Abstract
BackgroundNeuroendoscopy is an innovative technique for neurosurgery that can nonetheless result in traumatic brain injury. The accompanying neuroinflammation may lead to secondary tissue damage, which is the major cause of delayed neuronal death after surgery. The present study investigated the capacity of osthole to prevent secondary brain injury and the underlying mechanism of action in a mouse model of stab wound injury.MethodsA mouse model of cortical stab wound injury was established by inserting a needle into the cerebral cortex for 20 min to mimic neuroendoscopy. Mice received an intraperitoneal injection of osthole 30 min after surgery and continued for 14 days. Neurological severity was evaluated 12 h and up to 21 days after the trauma. Brains were collected 3–21 days post-injury for histological analysis, immunocytochemistry, quantitative real-time PCR, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and enzyme-linked immunosorbent assays.ResultsNeurological function improved in mice treated with osthole and was accompanied by reduced brain water content and accelerated wound closure relative to untreated mice. Osthole treatment reduced the number of macrophages/microglia and peripheral infiltrating of neutrophils and lowered the level of the proinflammatory cytokines interleukin-6 and tumor necrosis factor α in the lesioned cortex. Osthole-treated mice had fewer TUNEL+ apoptotic neurons surrounding the lesion than controls, indicating increased neuronal survival.ConclusionsOsthole reduced secondary brain damage by suppressing inflammation and apoptosis in a mouse model of stab wound injury. These results suggest a new strategy for promoting neuronal survival and function after neurosurgery to improve long-term patient outcome.
Highlights
Neuroendoscopy is an innovative technique for neurosurgery that can result in traumatic brain injury
Mice were randomly divided into five groups: groups 1–3 (SWI+Ost) were administered osthole by i.p. injection 30 min after surgery at 10, 20, and 30 mg/kg, respectively, dissolved in 0.1 % DMSO and phosphate buffered saline (PBS) [11, 27] followed by once daily injections for the 14 days (n = 30, 30, and 54 for groups 1, 2, and 3, respectively); mice in the SWI control group were given 0.1 % DMSO in PBS by i.p. injection (200 μl) each day for 14 days (n = 54), and naive C57BL/6J mice were used as controls (n = 54)
Osthole treatment lowered the neurological severity score (NSS) from 3 to 21 days in a dose-dependent manner; the most significant decrease was observed with 30 mg/kg osthole (0.77 ± 0.15 vs. 3.67 ± 1.28 in SWI controls at 21 dpi; P < 0.01) (Fig. 2a)
Summary
Neuroendoscopy is an innovative technique for neurosurgery that can result in traumatic brain injury. The accompanying neuroinflammation may lead to secondary tissue damage, which is the major cause of delayed neuronal death after surgery. Neuroendoscopy is a widely used neurosurgical option that employs a cylindrical retractor to access deep intracranial lesions [1]. Both retractors and surgical procedures have been improved to facilitate and reduce the invasiveness of the procedure [2,3,4]; in recent years, commercial products such as BrainPath (NICO Corporation, 2014) [5] have been adopted to treat hard-to-reach areas. Secondary brain injury may develop hours or even days later and is the main cause of delayed neuronal death after surgery [8, 9] and includes brain edema, reduction of regional blood flow, inflammation, apoptotic cell death, oxidative stress, and gliosis [10]. Since primary brain injury caused by retractor insertion is irreversible, the main objective of medical treatment
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