Ischemia-reperfusion (I/R) causes oxidative injury and ischemic fiber degeneration (IFD), due to injury of the neuron and axon, after enough ischemic times, i.e.4–5 hours of peripheral nerve ischemia 12. Maximal intercellular adhesion molecule-1 (ICAM-1) expression on endoneural vessels and polymorphonuclear monocytes reaches a peak at 24 th hour and macrophages increases nearly four fold at 48–72 hour of reperfusion after a 5 h of near-complete ischemia 3. All these cells are responsible for demyelinisation and IFD at prolonged reperfusion after enough ischemic times in peripheral nerves 45. Nerve lipid hydroperoxides reaches greatest levels at 3 hour and a gradual decline follows over the next month with reperfusion 6. An aggrevated reperfusion injury in Streptozocine induced diabetic rats could be seen with less severe ischemic times 7. Clinical experience related to I/R injury of peripheral nerve shows that neurologic recovery is possible, if reperfusion starts within 6 hours after ischemia 8.

Allow for protection of briefly ischemic tissues against the harmful effects of subsequent prolonged ischemia is a phenomennon called as Ischemic Preconditioning (IP)9. There are two distinct types of protection afforded by this adaptational reponse, i.e. acute and delayed preconditioning. The factors that initiate the acute and delayed preconditioning responses appear to be similiar. However, the protective effects of acute preconditioning are protein synthesis independent, while the effects of delayed preconditioning require protein synthesis. Adaptational responses to I/R injury have been demonstrated in different tissue types 1011121314. IP has not been studied in I/R model of peripheral nerve before. We aimed to study the effects of acute IP on I/R injury of peripheral nerve in rats.

Nerve pathology in acute ischemic injury has beeen delineated in peripheral nerve and reperfusion injury could amplify ischemic pathology. Nerve ischemia plays a major role in the development of pathological alteration in varous neuropathies and the effects of ischemia are amplified by reperfusion in various tissues. In nerve tissue, two types of edema is described after I/R; endoneural edema and intramyelinic edema 17. Endoneural edema reflects in blood-nerve barrier and possibly reflects endoneural events especially severity of IFD. Myelin appears to be particularly susceptible to activated free radicals, activated neutrophils and cytokine formation. Severe ischemia to nerve results in energy rundown followed by conduction failure and fiber degeneration. Inflammatory responses to IR have not only been confined to a few days (up to 7–14 days) of reperfusion, but also much more extended time (up to 42 days) of reperfusion 18. Between 7 days and 14 days of reperfusion, the IFD was reported to be the most prominent. Morphological changes of IFD at the light microscopic level occur in concert with endoneurial edema at the 7 and 14 day reperfusion time-points. I/R injury of sciatic nerve has been shown to increase proinlammatory cytokines which are primarly responsible demyelinization after reperfusion in peripheral nerves 19. Another important indicator of I/R injury of peripheral nerve is Nitric Oxide products which were found as increased at the first 24 hours of reperfusion in nerve tissue and their elevation has been reported to play an essential role in reducing the severity of the I/R injury by inhibiting neutrophil adhesion in postcapillary venules and by decreasing microvascular constriction 20. In our study, axonal changes at 7 th day were evaluated. It has been seen that IP treated group showed less cytoplasmic vacuolisation and edema formation than I/R group (p < 0.05). This finding was concominant to the finding of decreased oxidative injury (i.e. decreased MDA levels in nerve tissue) seen in IP pretreated group.

Previously protective effects of IP in intestine, liver, myocard, skeletal muscle and pancreas tissues has been shown 10111213142122. What play role in the protective effect of IP is not exactly known, but some putative mechanims, which are mostly dealed with countering the proinflammatory and proapoptotic effects generated during IR have been put forward 23. IP has been shown to decrease the formation of hydroxyl radicals during reperfusion 24. A reduced TNF-alpha and ICAM-1 mRNA expression seen after IP may account for the inhibitory effects of IP on leukocyte adhesion and ameloriated microcirculatory disturbance after IR in vivo 23242526.

The protective effects of IP against lesions caused by subsequent severe ischemia was primarly described in the heart by Murry et al 9. Increased antioxidant enzyme activities which may be an indirect indicator of the reduced injury after I/R has been shown in brain ischemic tolerance by IP 27. However to best of our knowledge, nobody has studied this phenomennon in peripheral somatic nerve. The benefical effect of IP in rat sciatic nerve was manifested by a reduction in MDA tissue levels at 3th hour of reperfusion and ischemic fiber degeneration (IFD) at 7 th postischemic day of reperfusion, in the present study. Lida et al. identified pathologically three phases as follows: phase 1-early reperfusion minimal edema; phase-2 7 th and 14 th day of reperfusion prominent fiber degeneration and endoneurial edema; phase-3 28 th and 42 th days abundant small regenerating fiber clusters, minimal edema 18. Our observation period is limited to up 7th day, i.e. phase-1. To best of our knowledge, this is the first semiquantitative study that shows an decreased IFD after IR due to the pretreatment with IP. Further studies are needed for understanding that IP may have strategic role in treatment of I/R related peripheral nerve injuries.