Metformin reduces oxandrolone- induced depression-like behavior in rats via modulating the expression of IL-1β, IL-6, IL-10 and TNF-α

Hammad, Alaa M.; Ibrahim, Yasmeen A.; Khdair, Sawsan I.; Hall, F. Scott; Alfaraj, Malek; Jarrar, Yazun; Abed, Abdulqader Fadhil

doi:10.1016/j.bbr.2021.113475

Cited by 21 publications

(8 citation statements)

References 59 publications

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“…Linagliptin, metformin, and their combination reduced TNF-a and IL-1b but not IL-6 levels. This is in line with other in-vitro and in-vivo studies which confirm that anti-diabetic drugs metformin and linagliptin inhibit pro-inflammatory cytokines (89)(90)(91)(92).…”

Section: Discussionsupporting

confidence: 92%

Linagliptin in Combination With Metformin Ameliorates Diabetic Osteoporosis Through Modulating BMP-2 and Sclerostin in the High-Fat Diet Fed C57BL/6 Mice

Nirwan

Vohora

2022

Front. Endocrinol.

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BackgroundDiabetic osteoporosis is a poorly managed serious skeletal complication, characterized by high fracture risk, increased bone resorption, reduced bone formation, and disrupted bone architecture. There is a need to investigate drugs that can improve bone health along with managing glycemic control. DPP-4 inhibitors and metformin have proven benefits in improving bone health. Here, we investigated the effects of linagliptin, a DPP inhibitor, and metformin alone and in combination to treat diabetic osteoporosis in high-fat-fed mice.MethodsC57BL/6 mice were kept on the high-fat diet (HFD) for 22 weeks to induce diabetic osteoporosis. Linagliptin (10mg/Kg), metformin (150mg/Kg), and their combination were orally administered to the diabetic mice from the 18th-22nd week. Femur and tibial bone microarchitecture together with bone mineral density (BMD) were evaluated using µCT and histopathological changes were assessed. Further, bone turnover biomarkers namely bone morphogenetic protein-2 (BMP-2), sclerostin, tartrate-resistant acid phosphatase (TRAP), osteocalcin, alkaline phosphatase (ALP), calcium, and pro-inflammatory cytokines were assessed. Additionally, metabolic parameters including body weight, fasting blood glucose (FBG), glucose & insulin tolerance, lipids profile, and leptin were measured.ResultsHFD feeding resulted in impaired bone microarchitecture, reduced BMD, distorted bone histology, and altered bone turnover biomarkers as indicated by the significant reduction in bone ALP, BMP-2, osteocalcin, and an increase in sclerostin, TRAP, and serum calcium. Interestingly, treatment with linagliptin and its combination with metformin significantly reverted the impaired bone architecture, BMD, and positively modulated bone turnover biomarkers, while metformin alone did not exhibit any significant improvement. Further, HFD induced diabetes and metabolic abnormalities (including an increase in body weight, FBG, impaired glucose and insulin tolerance, leptin, triglycerides, cholesterol), and pro-inflammatory cytokines (TNF-alpha and IL-1β) were successfully reversed by treatment with linagliptin, metformin, and their combination.ConclusionLinagliptin and its combination with metformin successfully ameliorated diabetic osteoporosis in HFD-fed mice possibly through modulation of BMP-2 and sclerostin. The study provides the first evidence for the possible use of linagliptin and metformin combination for managing diabetic osteoporosis.

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Section: Discussionsupporting

confidence: 92%

Linagliptin in Combination With Metformin Ameliorates Diabetic Osteoporosis Through Modulating BMP-2 and Sclerostin in the High-Fat Diet Fed C57BL/6 Mice

Nirwan

Vohora

2022

Front. Endocrinol.

