Sodium aescinate provides neuroprotection in experimental traumatic brain injury via the Nrf2-ARE pathway

Highlights

• Sodium aescinate provides neuroprotection after TBI.

• Sodium aescinate decreases TBI-induced oxidative stress.

• Sodium aescinate reduces TBI-induced neuron cell death and apoptosis.

• Sodium aescinate provides neuroprotection via the Nrf2-ARE pathway after TBI.

Abstract

Sodium aescinate (SA), a natural plant extract, has been proven to provide neuroprotection in neurological diseases. However, its role and the underlying pathophysiological mechanisms in traumatic brain injury (TBI) are still not well understood. The present study was aimed to investigate the protective effects of SA in both in vivo and in vitro TBI models. Mice or neurons were randomly divided into control, TBI, TBI + vehicle and TBI + SA groups. Neurologic severity score (NSS) was used to evaluate the neurological impairment. Brain water content and lesion volume were used to assess the brain injury degree. Malondialdehyde (MDA) and glutathione peroxidase (GPx) levels were used to estimate oxidative stress. Western blot was used to determine the protein levels. Nissl and terminal deoxynucleotidyl transferase-mediated dUTP nick 3’-end labeling (TUNEL) staining were used to measure cell death and apoptosis. Our results revealed that treatment of SA could improve neurological function, decrease cerebral edema and attenuate brain lesion after TBI. Furthermore, administration of SA suppressed TBI-induced oxidative stress, neuron cell death and apoptosis. In addition, SA activated the nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway after TBI. However, SA failed to provide neuroprotection following TBI in Nrf2^−/− mice. Taken together, our results provided the first evidence that SA treatment played a key role in neuroprotection after TBI through the Nrf2-ARE pathway.

Introduction

Traumatic brain injury (TBI) is one of the leading causes of disability and death in modern society, resulting in high medical costs (Brooks et al., 2013). It is defined as any head injury with traumatic etiology, such as penetrating or blunt trauma and non-accidental injury. The pathological process of TBI includes both primary and secondary brain injury. Although the primary brain damage is the major factor determining the patients’ outcomes, the secondary brain damage induced by multiple pathological processes, such as inflammation, cell death, apoptosis, oxidative stress, provides the possibility for clinical intervention (Ding et al., 2014; Zhang and Wang, 2017). Despite the efforts on searching effective methods to attenuate the secondary brain injury, patients suff ;ering with TBI always end up with poor prognosis (Sun et al., 2015). Therefore, new and effective strategies of treatment are urgently needed to reduce the heavy disease and economic burden.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a member of the basic leucine zipper (bZIP) family of transcription factors (Villeneuve et al., 2010). Under basal conditions, Nrf2 is retained in the cytoplasm by its inhibitor, Kelch-like ECH-associated protein 1 (Keap1) (Kobayashi et al., 2004). Once activated, Nrf2 dissociates from Keap1, translocates into the nucleus and promotes the transcription of antioxidative Phase II enzymes such as heme oxygenase-1 (HO-1) and nicotinamide adenine dinucleotide phosphate, quinine oxidoreductase-1 (NQO-1) by binding to antioxidant response element (ARE) (de Vries et al., 2008).

Sodium aescinate (SA) is a triterpene saponin that extracted from the seeds of chestnut (Chen et al., 2017). The therapeutic properties of SA such as anti-inflammatory, relieving tissue edema and recovering vascular permeability have been confirmed in previous studies (Zhang et al., 2015). In addition, SA has been suggested to obliterate the excessive reactive oxygen species (ROS) when cellular homeostasis was disturbed in the field of spinal cord injury (SCI) (Cheng et al., 2016), hepatocellular carcinoma (HCC) (Wang et al., 2012), and so on. However, the role of SA in TBI is seldom illustrated. The purpose of the present study was to determine whether SA administration after TBI could attenuate brain injury in TBI models.