Today's post from painresearchforum.org (see link below) takes a look at another interesting development involving using a topical salve to restore nerve function. The ever-suffering lab-mice have been the recipients of the trials thus far and it seems years away from something that might be given to human patients on prescription but it's an interesting story. Basically it involves applying a non-peptide GDNF receptor agonist (XIB4035) to for instance, the feet. How it works is tricky to understand and may even seem illogical to most people but every new finding is worth reading about and keeping in mind for the future. The best treatments have often emerged from such seemingly improbable sources.
Drug restores thermal nociception in two mouse models of small fiber neuropathy
By Stephani Sutherland on 19 Feb 2014
The term small fiber neuropathy (SFN) encompasses a mixed bag of conditions with a unifying element: damage or malfunction in unmyelinated peripheral nerves. In new work from Gabriel Corfas and colleagues at Harvard Medical School, Boston, US, a salve containing a compound that increases glial-derived neurotrophic factor (GDNF) activity restored lost pain sensation in two mouse models of SFN and prevented loss of nerve endings in one of them.
The work was published January 21 in the Proceedings of the National Academy of Sciences (PNAS).
The symptoms of SFN seem paradoxical: Many people experience both pain and numbness. Nerve damage can arise from diabetes, injury, autoimmune attack, or cancer (or its treatment), but many cases of SFN have mysterious origins.
“There is a desperate need in the field to develop pathogenesis-based specific treatments to treat painful symptoms in patients with peripheral neuropathies,” wrote Ahmet Höke of Johns Hopkins School of Medicine, Baltimore, US, in a commentary on the work published January 28 in PNAS (Höke, 2014).
While the current work did not look at painful symptoms of neuropathy—the experimenters measured loss of sensation to painful heat—it does hold out the possibility that a topical, small molecule treatment might be capable of rescuing lost innervation to the skin.
Derek Molliver, a neuroscientist at the University of Pittsburgh, US, says the potential is tremendous. “If you could apply something topically to restore nerve function, that would be phenomenal. Obviously, this would be worlds better than intrathecal injections.”
Co-first authors Kristian Hedstrom and Joshua Murtie used a mouse model of SFN the group had previously developed called line-D (Chen et al., 2003). The transgenic mice express non-functional receptors for the epidermal growth factor receptor ErbB specifically on non-myelinating Schwann cells, a type of glial cell that supports the peripheral axons of C-fiber neurons. When their support cells fail, C-fiber endings retract, and the sensory neurons eventually die. By a few weeks of age, the mice display deficits in the ability to sense painful heat.
In line-D mice, peripheral nerves are deficient in GDNF, and the new study shows that genetically augmenting GDNF production in the skin reversed the deficits in thermal nociception. Molliver pointed out that, like other models of peripheral neuropathy in which nerves lose contact with their target tissue, the line-D mouse actually models loss of trophic support, so the improvement with replacement of GDNF is perhaps not surprising.
Moving to a more pharmacological approach, the researchers asked whether topical application of a non-peptide GDNF receptor agonist (XIB4035) might have the same effect. They applied a cream containing XIB4035 to the hind paws of the mice beginning at three weeks of age and tested thermal nociception every seven days. While vehicle-treated line-D mice showed progressive loss of thermal nociception, line-D mice treated with XIB4035 showed no sensory loss. Line-D mice left untreated until four weeks already showed severe neuropathy symptoms that improved with XIB4035, but symptoms returned if treatment was halted, suggesting an ongoing need for the drug. Wild-type mice displayed normal sensation regardless of treatment.
The treatment also prevented the decrease in epidermal C-fiber density seen in the mutant mice, suggesting that treatment stabilized sensory nerves and prevented retraction. “Because XIB4035 was able to restore epidermal nerve fiber density in line-D, I am hopeful that it can have a positive effect as a regenerative therapy in peripheral neuropathies in people,” Höke told PRF in an email.
Image: Treatment with XIB4035 starting at postnatal day 28 increases labeling for isolectin-B4 (IB4), a marker for nonpeptidergic fibers, in the dorsal spinal cord. Left: Vehicle-treated wild-type mice display normal appearance of IB4+ (green) and TRPV1+ (red) nerve terminals. Center: Vehicle-treated line-D mice display complete absence of IB4 labeling. Right: XIB4035-treated line-D mice show presence of IB4+ fibers. No differences were observed in TRPV1 labeling between wild-type and line-D mice. Credit: From Hedstrom, Murtie, et al., 2014, © the authors.
To test a more clinically relevant mouse model of SFN, the team looked at streptozotocin-induced diabetic neuropathy. The diabetic mice showed a loss of thermal nociceptive sensation by the age of eight weeks. Mice treated with topical XIB4035 cream starting at the onset of diabetes displayed thermal sensitivity midway between that of healthy and untreated diabetic mice, which lasted throughout treatment. Interestingly, unlike in the line-D mice, XIB4035 treatment did not rescue intraepidermal nerve fiber density in the diabetic mice, suggesting that treatment improved sensation differently in the two models. “We were surprised by that finding,” said Corfas. More work needs to be done in order to understand how sensation was restored without regrowth of the missing fibers, he added.
Almost as an afterthought, Corfas told PRF, the team tested XIB4035 in a human neuroblastoma cell line to confirm the compound’s effects on human GDNF receptors. XIB4035 had previously been described as a competitive agonist at GDNF receptor α1 (GFRα1; Tokugawa et al., 2003), but unexpectedly—and unlike GFRα agonists—XIB4035 by itself had no effect on the receptor. Rather, the drug potentiated the effects of GDNF or artemin, another GFRα agonist. Further experiments confirmed that the drug bolstered activation of three different GFRα receptors by respective agonists, but had no effect on signaling by a different trophic factor, nerve growth factor (NGF), and its receptor TrkA, which are found on a different population of sensory neurons than GDNF-family receptors.
That last experiment could turn out to be the big boon that would give XIB4035 an advantage over an agonist as a therapeutic drug. “This finding led us to understand that this was a positive modulator,” Corfas told PRF. “As a modulator, its activity is restricted to the place where you have both ligands and receptors,” he said. “The drug gives a subtle but effective boost in signaling by endogenous molecules, rather than saturating the system in artificial ways.”
Previous reports had shown that GDNF and related trophic factors injected into the paw led to thermal hypersensitivity in healthy mice (Malin et al., 2006; Elitt et al., 2006). Importantly, the GDNF-augmenting treatment did not change mechanical or thermal sensitivity in healthy mice.
The effects the drug would have in animal models or patients with painful neuropathy remain to be seen. In any case, as Höke wrote, the enhancement of trophic factor signaling with this small molecule offers the hope of targeting the pathology of SFN itself.
Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California, US.
http://www.painresearchforum.org/news/37375-topical-compound-boosts-trophic-factor-actions-stem-neuropathy
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