GSK-3β inhibition alleviates arthritis pain via reducing spinal mitochondrial reactive oxygen species level and inflammation

Yang, He‐Yu; Sun, Xingming; Zhen, Shuqing; Yu, Liangzhu; Ding, Jieqiong; Liu, Ling; Xie, Min; Zhu, Haili

doi:10.1371/journal.pone.0284332

Cited by 3 publications

(2 citation statements)

References 44 publications

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“…In animal of several pain models, increased GSK-3β activity is accompanied by the mechanical and thermal hyperalgesia (Hu et al, 2023). While, inhibition of GSK-3β activity alleviates pain related behaviors (Peng et al, 2019;Yang et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

Curcumin relieves oxaliplatin‐induced neuropathic pain via reducing inflammation and activating antioxidant response

Zhang,

Sun,

et al. 2024

Cell Biology International

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Oxaliplatin (OXA) has shown high effectiveness in the treatment of cancers, but its anticancer clinical effects often induce neurotoxicity leading to neuropathic pain. Oxidative damage and NLRP3 inflammasome play important roles in neuropathic pain development. Here, neuropathic pain mouse model was constructed by continuous intraperitoneal injection of OXA. OXA administration induced mechanical pain, spontaneous pain, thermal hyperalgesia and motor disability in mice. The spinal cord tissues of OXA mice exhibited the suppressed antioxidative response, the activated NLRP3 inflammasome mediated inflammatory responses, and the increased GSK‐3β activity. Next, we injected curcumin (CUR) intraperitoneally in OXA mice for seven consecutive days. CUR‐treated mice showed increased mechanical pain thresholds, reduced number of spontaneous flinches, increased paw withdrawal latency, and restored latency to fall. While in the spinal cord, CUR treatment inhibited the NLRP3 inflammasome mediated inflammatory response, increased Nrf2/GPX4‐mediated antioxidant responses, and decreased mitochondrial oxidative generation. Additionally, CUR combined with GSK‐3β through four covalent bonds and reduced GSK‐3β activity. In conclusion, our findings suggest that CUR treatment inhibits GSK‐3β activation, increases Nrf2 mediated antioxidant responses, inhibits oxidative damage and inflammatory reaction, and alleviates OXA‐induced neuropathic pain.

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Section: Discussionmentioning

confidence: 99%

Curcumin relieves oxaliplatin‐induced neuropathic pain via reducing inflammation and activating antioxidant response

Zhang,

Sun,

et al. 2024

Cell Biology International

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“…Additionally, intrathecal injection of recombinant IL-1β [113,114] or IL-18 [115,116] enhanced hind paw sensitivity to mechanical and heat stimulation. The overproduction of IL-1β has been observed in the spinal dorsal horn of animals with other pathological pain conditions, including neuropathic pain [89,117], inflammatory pain [118,119], arthritis [120,121], bone cancer pain [116,122], and chemotherapy (like paclitaxel)-induced chronic pain [123,124]. IL-1β is synthesized and released from microglia [124][125][126] and astrocytes [126,127].…”

Section: Il-1β and Il-18mentioning

confidence: 99%

Emerging Molecular and Synaptic Targets for the Management of Chronic Pain Caused by Systemic Lupus Erythematosus

Weng

2024

IJMS

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Patients with systemic lupus erythematosus (SLE) frequently experience chronic pain due to the limited effectiveness and safety profiles of current analgesics. Understanding the molecular and synaptic mechanisms underlying abnormal neuronal activation along the pain signaling pathway is essential for developing new analgesics to address SLE-induced chronic pain. Recent studies, including those conducted by our team and others using the SLE animal model (MRL/lpr lupus-prone mice), have unveiled heightened excitability in nociceptive primary sensory neurons within the dorsal root ganglia and increased glutamatergic synaptic activity in spinal dorsal horn neurons, contributing to the development of chronic pain in mice with SLE. Nociceptive primary sensory neurons in lupus animals exhibit elevated resting membrane potentials, and reduced thresholds and rheobases of action potentials. These changes coincide with the elevated production of TNFα and IL-1β, as well as increased ERK activity in the dorsal root ganglion, coupled with decreased AMPK activity in the same region. Dysregulated AMPK activity is linked to heightened excitability in nociceptive sensory neurons in lupus animals. Additionally, the increased glutamatergic synaptic activity in the spinal dorsal horn in lupus mice with chronic pain is characterized by enhanced presynaptic glutamate release and postsynaptic AMPA receptor activation, alongside the reduced activity of glial glutamate transporters. These alterations are caused by the elevated activities of IL-1β, IL-18, CSF-1, and thrombin, and reduced AMPK activities in the dorsal horn. Furthermore, the pharmacological activation of spinal GPR109A receptors in microglia in lupus mice suppresses chronic pain by inhibiting p38 MAPK activity and the production of both IL-1β and IL-18, as well as reducing glutamatergic synaptic activity in the spinal dorsal horn. These findings collectively unveil crucial signaling molecular and synaptic targets for modulating abnormal neuronal activation in both the periphery and spinal dorsal horn, offering insights into the development of analgesics for managing SLE-induced chronic pain.

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GSK3-Driven Modulation of Inflammation and Tissue Integrity in the Animal Model

Kühl,

Brand,

Lichtinghagen

et al. 2024

IJMS

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Nowadays, GSK3 is accepted as an enzyme strongly involved in the regulation of inflammation by balancing the pro- and anti-inflammatory responses of cells and organisms, thus influencing the initiation, progression, and resolution of inflammatory processes at multiple levels. Disturbances within its broad functional scope, either intrinsically or extrinsically induced, harbor the risk of profound disruptions to the regular course of the immune response, including the formation of severe inflammation-related diseases. Therefore, this review aims at summarizing and contextualizing the current knowledge derived from animal models to further shape our understanding of GSK3α and β and their roles in the inflammatory process and the occurrence of tissue/organ damage. Following a short recapitulation of structure, function, and regulation of GSK3, we will focus on the lessons learned from GSK3α/β knock-out and knock-in/overexpression models, both conventional and conditional, as well as a variety of (predominantly rodent) disease models reflecting defined pathologic conditions with a significant proportion of inflammation and inflammation-related tissue injury. In summary, the literature suggests that GSK3 acts as a crucial switch driving pro-inflammatory and destructive processes and thus contributes significantly to the pathogenesis of inflammation-associated diseases.

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GSK-3β inhibition alleviates arthritis pain via reducing spinal mitochondrial reactive oxygen species level and inflammation

Cited by 3 publications

References 44 publications

Curcumin relieves oxaliplatin‐induced neuropathic pain via reducing inflammation and activating antioxidant response

Curcumin relieves oxaliplatin‐induced neuropathic pain via reducing inflammation and activating antioxidant response

Emerging Molecular and Synaptic Targets for the Management of Chronic Pain Caused by Systemic Lupus Erythematosus

GSK3-Driven Modulation of Inflammation and Tissue Integrity in the Animal Model

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