Glycogen synthase kinase 3-specific inhibitor AR-A014418 decreases neuropathic pain in mice: Evidence for the mechanisms of action

Mazzardo-Martins, Leidiane; Martins, Daniel Fernandes; Stramosk, Juliana; Cidral-Filho, Francisco José; Santos, Adair R.S.

doi:10.1016/j.neuroscience.2012.09.020

Cited by 51 publications

(43 citation statements)

References 49 publications

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“…62,63 We and others have shown that inhibition of GSK3β attenuates preexisting mechanical hypersensitivity induced by pSNL in mice 64 and rats. 25 We further demonstrated that GSK3β activities in the SDH are increased in rats with neuropathic pain induced by partial sciatic nerve ligation 25 and following paclitaxel treatment.…”

Section: Discussionmentioning

confidence: 91%

Adenosine Monophosphate–activated Protein Kinase Regulates Interleukin-1β Expression and Glial Glutamate Transporter Function in Rodents with Neuropathic Pain

et al. 2015

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Background Neuroinflammation and dysfunctional glial glutamate transporters (GTs) in the spinal dorsal horn (SDH) are implicated in the genesis of neuropathic pain. We determined if adenosine monophosphate-activated protein kinase (AMPK) in the SDH regulates these processes in rodents with neuropathic pain. Methods Hind paw withdrawal responses to radiant heat and mechanical stimuli were used to assess nociceptive behaviors. Spinal markers related to neuroinflammation and glial GTs were determined by Western blotting. AMPK activities were manipulated pharmacologically and genetically. Regulation of glial GTs was determined by measuring protein expression and activities of glial GTs. Results AMPK activities were reduced in the SDH of rats (n = 5) with thermal hyperalgesia induced by nerve injury, which were accompanied with the activation of astrocytes, increased production of interleukin-1beta and activities of glycogen synthase kinase 3β, and suppressed protein expression of glial glutamate transporter-1. Thermal hyperalgesia was reversed by spinal activation of AMPK in neuropathic rats (n = 10), and induced by inhibiting spinal AMPK in naïve rats (n = 7 to 8). Spinal AMPKα knockdown (n = 6) and AMPKα1 conditional knockout (n = 6) induced thermal hyperalgesia and mechanical allodynia. These genetic alterations mimicked the changes of molecular markers induced by nerve injury. Pharmacological activation of AMPK enhanced glial GT activity in mice with neuropathic pain (n = 8) and attenuated glial glutamate transporter-1 internalization induced by interleukin-1β (n = 4). Conclusion These findings suggest enhancing spinal AMPK activities could be an effective approach for the treatment of neuropathic pain.

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Section: Discussionmentioning

confidence: 91%

Adenosine Monophosphate–activated Protein Kinase Regulates Interleukin-1β Expression and Glial Glutamate Transporter Function in Rodents with Neuropathic Pain

et al. 2015

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“…The most recent report of GSK3β inhibition on pain processing has been shown in a mouse model of neuropathic pain through peripheral nerve injury [5]. Martins and coworkers (2012) have shown that intraperitoneal administration of a GSK3β inhibitor (AR-A014418) produces antihyperalgesic effects and decreases the proinflammatory cytokines IL-1β and TNF-α in the lumbar portion of the spinal cord (Lumbar 1 to Lumbar 6).…”

Section: Neuroinflammation and Pathological Painmentioning

confidence: 99%

“…In addition, they have shown that chronic inhibition of serotonin synthesis prior to GSK3β inhibition prevents the decrease in mechanical allodynia. While pharmacological inhibition of GSK3β has been shown to reduce hyperalgesia induced by nerve injury [5], it remains unknown if inhibition of GSK3β can prevent the development of allodynia following nerve injury. In an adult rat (Sprague Dawley) model of neuropathic pain induced by partial sciatic nerve ligation [206], with the same inhibitor (AR-A014418) and concentration (0.3 mg/kg), we found that chronic intraperitoneal administration from the day of surgery(1 injection/day) for 8 days significantly attenuates the development of mechanical allodynia induced by partial sciatic nerve ligation (Figure 5).…”

Section: Neuroinflammation and Pathological Painmentioning

confidence: 99%

“…The role of GSK3βin mediating peripheral and central nervous system inflammation in a multitude of neurological disorders has been extensively studied [2-6]. Studies of the role of GSK3β in pathological pain have recently just started [5,7]. In the brain, GSK3β is localized primarily to neurons [8], but has also been shown to be in glial cells [9].…”

