A New Light in Brain Injury Treatment: Drug Repositioning Targets Neuroregeneration ─Animal model reveals that probucol treatment after traumatic brain injury promotes neuroregeneration and ameliorates functional deficits in mice ─

Taipei---Traumatic brain injury (TBI), stemming from the impact of external mechanical forces on the head, emerges prominently in scenarios such as motor vehicle collisions, accidental falls, and instances of physical assault. Annually, approximately 650,000 people experience TBIs in Taiwan, with 100,000 cases categorized as moderate to severe. TBI survivors may face the enduring challenge of experiencing persistent neurological and cognitive functional deficits. Furthermore, their susceptibility to developing dementia is quadrupled compared to the risk in the general population. Nonetheless, existing treatment options remain constrained. Therefore, there is an immediate and imperative need for therapeutic drugs targeting TBI.

At present, traumatic brain injury is widely regarded as irreversible. The initial impact, together with subsequent pathological events, results in extensive damage of neural circuits beyond the primary lesion, including neuronal death, diffusive axonal injuries, dendritic degeneration, and synapse loss. Following brain injury, the recovery of neurological and cognitive functions is associated with the reorganization of the surviving neural networks, involving neurite outgrowth, dendritic remodeling, synaptogenesis, and neuronal replacement. However, because the innate capacity of neuroplasticity and neurogenesis is confined in the adult brain, the self-repair following TBI often transpires gradually and seldom leads to substantial restoration of functionality. Hence, utilizing neuroregenerative agents to enhance post-injury neuronal remodeling and neurogenesis may offer promising therapeutic benefits for TBI patients.

Dr. Shaw-Fang Yet’s research team at the Institute of Cellular and System Medicine at Taiwan’s National Health Research Institutes have adopted a drug-repositioning approach to search for existing drugs with neuroregenerative properties and explored their therapeutic potential in TBI. In the primary culture of cortical neurons, the research team found that probucol, a lipid-lowering drug with established safety profiles, promoted neurite outgrowth via the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) pathway, which is a major regulator of neuroplasticity and neurogenesis. In the mouse TBI model, the research team discovered that probucol treatment after brain injury enhanced BDNF expression and TrkB activation. Moreover, probucol treatment enhanced both post-TBI neuronal remodeling and hippocampal neurogenesis. Post-TBI dendritic repair/remodeling and synaptogenesis were promoted. The newborn neurons and proliferating neural precursor cells doubled, while the brain lesion was reduced by 33%. Furthermore, probucol improved post-injury motor functions, which was associated with probucol-mediated synaptogenesis. More importantly, probucol ameliorated TBI-induced cognitive impairment, such as memory dysfunction. The research findings were published in the British Journal of Pharmacology in June 2023.

This study not only uncovered neuroregenerative actions of probucol in mice but also provided the first evidence that post-TBI intervention with probucol exerted therapeutic effects. The research findings indicate that probucol could emerge as a hopeful repurposed pharmaceutical option for addressing TBI.