The Modulatory Effect of Metformin on Ethanol-Induced Anxiety, Redox Imbalance, and Extracellular Matrix Levels in the Brains of Wistar Rats

Bonea, Maria; Filip, Gabriela Adriana; Toma, Vlad-Alexandru; Bâldea, Ioana; Berghian, Alexandra Sevastre; Decea, Nicoleta; Olteanu, Diana; Moldovan, Remus; Crivii, Carmen; Vinași, Ramona Cristina; Miclutia, I.

doi:10.1007/s12031-020-01593-w

Cited by 8 publications

(5 citation statements)

References 84 publications

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“…In this study, we found increased TBARS levels by sucrose consump- to improve anxiety-related disturbances in different models, such as during methamphetamine 68,69 or ethanol withdrawal, 70 in streptozotocin-induced diabetic mice, 71 and in mice exposed to highfat diets. 72,73 The results of this study indicate that metformin is neuroprotective in the prediabetic state, consistent with a growing number of emerging studies in the preclinical and clinical literature demonstrating the benefits of metformin in different neurocognitive and neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 59%

“…In this line, the decrease in serum TG and oxidative stress by metformin treatment is probably associated with reverting anxiety disorders to control levels. Accordingly, metformin has previously been shown to improve anxiety‐related disturbances in different models, such as during methamphetamine 68,69 or ethanol withdrawal, 70 in streptozotocin‐induced diabetic mice, 71 and in mice exposed to high‐fat diets 72,73 …”

Section: Discussionmentioning

confidence: 99%

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Effects of metformin on behavioral alterations produced by chronic sucrose consumption in male rats

Rey,

Coirini,

Marchena

et al. 2023

J Neuroendocrinology

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Excessive consumption of sugary drinks negatively impacts the developing brain, producing long‐lasting behavioral and metabolic disorders. Here, we study whether treatment with the antihyperglycemic agent metformin prevents some of the anxiety and memory alterations produced by chronic sucrose consumption. Male Sprague–Dawley rats had unrestricted access to water (control group) and a bottle containing a 10% sucrose solution (sucrose group, SUC) for 35 days. In parallel, a group of animals from SUC received metformin (25 mg/kg or 50 mg/kg, orally; MET 25 and MET 50 groups, respectively). After 2 weeks of metformin treatment, the animals weighed less than controls. SUC and MET 50 groups compensated for the caloric intake from the sugary solution by consuming less chow. In contrast, total energy intake in MET 25 was higher than the rest of the groups, but they still weighed less than control and SUC groups, suggesting that at this concentration, metformin delays body growth. The animals were then tested for the open field (OF), elevated plus maze (EPM) and novel object location (NOL) tests. In the OF, SUC animals spent more time in the central zone of the arena, evidenced by an increased number of entries and the distance traveled there. In the EPM, SUC animals spent more time in the open arms and less time in the central square. Metformin treatment prevented the decreased anxiety observed in SUC animals in the OF and EPM. In the NOL test, SUC animals showed less interest in novelty and metformin treatment did not improve this alteration. The preference for open spaces in the OF and EPM were associated with increased serum triglycerides (TG) and malondialdehyde levels in the medial prefrontal cortex (mPFC) and the hippocampus (HIP), while poor memory performance was associated with high basal blood glucose levels. In conclusion, the decreased anxiety‐like behavior produced by chronic sucrose consumption was prevented by metformin treatment, through a mechanism that probably involves normalization of TG levels and decreased oxidative stress in mPFC and HIP.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Effects of metformin on behavioral alterations produced by chronic sucrose consumption in male rats

Rey,

Coirini,

Marchena

et al. 2023

J Neuroendocrinology

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“…Hence, this study was the first to report that Sau inhibited nNOS expression in vivo. To further elucidate this effect and because excessive oxidative stress during EtOHW contributes to affective disorders [ 52 ], neuronal PC12 cells were used, with H 2 O 2 acting as an oxidative stressor. H 2 O 2 stimulation increased nNOS protein expression in PC12 cells [ 38 , 39 ], which was dose-dependently inhibited by Sau at doses of 3, 10, and 30 μ M in the present study.…”

Section: Discussionmentioning

confidence: 99%

Sauchinone Blocks Ethanol Withdrawal-Induced Anxiety but Spares Locomotor Sensitization: Involvement of Nitric Oxide in the Bed Nucleus of the Stria Terminalis

