Floor plan - 2013 Annual Meeting - American Association for Hand ...

ASPN SCIENTIFIC PAPER SESSION E
Nonviral HVJ (Hemagglutinating Virus of Japan) Liposome Mediated Retrograde Gene
Transfer of Human Hepatocyte Growth Factor Improves Neuropathic Pain-Related
Phenomena in Rats
Institution where the work was prepared: National Defense Medical College, Tokorozawa, Japan
Toyokazu Tsuchihara1; Koichi Nemoto1; Hiroshi Arino1; Masatoshi Amako1; Kuniaki Nakanishi1; Morishita Ryuichi2;
(1)National Defense Medical College, (2)Osaka University Medical School
INTRODUCTION:
Peripheral nerve injury is relatively common and sometimes may cause chronic neuropathic pain characterized by hyperalgesia and allodynia.
However, neuropathic pain is extremely difficult to treat because of poor understanding of the underlying mechanisms. The purpose
of this study is to investigate the therapeutic effect of Human hepatocyte growth factor (HGF) delivered into the nervous system
by retrograde axonal transport using liposomes containing the hemagglutinating virus of Japan (HVJ).
MATERIAL/METHODS:
Male Wistar rats, approximately 6 weeks old were used (n=228). Chronic constriction injury (CCI) model in rats was made as an experimental
neuropathic pain model. HGF gene was delivered into the nervous system by retrograde axonal transport following its repeated
intramuscular transfer, using liposomes containing the HVJ. Evaluation methods were as follows: (a) the withdrawal threshold of the
hind paw in response to non-noxious mechanical stimuli; (b) the thermal threshold in response to noxious heat applied to the plantar
surface of the hind paw; (c) the blood flow of the sciatic nerve and the hind paw; (d) mRNA levels for P2X and P2Y receptors. P2X and
P2Y receptors, which are activated by extracellular ATP, may play important roles as nociceptive purinoceptors on sensory nerve terminals,
and (e) imaging study using light- and electron-micrographs.
RESULTS:
CCI (control) rats exhibited marked mechanical allodynia and thermal hyperalgesia, and decreased blood flow in sciatic nerve and hind
paw. All these changes were significantly reversed by HGF-gene transfer. In the sciatic nerve in HGF-transferred rats, the histgram of the
axons showed rightward shifts, the number of myelinated axons more than 5ìm in diameter was significantly increased, and the mean
diameter of unmyelinated axons was significantly increased (versus CCI rats). Levels of P2X3, P2X4, and P2Y1 receptor mRNAs were elevated
in the ipsilateral dorsal root ganglia and/or sciatic nerves by CCI, and these levels were decreased by HGF-gene transfer.
CONCLUSION:
We have demonstrated that transfer the human HGF gene into the nervous system via repeated intramuscular injection of nonviral
HGF-HVJ liposomes is an efficient way of preventing or limiting sensory nerve degeneration in a rat model of neuropathic pain. On this
basis, HGF gene transfer via retrograde transport may become a novel useful therapeutic tool for the treatment of neuropathic pain.
126