Probucol treatment after traumatic brain injury activates BDNF/TrkB pathway, promotes neuroregeneration and ameliorates functional deficits in mice

Abstract

Background and PurposeTraumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide, yet pharmacotherapies for TBI are currently lacking. Neuroregeneration is important in brain repair and functional recovery. In this study, probucol, a cholesterol‐lowering drug with established safety profiles, was examined for its therapeutic effects and neuroregenerative actions in TBI.Experimental ApproachMale mice were subjected to the controlled cortical impact model of TBI, followed by daily administration of probucol. Neurological and cognitive functions were evaluated. Histological analyses of the neocortex and hippocampus were performed to detect the lesion, dendritic degeneration (microtubule‐associated protein 2), synaptic density (synaptophysin), neurogenesis (doublecortin), brain‐derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) activation. Involvement of BDNF/TrkB pathway in probucol‐mediated effects was examined in primary cultures of cortical neurons.Key ResultsProbucol reduced brain lesion volume, enhanced the recovery of body symmetry, improved motor function and attenuated memory dysfunction after TBI. Meanwhile, probucol promoted post‐injury dendritic growth and synaptogenesis and increased hippocampal proliferating neuronal progenitor cells, along with the formation as well as the survival of newborn neurons. Moreover, probucol enhances BDNF expression and TrkB activation. In vitro, probucol promoted neurite outgrowth, which was inhibited by a selective TrkB antagonist ANA‐12.Conclusions and ImplicationsProbucol enhanced functional restoration and ameliorated cognitive impairment after TBI by promoting post‐injury neuronal remodelling and neurogenesis. Increased activation of BDNF/TrkB pathway by probucol, at least in part, contributed to the neuroregenerative effects of probucol. Together, it may be promising to repurpose probucol for TBI.

Probucol will become a new model for treating cerebral infarction with a high risk of hemorrhage: A narrative review

“…Two clinically controlled randomized trials, prospective and impact,[ 10 ] were used in the perspective and influential comprehensive analysis of two PUs for the secondary prevention of cardiovascular events. The trials were to examine the effects of PU on the thickness of carotid intima–media known as IMT and cardiovascular events in patients with CVD in Southeast Asia.…”

“…After more than 20 years of clinical research, it has been discovered that although PU lowers HDL-C levels, it does not worsen atherosclerosis. [ 3 4 5 6 7 8 9 10 ] In contrast, probucol had a strong antiatherosclerotic effect. Furthermore, PU has strong antiaging, restenosis prevention, and postoperative angioplasty treatment properties, which have piqued the interest of many clinicians in various professions.…”

Probucol attenuates high glucose-induced Müller cell damage through enhancing the Nrf2/p62 signaling pathway

“…PB can improve cognitive dysfunction caused by oxidative stress in diabetic rats through Nrf2 pathway activation [ 21 ]. Further, PB can induce autophagy, reduce nerve cell apoptosis, and promote neurological function recovery after spinal cord injury, also promote neuroregeneration and ameliorate functional deficits in traumatic brain injury [ 22 , 23 ]. PB has also been demonstrated to inhibit penile cell apoptosis and autophagy in diabetic rats [ 24 ].…”