Abstract
Semaphorin 3A (SEMA3A) is a member of the Semaphorins family, a class of membrane-associated protein that participates in the construction of nerve networks. SEMA3A has been reported to affect vascular permeability previously, but its influence in traumatic brain injury (TBI) is still unknown. To investigate the effects of SEMA3A, we used a mouse TBI model with a controlled cortical impact (CCI) device and a blood–brain barrier (BBB) injury model in vitro with oxygen-glucose deprivation (OGD). We tested post-TBI changes in SEMA3A, and its related receptors (Nrp-1 and plexin-A1) expression and distribution through western blotting and double-immunofluorescence staining, respectively. Neurological outcomes were evaluated by modified neurological severity scores (mNSSs) and beam-walking test. We examined BBB damage through Evans Blue dye extravasation, brain water content, and western blotting for VE-cadherin and p-VE-cadherin in vivo, and we examined the endothelial cell barrier through hopping probe ion conductance microscopy (HPICM), transwell leakage, and western blotting for VE-cadherin and p-VE-cadherin in vitro. Changes in miR-30b-5p were assessed by RT-PCR. Finally, the neuroprotective function of miR-30b-5p is measured by brain water content, mNSSs and beam-walking test. SEMA3A expression varied following TBI and peaked on the third day which expressed approximate fourfold increase compared with sham group, with the protein concentrated at the lesion boundary. SEMA3A contributed to neurological function deficits and secondary BBB damage in vivo. Our results demonstrated that SEMA3A level following OGD injury almost doubled than control group, and the negative effects of OGD injury can be improved by blocking SEMA3A expression. Furthermore, the expression of miR-30b-5p decreased approximate 40% at the third day and 60% at the seventh day post-CCI. OGD injury also exhibited an effect to approximately decrease 50% of miR-30b-5p expression. Additionally, the expression of SEMA3A post-TBI is regulated by miR-30b-5p, and miR-30b-5p could improve neurological outcomes post-TBI efficiently. Our results demonstrate that SEMA3A is a significant factor in secondary BBB damage after TBI and can be abolished by miR-30b-5p, which represents a potential therapeutic target.
Highlights
Traumatic brain injury (TBI) is a high-incidence disease that can harm human health, and with the development of society, the morbidity of this disease has tended to increase (Cope et al, 2012)
To determine if SEMA3A is associated with TBI, biochemical assays were performed in the above groups from 1st day to 14th day after TBI (Figure 1A)
We found that the expression of SEMA3A and related receptors, Plexin-A1 and Nrp-1, were dramatically elevated on the first day after TBI and peaked on the third day (Figures 1B–F)
Summary
Traumatic brain injury (TBI) is a high-incidence disease that can harm human health, and with the development of society, the morbidity of this disease has tended to increase (Cope et al, 2012). The primary injury of TBI leads to a series of effects including neural damage, intracerebral hemorrhage and primary blood–brain barrier (BBB) disruption, which result in subsequent pathological events in the central nervous system (CNS) (Blennow et al, 2012; Jiang et al, 2017). Secondary brain damage resulting from the interaction of primary pathological events and products is characterized by secondary BBB damage which occurs from hours to days following TBI (Marmarou, 2007; Ge et al, 2015). The secondary destruction of BBB by reason of the primary pathological events and products results in the further damage including brain edema, intracranial hypertension, inflammation and even poor neurological prognosis (Zweckberger et al, 2006; Ge et al, 2015; Xiong et al, 2017). An efficient therapeutic method that addresses the cause of secondary BBB damage is urgently needed
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