Section: Introductionmentioning

confidence: 99%

“…Accumulation of inflammatory cells including macrophages, neutrophils at the peripheral injury site and the dorsal root ganglion, proliferation and activation of microglia and astrocytes in the spinal dorsal horn, as well as the release of pro-inflammatory cytokines and other pro-inflammatory mediators in the injury site, the dorsal root ganglion and the spinal dorsal horn have all been shown to contribute to the development and maintenance of pathological pain [24-27]. Similarly, pharmacological inhibition of GSK3β has been recently shown to attenuate pathological pain induced by nerve injury or formalin injection [5,7]. …”

Section: Introductionmentioning

confidence: 99%

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Maixner

Weng

2013

Journal of Pharmaceut & Pharmacol

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Neuroinflammation is a crucial mechanism related to many neurological diseases. Extensive studies in recent years have indicated that dysregulation of Glycogen Synthase Kinase 3 Beta (GSK3β) contributes to the development and progression of these disorders through regulating the neuroinflammation processes. Inhibitors of GSK3β have been shown to be beneficial in many neuroinflammatory disease models including Alzheimer's disease, multiple sclerosis and AIDS dem entia complex. Glial activation and elevated pro-inflammation cytokines (signs of neuroinflammation) in the spinal cord have been widely recognized as a pivotal mechanism underlying the development and maintenance of many types of pathological pain. The role of GSK3β in the pathogenesis of pain has recently emerged. In this review, we will first review the GSK3β structure, regulation, and mechanisms by which GSK3βregulates inflammation. We will then describe neuroinflammationin general and in specific types of neurological diseases and the potential beneficial effects induced by inhibiting GSK3β. Finally, we will provide new evidence linking aberrant levels of GSK3β in the development of pathological pain.

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Promotion of degradative autophagy by 6‐bromoindirubin‐3′‐oxime attenuates neuropathy

2023

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Damage to the central or peripheral nervous system causes neuropathic pain. Endoplasmic reticulum (ER) stress plays a role in peripheral neuropathy. Increase in ER stress is seen in diabetic neuropathy. Inducers of ER stress also give rise to peripheral neuropathy. ER stress leads to the formation of autophagosome but as their degradation is also stalled during ER stress accumulation of autophagosomes is seen. Accumulation of autophagosomes has deleterious effects on cells. In the present study, we show that treatment with tunicamycin (TM) (ER stress inducer) in mice leads to peripheral neuropathy as assessed by Von Frey and Hot plate method. Administration of a promoter of autophagy viz. 6‐bromoindirubin‐3′‐oxime (6‐BIO) subsequent to ER stress induced by TM exhibits a decrease in peripheral neuropathy. 6‐BIO was also effective in reducing diabetic peripheral neuropathy. To understand the type of autophagy activated, SH‐SY5Y cells were treated with 6‐BIO after TM treatment. Levels of cathepsin D (CTSD), a marker for degradative autophagy was higher in cells treated with 6‐BIO after TM treatment compared to only TM‐treated SH‐SY5Y cells while levels of Rab8A,—a marker for secretory autophagy was reduced. Furthermore, in parallel during ER stress secretory, we noted increased levels of lysozyme in autophagosomes destined for secretion. Cells treated with 6‐BIO showed reduction of lysozyme in secretory autophagosomes. This shows that 6‐BIO increased degradative autophagy and reduced the secretory autophagy. 6‐BIO also reduced the caspase‐3 activity in 6‐BIO‐treated cells. Thus, 6‐BIO reduced neuropathy in animals by activating degradative autophagy and reducing the secretory autophagy.

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Glycogen synthase kinase 3-specific inhibitor AR-A014418 decreases neuropathic pain in mice: Evidence for the mechanisms of action

Cited by 51 publications

References 49 publications

Adenosine Monophosphate–activated Protein Kinase Regulates Interleukin-1β Expression and Glial Glutamate Transporter Function in Rodents with Neuropathic Pain

Adenosine Monophosphate–activated Protein Kinase Regulates Interleukin-1β Expression and Glial Glutamate Transporter Function in Rodents with Neuropathic Pain

Untitled

Promotion of degradative autophagy by 6‐bromoindirubin‐3′‐oxime attenuates neuropathy

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