A novel enzymatic mechanism for removing neurotoxic aldehydes after rodent spinal cord injury

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Abstract Oxidative stress plays a critical pathogenic role in functional loss after spinal cord injury (SCI), and lipid peroxidation-derived aldehydes have emerged as key culprits in sustaining such secondary injury, and contributing significantly to the pathological outcomes. Acrolein, the most reactive aldehyde, is highly toxic to neurons, elevated in SCI, and post-SCI neurological deficits can be significantly alleviated by lowering acrolein. As such, reducing acrolein has emerged as a novel and effective therapeutic strategy in SCI. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) is a key oxidoreductase and powerful endogenous anti-aldehyde machinery, clearing toxic aldehydes in both humans and rodents. Strong evidence suggests that ALDH2 is likely important for protecting neurons from aldehydes, especially during situations of aldehyde upregulation such as SCI. However, the role of ALDH2 in SCI pathogenesis has never been investigated. Furthermore, while capable of metabolizing aldehydes, ALDH2 could be damaged by aldehydes through protein-aldehyde adducts, suppressing ALDH2 activity and leading to subsequent aldehyde overload, a likely scenario in SCI. As such, relieving the inhibition and boosting activity of ALDH2 is a logical solution, and likely an effective strategy to curtail oxidative stress and related pathologies in SCI. Using a combination of newly acquired transgenic mice (ALDH2*2) and recently-discovered ALDH2 activator (Alda-1), we plan to validate the aldehyde-clearing and neuroprotective role of ALDH2 in a mouse model of SCI. The central hypothesis is that ALDH2 is suppressed after SCI which is worsened in transgenic mice with genetically ineffective ALDH2. Furthermore, ALDH2 activation by Alda-1 can restore and boost its aldehyde-detoxification function providing neuroprotection in SCI. As a group, we have discovered acrolein increases after SCI, generated ALDH2*2 mice, discovered Alda-1 as a selective activator of ALDH2 and ALDH2*2, and obtained preliminary data that Alda-1 can mitigate acrolein increases after injury. Thus, we are well prepared to realize the following Aims: Aim 1. To correlate ALDH2 activity with the level of acrolein (indicative of oxidative stress), inflammation, and relevant cellular and behavioral pathologies in SCI; Aim 2. To determine if ALDH2 inhibition could lead to acrolein elevation and aggravation of downstream pathologies in wild type and transgenic mice (ALDH2*2) after SCI; Aim 3. To ascertain if ALDH2 activity enhancement by the catalytic activator Alda-1 could suppress post-SCI acrolein hike and provide neuroprotection in both WT and ALDH2*2 mice. These efforts will not only solidify the critical role of ALDH2 in aldehyde detoxification, but also demonstrate the neuroprotective value of boosting ALDH2 in SCI as a potential therapeutic drug intervention. It is expected that the outcome of this study will significantly broaden and enhance anti-aldehyde strategies in combating post-SCI neurodegeneration and potentially bring treatment to millions of SCI victims.