Exogenous melatonin alleviates neuropathic pain-induced affective disorders by suppressing NF-κB/ NLRP3 pathway and apoptosis

Abstract

In this study, we aimed to evaluate the anti-inflammatory and anti-apoptotic effects of melatonin (MLT) on neuropathic pain (NP)-induced anxiety and depression in a rat model. Adult male rats were separated into four groups, i.e., Sham-VEH: healthy animals received a vehicle, Sham-MLT (10 mg/kg), and chronic constrictive injury (CCI)-VEH: nerve ligation received the vehicle, and CCI-MLT. Next, we used behavioral tests to evaluate pain severity, anxiety, and depression. Finally, rats were sacrificed for molecular and histopathological studies. Behavioral tests showed that NP could induce depressive- and anxiety-like behaviors. NP activated NF-κB/NLRP3 inflammasome pathways by upregulating NF-κB, NLRP3, ASC, active Caspase-1, also enhancing the concentrations of cytokines (IL-1β and IL-18) in the prefrontal cortex (PFC) and hippocampus (HC). NP upregulated Bax, downregulated Bcl2, and increased cell apoptosis in the HC and PFC. The rats treated with MLT eliminated the effects of NP, as the reduced pain severity, improved anxiety- and depressive-like behaviors, ameliorated NF-κB/NLRP3 inflammasome pathways, and modulated levels of cytokines in the HC and PFC. MLT could promote cell survival from apoptosis by modulating Bax and Bcl2. Therefore, it might be inferred that its anti-inflammatory and anti-apoptotic properties mediate the beneficial effects of MLT in NP-induced affective disorders.

Silencing of secreted phosphoprotein 1 attenuates sciatic nerve injury‐induced neuropathic pain: Regulating extracellular signal‐regulated kinase and neuroinflammatory signaling pathways

“…Bilateral sciatic nerve ligation was performed to establish a CCI rat model as previously described. 26,27 Briefly, the rats were anesthetized with 50 mg/kg sodium pentobarbital, and the sciatic nerves on both sides of the hind limbs were exposed and separated from the surrounding soft tissue. The sciatic nerves were ligated using 4-0 catgut thread at four sites (1 mm interval).…”

Role of NLRP3 Inflammasome in Post-Spinal-Cord-Injury Anxiety and Depression: Molecular Mechanisms and Therapeutic Implications

“…Chronic NP can induce the activation of the NF-κB/NLRP3 axis by elevating the concentrations of NF-κB, ASC, NLRP3, active Casp-1, as well as cytokines (IL-18 and IL-1β) in the HC and mPFC. Additionally, NP upregulates Bax, downregulates Bcl2, and increases apoptosis in the HC and mPFC . Inhibition of the NLRP3 inflammasome pathways may help improve the outcomes of SCI by targeting its crucial role in inducing neuroinflammation in post-SCI mental illnesses.…”

“…Additionally, NP upregulates Bax, downregulates Bcl2, and increases apoptosis in the HC and mPFC. 162 Inhibition of the NLRP3 inflammasome pathways may help improve the outcomes of SCI by targeting its crucial role in inducing neuroinflammation in post-SCI mental illnesses. Figure 2 illustrates the involvement of the NLRP3 inflammasome in the pathophysiology of post-SCI anxiety and depression.…”

Acellular spinal cord scaffold containing quercetin-encapsulated nanoparticles plays an anti-inflammatory role in functional recovery from spinal cord injury in rats

“…In ammasomes, multiprotein complexes consisting of sensor molecules, pro caspase-1 (pro Casp-1), and adapter proteins, are involved in the activation of in ammation in SCI (Mohammed et al, 2020). The NLR family pyrin domain-containing protein 3 (NLRP3) in ammasome, a type of in ammasome, activates Casp-1, which in turn processes and releases cytokines such as interleukin-1β (IL-1β) and IL-18 (Mokhtari et al, 2023). The NLRP3 in ammasome has been found to play a signi cant role in the pathophysiology of SCI (Babapour et al, 2021), making it a potential target for treatment strategies.…”