Activation of the AMP-Activated Protein Kinase Reduces Inflammatory Nociception

Russe, Otto Quintus; Möser, Christine V.; Kynast, Katharina L.; King, Tanya S.; Stephan, Heike; Geißlinger, Gerd; Niederberger, Ellen

doi:10.1016/j.jpain.2013.05.012

Cited by 78 publications

(77 citation statements)

References 39 publications

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“…Pretreatment by metformin inhibits inflammatory response factors; NFĸB, TNFα and COX-2 in the hippocampus of ischemic rats It has been reported that metformin can inhibit inflammatory pathways in neurons (Russe et al 2013). Our results indicated that cellular levels of NFĸB, TNFα and COX-2 increased in ischemic group compared with the sham group about 2.6, 1.9 and 1.6 folds, respectively (P<0.001) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The potential role of metformin in suppressing inflammation has been reported in various cell types such as pancreatic cells (Yue et al 2014), hepatocytes (Woudenberg-Vrenken et al 2013), neurons (Russe et al 2013) as well adipocytes (Grisouard et al 2011). Moreover, studies have established that activation of AMPK by other inducers; can attenuate cytokines against ischemic injuries in different organs (Jing et al 2013;Miller et al 2008).…”

Section: Introductionmentioning

confidence: 99%

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Pre-treatment with metformin activates Nrf2 antioxidant pathways and inhibits inflammatory responses through induction of AMPK after transient global cerebral ischemia

et al. 2014

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Global cerebral ischemia arises in patients who have a variety of clinical conditions including cardiac arrest, shock and asphyxia. In spite of advances in understanding of the brain ischemia and stroke etiology, therapeutic approaches to improve ischemic injury still remain limited. It has been established that metformin can attenuate cell death in cerebral ischemia. One of the main functions of metformin is proposed to be conducted via AMP-activated protein kinase (AMPK)-dependent pathway in the experimental cerebral ischemia model. It is also established that metformin can suppress inflammation and activate Nuclear factor erythroid 2-related factor (Nrf2) pathways in neurons. In the current study, the role of metformin in regulating inflammatory and antioxidant pathways in the global cerebral ischemia was investigated. Our results indicated that pretreatment of rats by metformin attenuated cellular levels of nuclear factor-κB, Tumor Necrosis Factor alpha and Cyclooxygenase-2 which are considered as three important proteins involved in the inflammation pathway. Pretreatment by metformin increased the level of Nrf2 and heme oxygenase-1 in the hippocampus of ischemic rats compared with untreated ischemic group. Moreover, pretreatment by metformin enhanced the level of glutathione and catalase activities compared with them in ischemic group. Such protective changes detected by metformin pretreatment were reversed by injecting compound c, an AMPK inhibitor. These findings suggested that metformin might protect cells through modulating inflammatory and antioxidant pathways via induction of AMPK. However, more experimental and clinical trial studies regarding neuroprotective potential of metformin and the involved mechanisms, especially in the context of cerebral ischemic injuries, are necessary.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pre-treatment with metformin activates Nrf2 antioxidant pathways and inhibits inflammatory responses through induction of AMPK after transient global cerebral ischemia

et al. 2014

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“…Previous study has shown that activation of AMPK might reduce inflammatory nociception (Russe et al, 2013). In addition, the activation of AMPK might be a new therapeutic target for the potential treatment of neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

Metformin attenuates hyperalgesia and allodynia in rats with painful diabetic neuropathy induced by streptozotocin

Liu

et al. 2015

European Journal of Pharmacology

107

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“…Inflammatory pain induced by subcutaneous injection of formalin or zymosan is attenuated by the systemic administration of AMPK activators. 11 Currently, the molecular and synaptic mechanisms by which AMPK regulates spinal nociceptive processing remain elusive.…”

Section: Introductionmentioning

confidence: 99%

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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Activation of the AMP-Activated Protein Kinase Reduces Inflammatory Nociception

Cited by 78 publications

References 39 publications

Pre-treatment with metformin activates Nrf2 antioxidant pathways and inhibits inflammatory responses through induction of AMPK after transient global cerebral ischemia

Pre-treatment with metformin activates Nrf2 antioxidant pathways and inhibits inflammatory responses through induction of AMPK after transient global cerebral ischemia

Metformin attenuates hyperalgesia and allodynia in rats with painful diabetic neuropathy induced by streptozotocin

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

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