Elsevier

Neurochemistry International

Volume 87, August 2015, Pages 85-91
Neurochemistry International

Alpha lipoic acid inhibits neural apoptosis via a mitochondrial pathway in rats following traumatic brain injury

https://doi.org/10.1016/j.neuint.2015.06.003Get rights and content

Highlights

Abstract

Alpha lipoic acid (ALA) is a powerful antioxidant that has proven protective effects against brain damage following a traumatic brain injury (TBI) in rats. However, the molecular mechanisms underlying these effects are not well understood. This study investigated the effect of ALA on neural apoptosis and the potential mechanism of these effects in the weight-drop model of TBI in male Sprague-Dawley rats that were treated with ALA (20 or 100 mg/kg) or vehicle via intragastric administration 30 min after TBI. Brain samples were collected 48 h later for analysis. ALA treatment resulted in a downregulation of caspase-3 expression, reduced the number of positive cells in the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay and improved neuronal survival. Furthermore, the level of malondialdehyde and glutathione peroxidase activity were restored, while Bcl-2-associated X protein translocation to mitochondria and cytochrome c release into the cytosol were reduced by ALA treatment. These results demonstrate that ALA improves neurological outcome in rats by protecting neural cell against apoptosis via a mechanism that involves the mitochondria following TBI.

Introduction

There are currently no effective treatments for traumatic brain injury (TBI) that improve clinical outcome, leading to high health care costs, morbidity, and mortality (Toklu et al., 2009). Secondary brain damage seems to contribute to the poor outcome of TBI patients (Jin et al, 2008, Park et al, 1999, Yan et al, 2008a), which, resulting from neural apoptosis, undermines short- as well as long-term outcome (Hu et al., 2009). Oxidative stress plays a major role in the pathogenesis of secondary brain injury following TBI (Ansari et al., 2008a). Mitochondria are the main cellular source of reactive oxygen species (ROS) and their impairment increases ROS production, damaging mitochondrial proteins, DNA, and lipids, disrupting cellular Ca2+ homeostasis, inducing apoptosis, and causing metabolic failure (Crow et al, 2004, Lemasters et al, 1999, Paradies et al, 2014, Robertson et al, 2009). Apoptotic mechanisms must be tightly regulated to prevent neuronal death after TBI (Keane et al., 2001); this includes the control of the mitochondrial pathway of apoptosis (Crow et al, 2004, Simpkins et al, 2010).

Antioxidant therapy represents a viable treatment approach for TBI. Alpha-lipoic acid (ALA) is a naturally occurring substance that acts as an essential cofactor for various enzymes required for oxidative metabolism (Smith et al., 2004), and also has therapeutic potential for treating mitochondria-related disorders (Reed, 1998, Tirosh et al, 2003). However, to date there have been no studies investigating the effect of ALA on the related mitochondrial pathway following brain injury. In this study, the role of ALA in the modulation of mitochondrial function and apoptotic mechanisms was examined in a rat model of TBI.

Section snippets

Animals

Adult male Sprague-Dawley rats weighing 250–280 g were obtained from the Animal Center of Jinling Hospital. The animals were maintained on a 12:12 h light/dark cycle under conditions of controlled temperature and humidity. All procedures were approved by the Animal Care and Use Committee of Southern Medical University and conformed to the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.

Rats were randomly assigned to five experimental groups: sham + vehicle,

ALA improves neurological function and reduces cerebral edema after TBI

The rats all survived from the procedure of induction of experimental TBI in this study. Neurological function was tested by beam-walking performance 24 and 48 h after TBI. Within 48 h of injury, the neurological score was lower in the TBI + vehicle group than in the sham + vehicle or the sham + ALA groups (P < 0.001) (Fig. 1A). Although lower than those of the sham + vehicle and sham + ALA groups, the neurological score was significantly improved by ALA treatment relative to the TBI + vehicle

Discussion

The present study investigated the protective effects of ALA in a rat model of TBI. ALA administered alleviated cerebral edema, improved neurological function, and inhibited apoptosis by mitigating TBI-induced oxidative stress and suppressing the mitochondrial apoptotic pathway in rats following TBI.

There are presently no effective strategies for mitigating brain damage caused by trauma (Liu et al., 2014), and the molecular basis for TBI-induced neurodegeneration remains obscure (Toklu et al.,

Conclusion

In conclusion, this study demonstrated that ALA exerts neuroprotective effects against TBI by mitigating oxidative stress and suppressing the mitochondrial apoptotic pathway via an inhibition of Bax translocation and cytochrome c release from the mitochondria. These findings indicate that ALA has potential therapeutic applications for preventing secondary brain damage following TBI.

Conflict of interest

The authors declare that they have no competing interests.

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (nos. 81371357, 81301180) and Jiangsu Planned Projects for Postdoctoral Research Funds (1401002A).

References (39)

  • XuJ. et al.

    Luteolin provides neuroprotection in models of traumatic brain injury via the Nrf2-ARE pathway

    Free Radic. Biol. Med

    (2014)
  • YanW. et al.

    Activation of Nrf2-ARE pathway in brain after traumatic brain injury

    Neurosci. Lett

    (2008)
  • ZhangD. et al.

    Inhibition of transforming growth factor beta-activated kinase 1 confers neuroprotection after traumatic brain injury in rats

    Neuroscience

    (2013)
  • M.A. Ansari et al.

    A time course of contusion-induced oxidative stress and synaptic proteins in cortex in a rat model of TBI

    J. Neurotrauma

    (2008)
  • J. Cahill et al.

    p53 may play an orchestrating role in apoptotic cell death after experimental subarachnoid hemorrhage

    Neurosurgery

    (2007)
  • ChenJ. et al.

    Melatonin-enhanced autophagy protects against neural apoptosis via a mitochondrial pathway in early brain injury following a subarachnoid hemorrhage

    J. Pineal Res

    (2014)
  • C. Cornelius et al.

    Traumatic brain injury: oxidative stress and neuroprotection

    Antioxid. Redox Signal

    (2013)
  • M.T. Crow et al.

    The mitochondrial death pathway and cardiac myocyte apoptosis

    Circ. Res

    (2004)
  • D.M. Feeney et al.

    Responses to cortical injury:I. Methodology and local effects of contusions in the rat

    Brain Res

    (1981)
  • Cited by (0)

    View full text