Spinal interleukin-10 therapy to treat peripheral neuropathic pain

Abstract

Introduction: Current research indicates that chronic peripheral neuropathic pain includes a role for glia and the actions of proinflammatory factors. This review briefly discusses the glial and cytokine responses that occur following peripheral nerve damage in support of utilizing anti-inflammatory cytokine interleukin-10 (IL-10) therapy to suppress chronic peripheral neuropathic pain. SPINAL NONVIRAL INTERLEUKIN-10 GENE THERAPY: IL-10 is one of the most powerful endogenous counter-regulators of proinflammatory cytokine function that acts in the nervous system. Subarachnoid (intrathecal) spinal injection of the gene encoding IL-10 delivered by nonviral vectors has several advantages over virally mediated gene transfer methods and leads to profound pain relief in several animal models. NONVIRAL GENE DELIVERY: Lastly, data are reviewed that nonviral deoxyribonucleic acid (DNA) encapsulated by a biologically safe copolymer, poly(lactic-co-glycolic) acid (PLGA), thought to protect DNA, leads to significantly improved therapeutic gene transfer in animal models, which additionally and significantly extends pain relief.

Conclusions: The impact of these early studies exploring anti-inflammatory genes emphasizes the exceptional therapeutic potential of new biocompatible intrathecal nonviral gene delivery approaches such as PLGA microparticles. Ultimately, ongoing expression of therapeutic genes is a viable option to treat chronic neuropathic pain in the clinic.

Figure 1. PLGA microparticles

(A) The distribution of PLGA microparticles encapsulating pDNA-IL-10 following a single intrathecal injection For verification that the microparticles could associate with phagocytic immune-cells in the subarachnoid matrix, after a single intrathecal injection of poly-L-glycolide-D-lactide (PLGA), a co-polymer (50:50 MW 75,000) used to microencapsulate a plasmid DNA vector encoding the anti-inflammatory gene, interleukin-10 (IL-10) was conducted. Ten days after subarachnoid (intrathecal) delivery of fluorescently labeled (rhodamine) microparticles encapsulating pDNA-IL-10, animals were deeply anesthetized, and transcardial saline followed by 4% paraformaldehyde perfusion procedures were conducted. Isolated spinal cords were post-fixed and 30 μm cryosections were collected. Spinal cord cross-sections and labeled microparticles (red; rhodamine), cellular nuclei (blue; DAPI), and phagocytic macrophage (green;ED-1) were examined and imaged using confocal microscopy (40X). Microparticles (red) are co-localized with macrophage (white arrow) within the meningeal tissue surrounding spinal cord. PLGA microparticles did not appear in depper spinal parenchyma. (B) A representative scanning electron micrograph image of PLGA microparticles encapsulating pDNA-IL-10 that were injected into the intrathecal space and produced enduring reversal from allodynia in rats with unilateral sciatic nerve damage from chronic constriction injury.