Jiao

Kim

Wang

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Both the positive (manifested by locomotor sensitization) and negative (withdrawal symptoms) reinforcing effects of ethanol (EtOH) involve central nitric oxide (NO) signaling. Sauchinone (a bioactive lignan in Saururus chinensis) has been shown to improve methamphetamine-induced behavioral and neurochemical changes via the NO signaling pathway. Thus, this study evaluated the effects of sauchinone on locomotor sensitization and anxiety during EtOH withdrawal (EtOHW). Male adult Sprague-Dawley rats were treated with 1.5 g/kg/day of EtOH (20%, vol/vol) via intraperitoneal injection for 28 days, followed by a 3-day withdrawal. During withdrawal, the rats were given intragastric sauchinone (2.5, 7.5, or 25 mg/kg/day) once a day. EtOH locomotor sensitization was determined by challenging EtOHW rats with 0.75 g/kg EtOH, while EtOHW-induced anxiety was assessed using the elevated plus maze (EPM). None of the three doses of sauchinone affected EtOH locomotor sensitization. However, in the EPM, treatment of EtOHW rats with sauchinone at 7.5 or 25 mg/kg/day increased both the number of entries into and the time spent in the open arms. Moreover, the two doses of sauchinone inhibited the oversecretion of plasma corticosterone during EtOHW. In the bed nucleus of the stria terminalis (BNST), EtOHW increased NO production, enhanced gene and protein expression of both inducible nitric oxide synthase (iNOS) and neuronal NOS (nNOS), and also elevated protein levels of corticotropin-releasing factor, which were all inhibited by 25 mg/kg/day sauchinone. In an in vitro experiment, sauchinone (3, 10, and 30 μM) inhibited H2O2-stimulated nNOS protein expression in neuronal PC12 cells. Finally, intra-BNST infusion of sodium nitroprusside, a NO donor, after sauchinone (25 mg/kg/day) administration, abolished its expected anxiolytic effect. Taken together, these results indicate that sauchinone attenuates anxiety-like behavior in rats during EtOHW but spares EtOH locomotor sensitization, and the anxiolytic effect is mediated via the NO signaling pathway in the BNST.

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“…This ectopic role of the Ngb was derived from the cytoglobin function noticed as a cancer progression protein that was over-expressed in different types of tumors (non-small cell lung cancer, esophageal cancer, or melanoma) [34,35]. Our study was performed to investigate the role of stress in Ngb expression as a pivotal protein in brain oxidative stress with expected involvements in anxiety, as was suggested by previous results and other studies [33,[36][37][38]. Alternatively, we have investigated the dynamic of the Ngb expression related to a gene-expression regulator methyl-CpG-binding protein 2 (MeCP2) and the time-dependent activation of the Ngb and CNP+ oligodendrocytes (2 ,3 -cyclic nucleotide 3 -phosphodiesterase OCs) couple.…”

Section: Introductionmentioning

confidence: 86%

The Effect of Repeated Restraint Stress on Neuroglobin-Oligodendrocytes Functions in the CA3 Hippocampal Area and Their Involvements in the Signaling Pathways of the Stress-Induced Anxiety

et al. 2022

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The present work shows the biochemical and structural fundamentals for the stress induced anxiety and stress adjustment response of the CA3 hippocampus area. Adult male Wistar rats were repeatedly exposed to a 3 h day restraint stress, for either 3 or 6 days. The concentration of corticosterone and testosterone in the CA3 hippocampus area was divergent, while oxidative stress was progressively increased during the stress exposure. The mitochondrial lysis in the CA3 neurons confirmed the oxidative stress events. Immunohistochemical findings showed that oligodendrocytes (OCs) proliferation and neuroglobin (Ngb) expression were stimulated, whereas MeCP2 expression was decreased as a balance reaction in stress exposure under corticosterone signaling. Remarkably, ultrastructural changes such as mitochondrial lysis, endoplasmic reticulum swelling, and perivascular lysis with platelets adherence to endothelium in the CA3 area were seen in the 6th day of restraining. The anxiety-like behavior was noticed 6 days later after stress exposure. These results suggest that the duration of the exposure, but not the intensity of the stress, is the key factor in the stress-buffering function by the CA3 hippocampus area via up-regulation of the Ngb-OCs bionome. The imbalance of the Ngb-OCs communication may be involved in the development of CA3-dependent anxious behavior.

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The Modulatory Effect of Metformin on Ethanol-Induced Anxiety, Redox Imbalance, and Extracellular Matrix Levels in the Brains of Wistar Rats

Cited by 8 publications

References 84 publications

Effects of metformin on behavioral alterations produced by chronic sucrose consumption in male rats

Effects of metformin on behavioral alterations produced by chronic sucrose consumption in male rats

Sauchinone Blocks Ethanol Withdrawal-Induced Anxiety but Spares Locomotor Sensitization: Involvement of Nitric Oxide in the Bed Nucleus of the Stria Terminalis

The Effect of Repeated Restraint Stress on Neuroglobin-Oligodendrocytes Functions in the CA3 Hippocampal Area and Their Involvements in the Signaling Pathways of the Stress-Induced Anxiety

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