Abstract
Ischemic neuropathy is common in subjects with critical limb ischemia, frequently causing chronic neuropathic pain. However, neuropathic pain caused by ischemia is hard to control despite the restoration of an adequate blood flow. Here, we used a rat model of ischemic-reperfusion nerve injury (IRI) to investigate possible effects of hepatocyte growth factor (HGF) against ischemic neuropathy. Hemagglutinating virus of Japan (HVJ) liposomes containing plasmids encoded with HGF was delivered into the peripheral nervous system by retrograde axonal transport following its repeated injections into the tibialis anterior muscle in the right hindlimb. First HGF gene transfer was done immediately after IRI, and repeated at 1, 2 and 3 weeks later. Rats with IRI exhibited pronounced mechanical allodynia and thermal hyperalgesia, decreased blood flow and skin temperature, and lowered thresholds of plantar stimuli in the hind paw. These were all significantly improved by HGF gene transfer, as also were sciatic nerve conduction velocity and muscle action potential amplitudes. Histologically, HGF gene transfer resulted in a significant increase of endoneurial microvessels in sciatic and tibial nerves and promoted nerve regeneration which were confirmed by morphometric analysis. Neovascularization was observed in the contralateral side of peripheral nerves as well. In addition, IRI elevated mRNA levels of P2X3 and P2Y1 receptors, and transient receptor potential vanilloid receptor subtype 1 (TRPV1) in sciatic nerves, dorsal root ganglia and spinal cord, and these elevated levels were inhibited by HGF gene transfer. In conclusion, HGF gene transfer is a potent candidate for treatment of acute ischemic neuropathy caused by reperfusion injury, because of robust angiogenesis and enhanced nerve regeneration.
Highlights
Ischemic neuropathy is common among patients with lower extremity peripheral artery disease [1,2]
We have investigated whether nonviral retrograde gene transfer of hepatocyte growth factor (HGF) might improve ischemic neuropathy using the rat model of ischemic-reperfusion nerve injury (IRI)
We have investigated whether nonviral retrograde gene transfer of HGF might improve symptoms of ischemic neuropathy using a rat model of ischemicreperfusion nerve injury (IRI), and demonstrated that HGF gene transfer resulted in 1) significant improvement of mechanical allodynia and thermal hyperalgesia, decreased skin blood flow and temperature, lowered plantar thresholds of electrical stimuli in the hind paw, and sciatic nerve conduction parameters, 2) enhanced nerve regeneration in the sciatic nerve histologically, 3) significant increases of the density of endoneurial microvessels in bilateral sciatic and tibial nerves, and 4) reduction of the elevated levels of P2X3 and P2Y1 receptor mRNA and transient receptor potential vanilloid receptor subtype 1 (TRPV1) mRNA in the sciatic nerve
Summary
Ischemic neuropathy is common among patients with lower extremity peripheral artery disease [1,2]. The incidence of critical limb ischemia caused by peripheral artery disease has been estimated to be approximately 500–1000 per million per year [3,4,5,6]. Clinical neurological deficits have been reported to occur in 22–88% of critical limb ischemia cases [7]. Sensory symptoms, such as numbness, painful paresthesia and burning [8,9], may last for a long time in spite of reestablishing an adequate blood flow [10,11].
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