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Anti-apoptotic and neuroprotective effects of alpha-lipoic acid on spinal cord ischemia–reperfusion injury in rabbits

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Abstract

Purpose

Radical oxygen species produced after injury counteracts antioxidant activity and frequently causes severe oxidative stress for the tissues. Alpha-lipoic acid is a powerful metabolic antioxidant with immunomodulatory effects which provides neuroprotection. The aim of this study is to investigate the neuroprotective and anti-apoptotic effects of alpha-lipoic acid on spinal cord ischemia–reperfusion.

Methods

Twenty-four adult, male, New Zealand rabbits were divided into sham (n = 8), control (n = 8), and treatment groups (n = 8). The abdominal aorta was clamped for 30 min by an aneurysm clip, approximately 1 cm below the renal artery and 1 cm above the iliac bifurcation in control and treatment groups. Only laparotomy was performed in the sham group. Twenty-five cubic centimeters of saline in control group and 100 mg/kg lipoic acid were administered intraperitoneally in the treatment group after closure of the incision. The animals were killed 48 h later. Spinal cord segments between L2 and S1 were harvested for analysis. Levels of nitric oxide, glutathione, malondialdehyde, advanced oxidation protein products, and superoxide dismutase were analyzed as markers of oxidative stress and inflammation. Caspase-3 activity was analyzed to detect the effect of lipoic acid on apoptosis.

Results

In all measured parameters of oxidative stress, administration of lipoic acid significantly demonstrated favorable effects. Both plasma and tissue levels of nitric oxide, glutathione, malondialdehyde, and advanced oxidation protein products significantly changed in favor of antioxidant activity. There was no significant difference between the plasma superoxide dismutase levels of the groups. Histopathological evaluation of the tissues also demonstrated significant decrease in cellular degeneration and infiltration parameters after lipoic acid administration. However, lipoic acid has no effect on caspase-3 activity.

Conclusions

Although further studies considering different dose regimens and time intervals are required, the results of the present study prove that alpha-lipoic acid has favorable effects on experimental spinal cord ischemia–reperfusion injury.

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Authors and Affiliations

  1. Department of Neurosurgery, Faculty of Medicine, Gazi University, Polikliniği Kat 1, Ankara, 06500, Turkey

    Hakan Emmez, Aydemir Kale, Mehmet Tönge, Emre Durdağ, Alp Özgün Börcek, Fikret Doğulu & M. Kemali Baykaner

  2. Department of Biochemistry, Faculty of Medicine, Gazi University, Ankara, 06500, Turkey

    Zuhal Yildirim & Nedret Kiliç

  3. Department of Histology and Embryology, Faculty of Medicine, Gazi University, Ankara, 06500, Turkey

    Lortlar Neşe Uçankuş

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  1. Hakan Emmez
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Comment

Currently, there is a tremendous research focus in animals and humans to improve the devastating effects of spinal cord injury. Some of the main strategies include avoidance of prehospital hypoxia and hypotension, early surgical decompression and spinal fracture stabilization, therapeutic hypothermia, neuroprotectants such as alpha-lipoic acid in this study, neurotrophic agents, cell transplantation, blocking myelin-based protein inhibitors, using neural scaffolds, anti-inflammatory agents, reducing glial scar formation, and new rehabilitation strategies.

H. Emmez and colleagues have reported a carefully conducted study using the antioxidant alpha-lipoic acid in an experimental spinal cord ischemia and reperfusion injury model in 24 rabbits. The animals were sacrificed 48 h after the injury was induced, and it was found that tissue and spinal cord tissue levels of various markers of oxidative stress were significantly improved and there was less cellular degeneration and inflammatory change in the affected spinal cord after intraperitoneal alpha-lipoic acid was administered shortly after 30 min of ischemia.

This experiment is a long way from the use of this agent in human spinal cord injury but is an important step along the way. There is a component of ischemia–reperfusion injury in human spinal cord injury, but there is also the mechanical injury. The ischemia–reperfusion injury model the authors have used is not therefore a complete model of human spinal cord injury. This antioxidant should be further investigated experimentally with different dose scales, administered at different time intervals after the trauma, for longer observation periods, and with different models such as weight drop or clamping that more closely replicate mechanical injury to the spinal cord or parts of it before sacrifice of the animals. Clearly there are ethical challenges to keeping animals alive longer after partial or complete spinal cord injury. We encourage the authors to continue their excellent research on this promising therapeutic agent.

Jeffrey V Rosenfeld

Departments of Neurosurgery and Surgery, The Alfred Hospital and Monash University, Melbourne, Australia.

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Emmez, H., Yildirim, Z., Kale, A. et al. Anti-apoptotic and neuroprotective effects of alpha-lipoic acid on spinal cord ischemia–reperfusion injury in rabbits. Acta Neurochir 152, 1591–1601 (2010). https://doi.org/10.1007/s00701-010-0703-9

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