Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • Spinal cord injury leads to an extensive inflammatory cascad

    2019-08-21

    Spinal cord injury leads to an extensive inflammatory cascade on spinal cord and the release of pro-inflammatory cytokines can sensitize neurons, activating signaling pathways that will result in thermal and mechanical hypersensitivity [39]. In this regard, Guo and collaborators (2014) demonstrated that the blockade of ETAR and ETBR significantly reduced the Probenecid levels of TNF-α, IL-1β, IL-6 and iNOS, which could possibly influence the pain control exerted by the endothelin system. On that note, the involvement of ETAR on neuropathic pain after SCI seems more pronounced once we administrated inthratecally its peptide antagonist, BQ-123, indicating that there might be an interaction between endogenous ET-1 and ETAR on sensitization and this is in accordance to previous studies from our group that demonstrated that ETAR antagonist has reduced mechanical sensitivity in different nociceptive models [12], [40]. However, the antagonist of ETBR, BQ788, was unable to reduce mechanical sensitivity post-SCI. Even though ETBR has been related to inflammatory and central pain by the action of ET-1 [41], [42], [43], [44], we observe evidence that indicates that such responses post-SCI were mediated mainly by ETA receptors. Therefore, regarding the tactile responses after oral treatment of bosentan, blockade of ETAR/ETBR inhibited SCI-induced pain responses, suggesting once again the participation of endothelin receptors in bringing about these responses. Nevertheless, bosentan is already used in clinic for pulmonary arterial hypertension and is known to cross brain-blood barrier [45], [46]. Likewise, McKenzie and collaborators (1995) have demonstrated that the systemic administration of bosentan before SCI attenuated barrier breakdown along the axis of the spinal cord therefore demonstrating that endothelin has a role on modulation of barrier permeability after SCI. On that matter, it has been suggested that endothelin may contribute to this abnormal permeability through facilitation of secondary posttraumatic ischemia once there is a reduction in spinal cord blood flow at the impact site. It has been suggested that brain-spinal cord barrier disruption after SCI may even create an ideal opportunity for the influx of inflammatory mediators and proteins not usually permitted in the CNS. Conversely, this disruption provides a unique opportunity for therapeutic intervention [47].
    Conclusion In summary, we provided evidence that spinal cord injury animals do develop mechanical allodynia as well as an upregulation of mainly ETAR after spinal cord injury that are associated with the pain processing. Thus, endothelial receptors antagonists might constitute an attractive pharmacological tool for the treatment of neuropathic pain following SCI.
    Conflict of interest
    Acknowledgments This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Programa de Apoio aos Núcleos de Excelência (PRONEX) and by Fundação de Apoio a Pesquisa do Estado de Santa Catarina (FAPESC) (Brazil). S. Forner, A.C. Martini and E.L. de Andrade received a fellowship from CNPq.
    Introduction Endothelin (ET) is a short peptide found in vascular epithelial cells by the group of Dr. Yanagisawa and Dr. Masaki more than 10 years ago (Yanagisawa et al., 1988). It has very potent vasoconstricting effects and was originally thought to be involved in circulatory regulation. However, many other aspects of the pathophysiological role of ET have been uncovered since then (Kedzierski and Yanagisawa, 2001). There are three ETs, ET1, ET2 and ET3, and two closely related receptors, ETA and ETB, and their contribution in the development are extensively studied in gene knock out (KO) experiments. Both receptors mediate neuronal crest cell development and migration but differ in their site of action. In the case of ETA KO, the mice have craniofacial defects in which the lack of a jaw is the most obvious anomaly (Clouthier et al., 1998). Another phenotype is a strange aorta that is seen in half of the mice. ETA KO mice die soon after birth from asphyxia, because they cannot breath without jaws. In the case of ETB KO, developmental failure of epidermal melanocytes leads to colorless spotted skin and enteric neuron defect results in megacolon, because the GI tract can not undergo peristaltic movement to convey digested foods Hosoda et al., 1994, Shin et al., 1999. Since most of these transgenic animals were often lethal at shortly after birth, studies of the ET system after birth have been hampered. We have attempted to investigate the function of the ET system, employing highly specific antagonists to avoid the drawbacks in the gene knockout model such as lethality, adaptation/compensation and so on. We employed newly developed antagonists, specific for endothelin ETA receptor, to test whether this drug could mimic the phenotype with corresponding gene KO mice. And we have investigated physiological function of ETA in the post natal period when the ETA KO mice would die from asphyxia.