JAK-STAT3 pathway regulates spinal astrocyte proliferation and neuropathic pain maintenance in rats

Abstract

Neuropathic pain, a debilitating pain condition, is a common consequence of damage to the nervous system. Optimal treatment of neuropathic pain is a major clinical challenge because the underlying mechanisms remain unclear and currently available treatments are frequently ineffective. Emerging lines of evidence indicate that peripheral nerve injury converts resting spinal cord glia into reactive cells that are required for the development and maintenance of neuropathic pain. However, the mechanisms underlying reactive astrogliosis after nerve injury are largely unknown. In the present study, we investigated cell proliferation, a critical process in reactive astrogliosis, and determined the temporally restricted proliferation of dorsal horn astrocytes in rats with spinal nerve injury, a well-known model of neuropathic pain. We found that nerve injury-induced astrocyte proliferation requires the Janus kinase-signal transducers and activators of transcription 3 signalling pathway. Nerve injury induced a marked signal transducers and activators of transcription 3 nuclear translocation, a primary index of signal transducers and activators of transcription 3 activation, in dorsal horn astrocytes. Intrathecally administering inhibitors of Janus kinase-signal transducers and activators of transcription 3 signalling to rats with nerve injury reduced the number of proliferating dorsal horn astrocytes and produced a recovery from established tactile allodynia, a cardinal symptom of neuropathic pain that is characterized by pain hypersensitivity evoked by innocuous stimuli. Moreover, recovery from tactile allodynia was also produced by direct suppression of dividing astrocytes by intrathecal administration of the cell cycle inhibitor flavopiridol to nerve-injured rats. Together, these results imply that the Janus kinase-signal transducers and activators of transcription 3 signalling pathway are critical transducers of astrocyte proliferation and maintenance of tactile allodynia and may be a therapeutic target for neuropathic pain.

Lower Serum Levels of miR-29c-3p and miR-19b-3p as Biomarkers for Alzheimer’s Disease

“…Compared with the rats in the AD+vector group, the rats in the AD+miR-29c-3p group and the AD+miR-19b-3p group showed significantly shorter escape latencies (P < 0.05) and inhibit neuronal differentiation of neural progenitor cells (Schwaiger et al 2000;Choi et al 2003;Sriram et al 2004;Okada et al 2006). STAT3 activation can result in excessive gliosis (Kwak et al 2010;Tsuda et al 2011), which is often observed in patients with AD. Therefore, we hypothesize that miR-19b-3p and miR-29c-3p may participate in the occurrence and development of AD by regulating STAT3 expression.…”

The glial scar in spinal cord injury and repair

“…is an effective avenue to control the development and maintenance of glial scars [72,73] . A wide spectrum of extracellular triggers is able to activate intracellular STAT3, particularly type i and ii interferons, neurocytokines, and growth factors including EGF and platelet-derived growth factor [74] .…”

Cell Cycle Activation Contributes to Increased Neuronal Activity in the Posterior Thalamic Nucleus and Associated Chronic Hyperesthesia after Rat Spinal Cord Contusion

“…Little is known about the role of cell cycle genes in neuropathic pain. Recently, the pan-CDK inhibitor, flavopiridol, administered intrathecally, was reported to reduce tactile allodynia after spinal nerve injury through inhibition of astrocyte proliferation [44]. Roscovitine, a more selective CDK inhibitor, reduced heat-induced hyperalgesia induced by complete Freund's adjuvant or formalin-induced nociceptive responses in rats [45,46].…”