<p>Melatonin MT2 receptor agonist IIK-7 produces antinociception by modulation of ROS and suppression of spinal microglial activation in neuropathic pain rats</p>

Abstract

Background In recent years, several melatonin (MLT) receptor agonists have been approved by FDA for the treatment of sleep disorders and depression. Very few studies have shed light on their efficacy against neuropathic pain (NP). IIK-7 is an MT-2 agonist known to promote sleep. Whether IIK-7 suppresses NP has not been reported, and the signaling profile is unknown. Objective To investigate the effect of melatonin type 2 receptor agonist IIK-7 on partial sciatic nerve transection-induced NP in rats and elucidate the underlying molecular mechanisms. Methods NP was induced by the PSNT in the left leg of adult male Wistar rats. On post-transection day 7, rats were implanted with intrathecal (i.t) catheter connected to an infusion pump and divided in to four groups: sham-operated/vehicle, PSNT/vehicle, PSNT/0.5 μg/hr IIK-7 and PSNT/0.5 μg IIK-7/1 μg 4-p/hr. To test the MT-2 dependence on IIK-7 activity, the animals were implanted with a single i.t catheter and injected MT-2 antagonist 4-Phenyl-2-propionamidotetralin (4-p) 20 mins prior to IIK-7 injection on day 7 after PSNT. The antinociceptive response was measured using a mechanical paw withdrawal threshold. Activation of microglial cells and the expression of NP-associated proteins in the spinal cord dorsal horn was assessed by immunofluorescence assay (IFA) and Western blotting (WB). Reactive oxygen species (ROS) scavenging ability of IIK-7 was evaluated by using bone marrow-derived macrophages (BMDM). Results Treatment with the MT-2 agonist IIK-7 significantly alleviated PSNT-induced mechanical allodynia and glial activation along with the inhibition of P44/42 MAPK, HMGB-1, STAT3, iNOS and casp-3 proteins. Conclusion IIK-7 attenuates NP through the suppression of glial activation and suppression of proteins involved in inflammation and apoptosis. MT-2 receptor agonists may establish a promising and unique therapeutic approach for the treatment of NP.

Claudin-5 Affects Endothelial Autophagy in Response to Early Hypoxia

“…ROS are produced by various sources in the CNS, including mitochondria, NADPH oxidase, and NOS, especially under hypoxia conditions ( Yamamoto et al, 2006 ; Kuthati et al, 2019 ). We used DCFH-DA to measure intracellular ROS and then analyzed these levels by flow cytometry.…”

“…ROS are produced by various sources in the CNS, including mitochondria, NADPH oxidase, and NOS, especially under hypoxia conditions (Yamamoto et al, 2006;Kuthati et al, 2019).…”

<p>Role of Melatonin in the Regulation of Pain</p>

“…14 Another study shows that MT2 receptor agonist, IIK-7, can relieve neuropathic pain through the inhibition of glial activation and downregulation of proteins involved in inflammation such as inducible nitric oxide synthase (iNOS) and caspase-3. 107 In addition, MT2 receptor agonists are considered to be effective in the treatment of neuropathic pain and have several advantages over melatonin. 108 MT receptors could transmit signals through the pertussis toxinsensitive Gi/o protein and delivered to second messenger systems or through Gq/11-phospholipase C (PLC) and PKC-dependent mechanism to modulate Ca 2+ signaling.…”

Therapeutic effects of peripherally administrated neural crest stem cells on pain and spinal cord changes after sciatic nerve transection

“…It has been demonstrated that PNI changes both primary afferent and second-order spinal cord neurons, leading to sensitization and abnormal responses to peripheral stimuli [8]. Chronic patient deficits are associated with dysregulation of brain and spinal cord circuitry following PNI [9,10].…”

“…Poor response to common PNI therapies can unfortunately cause neuropathic pain and the development of central sensitization [8,18,19]. Although the mechanism underlying the alleviation of pain behavior is not yet fully understood, stem cells have been shown to regulate pain behavior [20,21].…”