Glial Cell Line–Derived Neurotrophic Factor Gene Transfer Exerts Protective Effect on Axons in Sciatic Nerve Following Constriction-Induced Peripheral Nerve Injury

Abstract

Damage to peripheral nerves following trauma or neurodegenerative diseases often results in various sensory and motor abnormalities and chronic neuropathic pain. The loss of neurotrophic factor support has been proposed to contribute to the development of peripheral neuropathy. The main objective of this study was to investigate the protective effect of glial cell line-derived neurotrophic factor (GDNF) using peripheral gene delivery in a rat model of constriction-induced peripheral nerve injury. In this study, it was shown that mechanical and thermal hypersensitivity increased on the injured limb at day 7 after chronic constrictive injury (CCI) was induced. The neurological changes were correlated with the structural changes and loss of GDNF/Akt signaling, particularly in the distal stump of the injured sciatic nerve. Subsequently, recombinant adenovirus was employed to evaluate the potential of intramuscular GDNF gene delivery to alleviate the CCI-induced nerve degeneration ad neuropathic pain. After CCI for 3 days, intramuscular injection of adenovirus encoding GDNF (Ad-GDNF) restored the protein level and activity of GDNF/Akt signaling pathway in the sciatic nerve. This was associated with an improved myelination profile and behavioral outcomes in animals with CCI. In conclusion, the present study demonstrates the involvement of GDNF loss in the pathogenesis of CCI-induced neuropathic pain and the therapeutic potential of intramuscular GDNF gene delivery for the treatment of peripheral nerve degeneration.

GDNF induces mechanical hyperalgesia in muscle by reducing IBK in isolectin B4-positive nociceptors

“…It has been shown that intrathecal delivery of GDNF can reduce pain in certain neuropathic states (Bennett et al, 1998, Boucher et al, 2000), and also that restoration of GDNF in muscle tissue can reduce mechanical allodynia and thermal sensitivity following chronic-constriction injury (Shi et al , 2011). However it has also been shown that GDNF can have pro-algesic effects: mice over-expressing GDNF had decreased mechanical (but not thermal) thresholds in skin (Albers et al , 2006); an antibody to GDNF reduced the hyperalgesia associated with complete Freund’s adjuvant injection (Fang et al , 2003); injection of GDNF in the hindpaw also produced an acute thermal hyperalgesia within 1 hr (Malin et al, 2006, Bogen et al, 2008); and inflammation increases GDNF production in the dorsal root ganglion (Amaya et al , 2004).…”

“…GDNF has also been shown to increase the proportion of cells responsive to the TRPA1 agonist allylisothiocyanate (Ciobanu et al , 2009). Thus, while it has been suggested that GDNF has analgesic effects in multiple models of neuropathic pain (Bennett et al, 1998, Boucher et al, 2000, Adler et al, 2009), it may produce pronociceptive effects (Albers et al, 2006, Shi et al, 2011) and contribute to pain in the setting of inflammation (Fang et al , 2003). …”

Gamma Knife Irradiation of Injured Sciatic Nerve Induces Histological and Behavioral Improvement in the Rat Neuropathic Pain Model

“…6B). GDNF, one of the most potent neurotrophic factors influencing the survival and maintenance of neurons [40], [41], has been reported to enhance axonal regeneration and re-myelination following nerve injury [40], [42], [43]. GDNF protein elevation in GK-irradiated injured nerves may promote regeneration and re-myelination.…”

Trigeminal Nerve Injury ErbB3/ErbB2 Promotes Mechanical Hypersensitivity

“…Fluorescent intensity was analyzed offline using an advanced image-analysis system MetaMorph (Molecular Devices, Sunnyvale, CA). The numbers of axons with intact myelin sheaths in the best five representative sections of three rats from each group were counted 18,19 . The person who counted the number of myelinated axons was blinded to experimental groups.…”