Increase in Reactive Oxygen Species and Activation of Akt Signaling Pathway in Neuropathic Pain

Abstract

Neuropathic pain occurs as a result of peripheral or central nervous system injury. Its pathophysiology involves mainly a central sensitization mechanism that may be correlated to many molecules acting in regions involved in pain processing, such as the spinal cord. It has been demonstrated that reactive oxygen species (ROS) and signaling molecules, such as the serine/threonine protein kinase Akt, are involved in neuropathic pain mechanisms. Thus, the aim of this study was to provide evidence of this relationship. Sciatic nerve transection (SNT) was used to induce neuropathic pain in rats. Western blot analysis of Akt and 4-hydroxy-2-nonenal (HNE)-Michael adducts, and measurement of hydrogen peroxide (H(2)O(2)) in the lumbosacral spinal cord were performed. The main findings were found seven days after SNT, when there was an increase in HNE-Michael adducts formation, total and p-Akt expression, and H(2)O(2) concentration. However, one and 15 days after SNT, H(2)O(2) concentration was raised in both sham (animals that were submitted to surgery without nerve injury) and SNT groups, showing the high sensibility of this ROS to nociceptive afferent stimuli, not only to neuropathic pain. p-Akt also increased in sham and SNT groups one day post injury, but at 3 and 7 days the increase occurred exclusively in SNT animals. Thus, there is crosstalk between intracellular signaling pathways and ROS, and these molecules can act as protective agents in acute pain situations or play a role in the development of chronic pain states.

Role for pAKT in rat urinary bladder with cyclophosphamide (CYP)-induced cystitis

“…Numerous studies have demonstrated activation of AKT in DRG and spinal cord neurons following peripheral nerve injury or inflammation (26,58,59,60,71). In the present study, neither AKT nor pAKT was observed in the suburothelial nerve plexus of control or CYP-treated bladder whole mounts.…”

“…More recently, studies have demonstrated novel roles for AKT signaling in altered sensory/pain processing. For example, basal AKT phosphorylation is present in rodent lumbosacral dorsal root ganglia (DRG) (58,59) and superficial laminae of the spinal cord (26,60) and significantly increases following peripheral nerve injury or inflammation (26,58,59,60,71). Additionally, colocalization of pAKT with markers of unmyelinated, pain-transducing C-fibers such as IB4, TrkA, calcitonin gene-related peptide (CGRP), and transient potential vanilloid-1 channel (TRPV1) (58,59,71,74) has been demonstrated.…”

“…Recent studies have demonstrated additional roles for activated (phosphorylated; p) AKT in the initiation and maintenance of neuropathic pain and visceral inflammation (53,59,60,71). Immunohistochemical techniques demonstrate AKT activation in pain transducing C-fiber primary afferents and dorsal horn neurons following peripheral neuronal injury or tissue inflammation (26,58,59,60,71). In visceral inflammation, pAKT levels increase in the spinal cord dorsal horn following chemically induced colitis (53).…”

Ramalin inhibits VCAM-1 expression and adhesion of monocyte to vascular smooth muscle cells through MAPK and PADI4-dependent NF-kB and AP-1 pathways

“…It was reported that ROS activates various transcription factors in cultured VSMCs and may function as a signaling molecule in various pathways leading to MAPK, NF-κB, and AP-1 activation. 42,[44][45][46][47][48] . Furthermore, ROS has been implicated to enhance the transcription by activation of NF-κB and AP-1, leading to increased adhesion molecule expression.…”

Effect of intermittent normobaric hyperoxia for treatment of neuropathic pain in Chinese patients with spinal cord injury

“…First, normobaric hyperoxia treatment has been found to inhibit gp91(phox) expression, Akt activation, NADPH oxidase activity and MMP-2/9 induction; [25][26][27] while Akt activation, NADPH oxidase activity and MMP-2/9 induction have been proven to have important roles in the formation and development of neuropathic pain. [28][29][30][31] Second, InHO can increase the expression of tumor necrosis factor-α converting enzyme, which can convert the transmembrane tumor necrosis factor-α into soluble tumor necrosis factor-α. 21 Transmembrane tumor necrosis factor-α increases hypersensitivity of phenotype of sensory neurons and activate microglia.…”