Abstract
BackgroundInteraction of CD200 with its receptor CD200R has an immunoregulatory role and attenuates various types of neuroinflammatory diseases.MethodsImmunofluorescence staining, western blot analysis, and RT-PCR were used to investigate the modulatory effects of CD200 fusion protein (CD200Fc) on activation of microglia and astrocytes as well as synthesis of pro- (TNF, IL-1β, IL-6) and anti-inflammatory (IL-4, IL-10) cytokines in the L4–L5 spinal cord segments in relation to behavioral signs of neuropathic pain after unilateral sterile chronic constriction injury (sCCI) of the sciatic nerve. Withdrawal thresholds for mechanical hypersensitivity and latencies for thermal hypersensitivity were measured in hind paws 1 day before operation; 1, 3, and 7 days after sCCI operation; and then 5 and 24 h after intrathecal application of artificial cerebrospinal fluid or CD200Fc.ResultsSeven days from sCCI operation and 5 h from intrathecal application, CD200Fc reduced mechanical and thermal hypersensitivity when compared with control animals. Simultaneously, CD200Fc attenuated activation of glial cells and decreased proinflammatory and increased anti-inflammatory cytokine messenger RNA (mRNA) levels. Administration of CD200Fc also diminished elevation of CD200 and CD200R proteins as a concomitant reaction of the modulatory system to increased neuroinflammatory reactions after nerve injury. The anti-inflammatory effect of CD200Fc dropped at 24 h after intrathecal application.ConclusionsIntrathecal administration of the CD200R1 agonist CD200Fc induces very rapid suppression of neuroinflammatory reactions associated with glial activation and neuropathic pain development. This may constitute a promising and novel therapeutic approach for the treatment of neuropathic pain.
Highlights
Interaction of CD200 with its receptor CD200R has an immunoregulatory role and attenuates various types of neuroinflammatory diseases
CD200Fc reduces mechanical and thermal hypersensitivity of nerve-injured rats As CD200Fc appears to be beneficial when administered in cases of various diseases with an inflammatory component [34, 36, 40], we investigated whether the CD200R1 agonist has effects on Peripheral neuropathic pain (PNP) behavioral signs in the Sterile chronic constriction injury (sCCI) model
All hind paws of rats subjected to sCCI of the sciatic nerve displayed significantly decreased thresholds of mechanical (Fig. 1a) and withdrawal latencies of thermal hypersensitivity (Fig. 1b) at days 1, 3, and 7 post-operation when compared with 1 day before operation
Summary
Interaction of CD200 with its receptor CD200R has an immunoregulatory role and attenuates various types of neuroinflammatory diseases. Sterile chronic constriction injury (sCCI) of the sciatic nerve is a model for study of cellular and molecular changes inducing PNP after traumatic nerve injury with dominant molecular signaling from Wallerian degeneration [6]. It is well documented that hypersensitivity and ongoing pain due to peripheral nerve injury are associated with cellular and molecular changes in the dorsal horn (DH) of the spinal cord related to activation of microglial cells and astrocytes and alteration of pro- and anti-inflammatory cytokines produced by neurons, activated glia, and invaded immune cells [7,8,9,10,11,12]. There is a growing body of evidence that unilateral nerve injury results in bilateral neuroinflammatory reaction in the dorsal root ganglia and spinal cord DH [10, 13,14,15], illustrating signaling from the site of Wallerian degeneration to other compartments of the nervous system [16]
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