Activation of AMPK by metformin improves withdrawal signs precipitated by nicotine withdrawal

Brynildsen, Julia K.; Lee, Bridgin G.; Perron, Isaac J.; Jin, Sunghee; Kim, Sangwon F.; Blendy, Julie A.

doi:10.1073/pnas.1707047115

Cited by 41 publications

(27 citation statements)

References 37 publications

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“…Several reports have demonstrated that activation of adenosine monophosphate-activated protein kinase (AMPK) improves renal function in experimental models of acute kidney injury (AKI) (34) and CKD (35). The effects of metformin are mainly driven by the activation of AMPK, which regulates downstream signaling pathways (36). It was reported that AMPK also affects proteasomal degradation, and AMPK activation by metformin leads to an inhibition of proteasomal function (37).…”

Section: Discussionmentioning

confidence: 99%

Metformin attenuates renal interstitial fibrosis through upregulation of Deptor in unilateral ureteral obstruction in rats

Wang

et al. 2020

Exp Ther Med

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Renal interstitial fibrosis (RIF) is a common pathological process that accompanies chronic kidney disease (CKD) and that progresses to end-stage renal failure (ESRD). Accumulating evidence has revealed that persistent mammalian target of rapamycin (mTOR) activation in kidneys is closely associated with the occurrence and progression of CKD. The DEP domain-containing mTOR interacting protein (Deptor) is an endogenous negative regulator of mTOR. Metformin can attenuate renal fibrosis in an animal model of diabetic nephropathy. Previous studies demonstrated that metformin can attenuate renal fibrosis in several models of CKD. However, the precise mechanisms of this effect are not well understood. The present study aimed to examine the mechanism of action of metformin on unilateral ureteral obstruction (UUO)-induced RIF in rats in vivo. Sprague-Dawley rats were randomly divided into a sham-operated group, three UUO groups examined at different time points (3, 7 and 14 days after UUO surgery), and three metformin-treated groups, treated with three different concentrations of metformin. The metformin-treated groups were administered metformin orally every day for 14 consecutive days following surgery. The protein expression levels of Deptor, α-smooth muscle actin (α-SMA), phosphorylated (p-)mTOR, p-ribosomal protein S6 kinase (p-p70S6K) and CD68 were assessed. The present results suggested that, following UUO, there was a significant reduction of Deptor expression, and an increase in collagen deposition in the extracellular matrix over time, accompanied by an increased expression of several proteins including CD68, α-SMA, p-mTOR and p-p70S6K. Notably, metformin treatment reversed these effects. In conclusion, the present results suggested that metformin attenuated RIF of UUO rats, and the mechanism of action was found to be associated with the increase in Deptor expression and inhibition of the mTOR/p70S6K pathway in the kidneys of UUO rats.

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Section: Discussionmentioning

confidence: 99%

Metformin attenuates renal interstitial fibrosis through upregulation of Deptor in unilateral ureteral obstruction in rats

Wang

et al. 2020

Exp Ther Med

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“…Metformin is a medicine commonly used in diabetes treatment and has become the most prescribed oral hypoglycemic agent which needs to be taken over a long period of time 6. It has also been found to be functional in cardiovascular diseases 7-8, cancer 9-11 and other diseases, and it can even help to eliminate nicotine withdrawal syndrome 12. But long-term use or overdose of metformin can cause some side effects, such as heartburn, stomach pain, and liver or kidney problems 13, 14.…”

Section: Introductionmentioning

confidence: 99%

A Turn-On Optoacoustic Probe for Imaging Metformin-Induced Upregulation of Hepatic Hydrogen Sulfide and Subsequent Liver Injury