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“…It is generally accepted that metformin inhibits pro-inflammatory cytokine release, such as IL-1β, IL-6, and TNF-α, to have anti-inflammatory effects [ 37 , 38 , 39 , 40 , 41 ]. Destabilization of the atherosclerotic plaque is associated with increased inflammatory cytokine production [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Metformin Directly Binds to MMP-9 to Improve Plaque Stability

Chen

Wang

et al. 2023

JCDD

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Vulnerable atherosclerotic plaque rupture is the principal mechanism that accounts for myocardial infarction and stroke. High matrix metalloproteinase-9 (MMP-9) expression and activity have been proven to lead to plaque instability. Metformin, a first-line treatment for type 2 diabetes, is beneficial to plaque vulnerability. However, the mechanism underlying its anti-atherogenic effect remains unclear. Molecular docking and surface plasmon resonance experiments showed that metformin directly interacts with MMP-9, and incubated MMP-9 overexpressing HEK293A cells with metformin (1 μmol·L−1) significantly attenuates MMP-9’s activity using zymography and MMP activity assays. Moreover, metformin treatment drives MMP-9 degradation. Next, we constructed a carotid artery atherosclerotic plaque model and administered consecutive 14-day metformin (200 mg·kg−1·d−1) treatment by intragastric gavage. Immunofluorescence staining of the right carotid common artery and serum MMP activity assay results showed that metformin treatment decreased local plaque MMP-9 protein level and circulating MMP-9 activity, respectively. Histochemical staining revealed that after metformin treatment, the collagen content in plaque was significantly preserved, and the plaque vulnerability index decreased. These findings suggested that metformin improved atherosclerotic plaque stability by directly binding to MMP-9 and driving its degradation.

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“…As a first-line biguanide class of oral antidiabetic drugs, MF has been shown to have anti-inflammatory, anti-cancer, cardioprotective, hepatoprotective, and antioxidant effects. Currently, it is being investigated as a drug directly acting on the CNS [ 43 , 65 , 66 , 67 , 68 ]. MF can easily cross the BBB, accumulate in the mitochondria, and activate the NRF2 antioxidant pathway, which eventually enhances the expression of antioxidant enzyme genes such as SOD, Glutathione peroxidase 1 (Gpx1), and catalase (CAT) [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

Antidiabetic Drugs Can Reduce the Harmful Impact of Chronic Smoking on Post-Traumatic Brain Injuries

Sivandzade

Alqahtani

Dhaibar

et al. 2023

IJMS

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Traumatic Brain Injury (TBI) is a primary cause of cerebrovascular and neurological disorders worldwide. The current scientific researchers believe that premorbid conditions such as tobacco smoking (TS) can exacerbate post-TBI brain injury and negatively affect recovery. This is related to vascular endothelial dysfunction resulting from the exposure to TS-released reactive oxygen species (ROS), nicotine, and oxidative stress (OS) stimuli impacting the blood–brain barrier (BBB) endothelium. Interestingly, these pathogenic modulators of BBB impairment are similar to those associated with hyperglycemia. Antidiabetic drugs such as metformin (MF) and rosiglitazone (RSG) were shown to prevent/reduce BBB damage promoted by chronic TS exposure. Thus, using in vivo approaches, we evaluated the effectiveness of post-TBI treatment with MF or RSG to reduce the TS-enhancement of BBB damage and brain injury after TBI. For this purpose, we employed an in vivo weight-drop TBI model using male C57BL/6J mice chronically exposed to TS with and without post-traumatic treatment with MF or RSG. Our results revealed that these antidiabetic drugs counteracted TS-promoted downregulation of nuclear factor erythroid 2-related factor 2 (NRF2) expression and concomitantly dampened TS-enhanced OS, inflammation, and loss of BBB integrity following TBI. In conclusion, our findings suggest that MF and RSG could reduce the harmful impact of chronic smoking on post-traumatic brain injuries.

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Metformin reduces oxandrolone- induced depression-like behavior in rats via modulating the expression of IL-1β, IL-6, IL-10 and TNF-α

Cited by 21 publications

References 59 publications

Linagliptin in Combination With Metformin Ameliorates Diabetic Osteoporosis Through Modulating BMP-2 and Sclerostin in the High-Fat Diet Fed C57BL/6 Mice

Linagliptin in Combination With Metformin Ameliorates Diabetic Osteoporosis Through Modulating BMP-2 and Sclerostin in the High-Fat Diet Fed C57BL/6 Mice

Metformin Directly Binds to MMP-9 to Improve Plaque Stability

Antidiabetic Drugs Can Reduce the Harmful Impact of Chronic Smoking on Post-Traumatic Brain Injuries

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