Alpha-lipoic acid provides neuroprotection from ischemia-reperfusion injury of peripheral nerve

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Abstract

Background: Reperfusion aggravates nerve ischemic fiber degeneration, likely by the generation of reduced oxygen species. We therefore evaluated if racemic α-lipoic acid (LA), a potent antioxidant, will protect peripheral nerve from reperfusion injury, using our established model of ischemia-reperfusion injury. Methods: We used male SD rats, 300±5 g. Ischemia was produced by the ligature of each of the supplying arteries to the sciatic-tibial nerve of the right hind-limb for predetermined periods of time (either 3 or 5 h), followed by the release of the ligatures, resulting in reperfusion. LA was given intraperitoneally daily for 3 days for both pre- and post-surgery. Animals received either LA, 100 mg/kg/day, or the same volume of saline intraperitoneally. Clinical behavioral score and electrophysiology of motor and sensory nerves were obtained at 1 week after ischemia-reperfusion. After electrophysiological examination, the sciatic-tibial nerve was fixed in situ and embedded in epon. We evaluated for ischemic fiber degeneration (IFD) and edema, as we described previously. Results: Distal sensory conduction (amplitude of sensory action potential and sensory conduction velocity (SCV) of digital nerve) was significantly improved in the 3-h ischemia group, treated with LA (P<0.05). LA also improved IFD of the mid tibial nerve (P=0.0522). LA failed to show favorable effects if the duration of ischemia was longer (5-h ischemia). Conclusion: These results suggest that α-lipoic acid is efficacious for moderate ischemia-reperfusion, especially on distal sensory nerves.

Introduction

Ischemic injury to peripheral nerve is aggravated by reperfusion, resulting in lipid peroxidation and fiber degeneration [1], [2]. In other tissues, including brain, the major mechanism of reperfusion injury is considered to be due to reduced oxygen species [3]. α-Lipoic acid (LA) is a powerful lipophilic antioxidant in vitro and in vivo [4]. It is reported to be efficacious in the experimental ischemia-reperfusion injury in brain [5], [6], [7], heart [8], [9] and in experimental diabetic neuropathy [10], [11], where oxidative stress is present. We therefore evaluated if LA will ameliorate ischemia-reperfusion (IR) injury of peripheral nerve subjected to different durations of ischemia followed by reperfusion. We used our established model of IR injury [12].

Section snippets

Animals

We used 44 male Sprague–Dawley rats weighing 300±5 g.

Surgery

The surgical procedure for producing IR injury has been previously detailed. In essence we ligated each of the supplying arteries to the sciatic-tibial nerve of the right hind-limb for predetermined periods of ischemia (either 3 or 5 h), followed by reperfusion, resulting from the release of the ligatures.

The rat was anesthetized with intraperitoneal pentobarbital (60 mg/kg). Additional doses of pentobarbital were used if anesthesia lightened

Behavioral score

The behavioral score for 3-CONT and 3-LA were 5.8±0.8 and 7.8±1.0, respectively (Fig. 1A). The behavioral score for 5-CONT and 5-LA were 2.5±0.8 and 3.8±0.7, respectively (Fig. 1B). Behavioral score was consistently normal (11.0) for contralateral side. The improvement with LA did not reach statistical significance.

Electrophysiology

In the present study, the results of the amplitude of nerve compound action potential was expressed as a percentage of the left side. For SCV, we used absolute values of m/s. The

Discussion

The main findings of the present study are that LA provided some neuroprotection of peripheral nerve from ischemia-reperfusion injury (IR injury) in nerves subjected to 3 h of ischemia, but failed to do so in those subjected to 5 h of ischemia. Treatment with LA significantly improved distal sensory conduction in the group subjected to 3 h of ischemia. In contrast, LA treatment did not improve CMAP in the 3-h ischemia group (3-LA). In the pathological studies, IFD grade at mid tibial nerve

Acknowledgments

Supported in part by grants from NINDS (NS22352) and Mayo funds.

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