Effective control of neuropathic pain by transient expression of hepatocyte growth factor in a mouse chronic constriction injury model

Abstract

Hepatocyte growth factor (HGF) is a multifunctional protein that contains angiogenic and neurotrophic properties. In the current study, we investigated the analgesic effects of HGF by using a plasmid DNA that was designed to express 2 isoforms of human HGF—pCK-HGF-X7 (or VM202)—in a chronic constriction injury (CCI) –induced mouse neuropathic pain model. Intramuscular injection of pCK-HGF-X7 into proximal thigh muscle induced the expression of HGF in the muscle, sciatic nerve, and dorsal root ganglia (DRG). This gene transfer procedure significantly attenuated mechanical allodynia and thermal hyperalgesia after CCI. Injury-induced expression of activating transcription factor 3, calcium channel subunit α2δ1, and CSF1 in the ipsilateral DRG neurons was markedly down-regulated in the pCK-HGF-X7–treated group, which suggested that HGF might exert its analgesic effects by inhibiting pain-mediating genes in the sensory neurons. In addition, suppressed CSF1 expression in DRG neurons by pCK-HGF-X7 treatment was accompanied by a noticeable suppression of the nerve injury–induced glial cell activation in the spinal cord dorsal horn. Taken together, our data show that pCK-HGF-X7 attenuates nerve injury–induced neuropathic pain by inhibiting pain-related factors in DRG neurons and subsequent spinal cord glial activation, which suggests its therapeutic efficacy in the treatment of neuropathic pain.—Nho, B., Lee, J., Lee, J., Ko, K. R., Lee, S. J., Kim, S. Effective control of neuropathic pain by transient expression of hepatocyte growth factor in a mouse chronic constriction injury model.

Hepatocyte Growth Factor Regulates Macrophage Transition to the M2 Phenotype and Promotes Murine Skeletal Muscle Regeneration

“…pCK-HGF-X7 (or VM202) is a plasmid designed to produce two isoforms of human HGF, HGF723 (or dHGF), and HGF728 (or cHGF), at high levels in vivo (Cho et al, 2008; Pyun et al, 2010; Hahn et al, 2011), and it has been known to work in a variety of clinical studies and animal models (Cho et al, 2008; Pyun et al, 2010; Hahn et al, 2011; Kessler et al, 2015; Kibbe et al, 2016). The in vivo protein expression kinetics of this plasmid in the muscle have been well established previously (Supplementary Figure S4A) (Cho et al, 2008; Pyun et al, 2010; Hahn et al, 2011; Nho et al, 2018).…”

Intrathecal delivery of recombinant AAV1 encoding hepatocyte growth factor improves motor functions and protects neuromuscular system in the nerve crush and SOD1-G93A transgenic mouse models

“…HGF is also expected to generate non-autonomous effects by acting on glial cells such as astrocytes and microglia. We previously showed that HGF produced from plasmid DNA expression vector could lower the level of ATF3 and CSF1 in DRG and change the distribution of activated microglia in the dorsal horn in the mouse chronic constriction injury model [33]. Others also reported that treatment of primary astrocytes with HGF in vitro reduced the protein level of EAAT2, a glutamate transporter, and enhance the expression level of total Met in reactive astrocytes in the spinal cord [20, 48].…”

Elevated inflammatory proteins in cerebrospinal fluid from patients with painful knee osteoarthritis are associated with reduced symptom severity

“…To our knowledge, one has been reported to be antinociceptive (HGF), one to be anti-or pronociceptive (VEGFA), three to be pronociceptive (SCF, CSF-1, CX3CL1), and two have, to our knowledge, not previously been associated with pain (LIF-R, TWEAK). More specifically, intramuscular injection of plasmid construct containing human HGF reduced pain behavior in a mouse chronic constriction nerve injury model and reduced pain in patients with painful diabetic neuropathy (Kessler et al, 2015;Nho et al, 2018). The VEGFA pre-mRNA can be alternatively spliced into VEGFA 165a with pronociceptive and VEGFA 165b, with antinociceptive effects, respectively, and the antinociceptive VEGFA isoform 165b prevented the development of neuropathic pain in rodents and has been proposed as a novel target for drug development (Hulse et al, 2014;Hulse et al, 2016;Hulse, 2017).…”