Gwak, YS, Kang, J, Unabia, GC and Hulsebosch, CE. Spatial and temporal activation of spinal glial cells: role of gliopathy in central neuropathic pain following spinal cord injury in rats. Exp Neurol 234: 362-372
Department of Neuroscience and Cell Biology, University of Texas Medical Branch at Galveston, TX 77555, USA.Experimental Neurology (Impact Factor: 4.7). 10/2011; 234(2):362-72. DOI: 10.1016/j.expneurol.2011.10.010
In the spinal cord, neuron and glial cells actively interact and contribute to neurofunction. Surprisingly, both cell types have similar receptors, transporters and ion channels and also produce similar neurotransmitters and cytokines. The neuroanatomical and neurochemical similarities work synergistically to maintain physiological homeostasis in the normal spinal cord. However, in trauma or disease states, spinal glia become activated, dorsal horn neurons become hyperexcitable contributing to sensitized neuronal-glial circuits. The maladaptive spinal circuits directly affect synaptic excitability, including activation of intracellular downstream cascades that result in enhanced evoked and spontaneous activity in dorsal horn neurons with the result that abnormal pain syndromes develop.
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- "Reactive gliosis along with the release of pro-inflammatory cytokines is a hallmark of human and experimental CNS injury (Yang et al., 2004Yang et al., , 2005 Fleming et al., 2006; Burda and Sofroniew, 2014) and represents one of the main mechanisms contributing to the genesis and maintenance of chronic pain after SCI (Hulsebosch et al., 2009; Gwak et al., 2012). In fact, it is now becoming clear that cytokines are key signaling molecules between glia and neurons, capable of modulating neuronal function (Viviani et al., 2014; Vezzani and Viviani, 2015) and enhancing pain transmission (Guo et al., 2007; Gwak et al., 2012; Ji et al., 2014; Tiwari et al., 2014). In this regard, we have recently reported an increased number of GFAP immunoreactive astrocytes and OX-42 immunoreactive microglial cells detected in the dorsal horn of animals subjected to a spinal cord lesion , both in the acute and the chronic phase after injury (Coronel et al., 2014). "
ABSTRACT: Neuropathic pain is a frequent complication of spinal cord injury (SCI), still refractory to conventional treatment. Glial cell activation and cytokine production contribute to the pathology of central neuropathic syndromes. In this study we evaluated the effects of progesterone, a neuroactive steroid, on pain development and the spinal expression of IL-1β, its receptors (IL-1RI and IL-1RII) and antagonist (IL-1ra), IL-6 and TNFα, and NR1 subunit of NMDAR. Our results show that progesterone, by modulating the expression of pro-inflammatory cytokines and neuronal IL-1RI/NR1 colocalization, emerges as a promising agent to prevent chronic pain after SCI.
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- "In healthy animals, the rubro-olivary system is hypothesized to manage the transition of control from the CST to the RST when a movement has been successfully learned and becomes automated (Kennedy, 1990). Axonal growth support may also be provided through proliferating astrocytes (Gwak et al., 2012), which are able to bridge the lesion area at the smaller injured right side (Fig. 1A″). They may provide a passage for re-growing or sprouting axons whereas the more severed left side lacks such growth support (Fig. 1A″). "
ABSTRACT: Spinal cord injury (SCI) affects approximately 3 million people around the world, who are desperately awaiting treatment. The pressing need for the development of therapeutics has spurred medical research for decades. To respond to this pressing need, our group developed a potential therapeutic to reduce the presence of proteoglycans at the injury site after acutely traumatizing the spinal cord of rats. With the aid of a DNA enzyme against the mRNA of xylosyltransferase-1 (DNAXT-1as) we adjourn the glycosylation and prevent the assembly of the proteoglycan core protein into the extracellular matrix. Hence, endogenous repair is strengthened due to the allocation of a more growth permissive environment around the lesion site. Here, we present data on a long term study of animals with a dorsal hemisection treated with DNAXT-1as, DNAXT-1mb (control DNA enzyme) or PBS via osmotic minipumps. After successful digestion of the XT-1 mRNA shown by qPCR we observed an overall behavioral improvement of DNAXT-1as treated rats at 8, 10 and 14. weeks after insult to the spine compared to the control animals. This is accompanied by the growth of the cortical spinal tract (CST) in DNAXT-1as treated animals after a 19. week survival period. Furthermore, after evaluating the lesion size tissue-protective effects in the DNAXT-1as treated animals compared to DNAXT-1mb and PBS treated rats are revealed. The results yield new insights into the regeneration processes and provide confirmation to involve DNA enzyme administration in future therapeutic strategies to medicate SCI.
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- "In sum, observations from SCI pain models, supported by a larger body of similar evidence from peripheral neuropathic pain models (e.g., Colburn et al., 1999; Sweitzer et al., 1999; Zhuang et al., 2005) indicate that interactions among astrocytes, microglia, and neurons are critical for the development and maintenance of neuropathic SCI pain (Gwak et al., 2012; Ji et al., 2013). Important interactions may also involve satellite glial cells in sensory ganglia, which are closely related to astrocytes and are known to contribute to behavioral hypersensitivity in peripheral models of neuropathic pain (Huang et al., 2013; Ji et al., 2013; Ohara et al., 2009; Xie et al., 2009), but contributions of satellite glial cells to painful consequences of SCI have yet to be reported. "
ABSTRACT: Neuropathic pain after spinal cord injury (SCI) is common, often intractable, and can be severely debilitating. A number of mechanisms have been proposed for this pain, which are discussed briefly, along with methods for revealing SCI pain in animal models, such as the recently applied conditioned place preference test. During the last decade, studies of animal models have shown that both central neuroinflammation and behavioral hypersensitivity (indirect reflex measures of pain) persist chronically after SCI. Interventions that reduce neuroinflammation have been found to ameliorate pain-related behavior, such as treatment with agents that inhibit the activation states of microglia and/or astroglia (including IL-10, minocycline, etanercept, propentofylline, ibudilast, licofelone, SP600125, carbenoxolone). Reversal of pain-related behavior has also been shown with disruption by an inhibitor (CR8) and/or genetic deletion of cell cycle-related proteins, deletion of a truncated receptor (trkB.T1) for brain-derived neurotrophic factor (BDNF), or reduction by antisense knockdown or an inhibitor (AMG9810) of the activity of channels (TRPV1 or Nav1.8) important for electrical activity in primary nociceptors. Nociceptor activity is known to drive central neuroinflammation in peripheral injury models, and nociceptors appear to be an integral component of host defense. Thus, emerging results suggest that spinal and systemic effects of SCI can activate nociceptor-mediated host defense responses that interact via neuroinflammatory signaling with complex central consequences of SCI to drive chronic pain. This broader view of SCI-induced neuroinflammation suggests new targets, and additional complications, for efforts to develop effective treatments for neuropathic SCI pain.