzA significantly reduced acrolein levels in both the acute and chronic stages of SCI with minimal MAO inhibition. In addition, PhzA reduced excessive microglial and astrocytic activation, dampening inflammation and gliosis. Furthermore, PhzA-treated rats exhibited significant improvements in motor function and reduction in mechanical hypersensitivity for up to 28 days post-injury compared to untreated rats. These findings further underscore the crucial role of aldehydes in SCI pathology and strengthen the notion that acrolein could serve as an effective therapeutic target for mitigating post-SCI neurodegeneration. These results also indicate that the expansion of acrolein-scavenging drug discovery through structure-based modification of existing repurposed drugs, such as with Phz, is a viable strategy with the benefit of a likely accelerated path towards clinical application. This effort may also benefit a range of neuronal diseases and injuries beyond SCI where acrolein is implicated, advancing the health of millions of patients.