An Experimental Study on Repeated Brief Ischemia in Promoting Sciatic Nerve Repair and Regeneration in Rats

Highlights

• This study was conducted to investigate the potential protective effects of repeated brief ischemia on peripheral nerve regeneration using a rat model of experimental sciatic nerve transection injury.

• The mechanism possibly in part because it can improve vascular endothelial growth factor and the physiologic state of Schwann cells in ischemic environment and then accelerate the ability of neurite outgrowth.

• Our results may provide new insight into this possible therapeutic strategy for nerve repair.

Background

Research has shown that ischemic preconditioning reduced the severity of ischemia-reperfusion injury in brain in rats, we have a hypothesis that repeated brief ischemia has positive effects on peripheral nerve damage. This study was conducted to investigate the potential protective effects of repeated brief ischemia on peripheral nerve regeneration using a rat model of experimental sciatic nerve transection injury.

Methods

Treatment groups (groups A–D) received repeated, brief ischemia every 1 day/2 days/3 days/7 days. After surgery for 4, 8, 12 weeks, we evaluated sciatic functional index test, gastrocnemius muscle wet mass, axon and nerve fiber diameter, density, G-ratio, immunohistochemistry of S-100, vascular endothelial growth factor (VEGF), and the ultrastructure of the nerves.

Results

Sciatic functional index test and muscle wet mass were improved on the repeated brief ischemia groups. Ischemia treatment resulted in a significant increase in axon and nerve fiber density as well as S-100 and VEGF-positive cell, which indicated that repeated brief ischemia promotes Schwann cell proliferation and reconstruction.

Conclusions

This study exhibits the positive effects of repeated brief ischemia in sciatic nerve transection injury, possibly in part because it can improve VEGF and the physiologic state of Schwann cells in the ischemic environment and then accelerate the ability of neurite outgrow.

Introduction

Despite more than a century of experience in modern surgical management for peripheral nerves, the treatment of transection injury of the nerve remains troublesome.1, 2 Alternative techniques have been proposed to speed up the nerve regeneration process. At present, clinical and experimental research have achieved remarkable progress in biologic and cellular strategies for anatomic restitution and the locomotor recovery of peripheral nerve injury. Unfortunately, functional recovery is poor, either in motor or in sensor factors. Hence, it is imperative to develop better approaches for nerve reparation.

Recent research has shown that ischemic preconditioning reduced the severity of ischemia-reperfusion injury in the brain of rats.³ Some researchers believe that ischemic preconditioning promotes the expression of many growth factors, such as brain-derived neurotrophic factor, nerve growth factor,⁴ and vascular endothelial growth factor (VEGF)⁵ in the hippocampus. Those factors have been shown to enhance peripheral nerve regeneration and promote axonal growth rate.6, 7, 8 Thus, we have a hypothesis that repeated brief ischemia has positive effects on peripheral nerve damage. To test this assumption, we established a rat sciatic nerve injury model, provided chronic repeated brief ischemia at different frequencies, and observed morphologic, functional, and physiologic changes that occur in the transected nerve. Furthermore, we measured the expression of Schwann cells (Scs) and VEGF to examine the possible mechanism underlying the protective effect of repeated brief ischemia on nerve reparation. We aimed to study the effects of delayed repeated brief ischemia on speeding up the nerve regeneration process in the rat sciatic nerve damage model. Our results may provide new insight into this possible therapeutic strategy for nerve repair.