Sun¹,

Wu²,

Chen³

et al. 2019

Theranostics

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Metformin is currently the most prescribed oral agent for diabetes treatment; however the overdose or long-term use may cause some severe side effects such as liver injury. Researches indicate that metformin-induced liver injury is closely related to upregulation of hepatic H2S. Hence, monitoring hepatic H2S generation induced by metformin could be an effective approach for evaluating hepatoxicity of the drug.Methods: We present a novel turn-on and dual-mode probe for detecting and imaging metformin-induced liver injury by specifically tracking the upregulation of hepatic H2S with fluorescent and optoacoustic methods. After reaction with H2S, the strong electron-withdrawing group dinitrophenyl ether (which acts as both the recognition moiety and the fluorescence quencher) was cleaved and replaced by an electron-donating group hydroxyl. This correspondingly leads to the changes of the probe's electronic state and absorption red-shifting as well as the subsequent turn-on fluorescent and optoacoustic signals.Results: The probe was applied to the colon tumor-bearing mice model and the metformin-induced liver injury mice model to achieve tumor imaging and liver injury assessment. The biosafety of the probe was verified by histological analysis (hematoxylin and eosin staining) and serum biochemical assays.Conclusion: The probe responds quickly to H2S in tumors and the liver, and MSOT imaging with the probe offers cross-secitonal and 3D spatial information of liver injury. This study may provide an effective approach for accessing medication side effects by tracking drug-metabolism-related products.

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“…Withdrawal from repeated use of NIC in rodents produces substantial anxiety-like behaviors in various instrumental tests, including the EPM test; these tests have been validated in previous studies in our laboratory and by other groups [12,29]. As expected, in the present study, the ethological phenotype of anxiety was observed in the EPM test in that the NIC withdrawal rats exhibited decreased numbers of entries into open arms and spent less time in the open arms of the EPM compared to saline-treated controls.…”

Section: Discussionmentioning

confidence: 82%

Isoliquiritigenin Attenuates Anxiety‐Like Behavior and Locomotor Sensitization in Rats after Repeated Exposure to Nicotine

Wang

Kim

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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As important components of positive and negative reinforcement, locomotor sensitization and withdrawal anxiety following repeated exposure to nicotine (NIC) constitute crucial risk factors for relapse to NIC use after abstinence. Glycyrrhiza radix (G. radix), an important tonic used in traditional Oriental medicine, has not only anxiolytic effects but also reduces NIC-induced locomotor sensitization. Isoliquiritigenin (ISL), a bioactive ingredient of G. radix, also exhibits neuropharmacological effects, including anxiolytic action. Previously, we reported that ISL suppressed cocaine-induced extracellular dopamine release in the nucleus accumbens shell (NaccSh) and attenuated methamphetamine-induced neurotoxicity. e present study was performed to evaluate the effects of ISL on both NIC withdrawal anxiety and locomotor sensitization. Adult male rats received subcutaneous administration of NIC hydrogen tartrate (0.4 mg/kg, twice a day) for 7 days followed by 4 days of withdrawal. During the period of NIC withdrawal, the rats received four intragastric treatments with ISL (3, 10, or 30 mg/kg/day). All three doses of ISL significantly inhibited NIC withdrawal-induced anxiety-like behaviors in the elevated plus maze (EPM) test, but only the 10 mg/kg/day and 30 mg/kg/day ISL doses attenuated locomotor sensitization induced by a challenge dose of NIC. Intracerebroventricular ISL also inhibited both NIC-induced withdrawal anxiety and locomotor sensitization, but intra-NaccSh injection of ISL blocked only NIC locomotor sensitization, which was abolished by post-ISL infusion of tert-butyl hydroperoxide (an oxidant) or N-methyl-Daspartate (NMDA) into the NaccSh. Moreover, there was increased protein expression of phosphorylated Erk1/2 in the NICsensitized NaccSh, which was suppressed by ISL. Taken together, these results suggest that ISL can inhibit repeated NIC-induced withdrawal anxiety and locomotor sensitization, and the latter is mediated by antagonizing accumbal reactive oxygen species and NMDA receptor signaling.

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Activation of AMPK by metformin improves withdrawal signs precipitated by nicotine withdrawal

Cited by 41 publications

References 37 publications

Metformin attenuates renal interstitial fibrosis through upregulation of Deptor in unilateral ureteral obstruction in rats

Metformin attenuates renal interstitial fibrosis through upregulation of Deptor in unilateral ureteral obstruction in rats

A Turn-On Optoacoustic Probe for Imaging Metformin-Induced Upregulation of Hepatic Hydrogen Sulfide and Subsequent Liver Injury

Isoliquiritigenin Attenuates Anxiety‐Like Behavior and Locomotor Sensitization in Rats after Repeated Exposure to Nicotine

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