Development of BACE2-IN-1/tranylcypromine-based compounds to induce steroidogenesis-dependent neuroprotection.

Traumatic brain injury (TBI) constitutes a significant burden on global healthcare systems, especially affecting younger populations, where it is a leading cause of disability and mortality. Current treatments for TBI mainly focus on preventing further brain damage and controlling symptoms. However, despite these approaches, several clinical needs remain unmet. Revelations from single-cell RNA sequencing (scRNA-seq) performed to determine cell-type heterogeneity and gene expression changes in brain tissue indicated that brain trauma increases the expression of lysine-specific demethylase 1 (LSD1) and secretase 2 (BACE2). To capitalize on this finding, a medicinal chemistry campaign was conducted to pragmatically insert tranylcypromine, an LSD1 inhibitor, into a carefully designed BACE2 inhibitory template (BACE2-IN-1). Additionally, tranylcypromine was structurally modified to enhance the effects of LSD1 inhibition in TBI. As a result, a tractable neuroprotective agent, BACE2-IN-1/tranylcypromine-based compound 4, was identified, showing potential to maintain Neuro-2a cell survival by alleviating mitochondrial damage after oxidative stress. Compound 4 also restored TBI-mediated inhibition of the cholesterol biosynthetic pathway (mevalonate pathway) and damage of redox metabolism, increasing neuroprotective effects. Furthermore, behavioral assays, including nest-building and cognitive performance tests, demonstrated significant improvement in mice post-TBI following treatment with compound 4. Taken together, the outcomes of this study validate the favorable effects of inhibiting LSD1 and beta-secretase in mitigating mitochondrial stress and promoting neurometabolic recovery in TBI. These findings pave the way for the development of rationally designed inhibitors as promising neuroprotective agents, potentially addressing unmet clinical needs in TBI treatment.