Long-term metformin therapy improves neurobehavioral functions and antioxidative activity after cerebral ischemia/reperfusion injury in rats

Fatemi, Iman; Saeed-Askari, Pooya; Hakimizadeh, Elham; Kaeidi, Ayat; Esmaeil-Moghaddam, Sogand; Pak-Hashemi, Mohammad; Allahtavakoli, Mohammad

doi:10.1016/j.brainresbull.2020.07.015

Cited by 9 publications

(7 citation statements)

References 43 publications

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“…Memory impairment is one of the most important clinical manifestations of aging and age‐related neurological disorders [29]. Previous experimental reports have revealed that memory impairment is observed in both natural and d ‐gal‐induced aging animals [28, 30]. It is well established that the overproduction of ROS in aged humans and other animals is mainly responsible for memory performance decline [31].…”

Section: Discussionmentioning

confidence: 99%

Gemfibrozil, a lipid‐lowering drug, reduces anxiety, enhances memory, and improves brain oxidative stress in d‐galactose‐induced aging mice

Hakimizadeh

Zamanian

Борисов

et al. 2022

Fundamemntal Clinical Pharma

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Gemfibrozil (GFZ) is a lipid‐lowering drug with several other effects, such as antioxidant and anti‐inflammatory activities. In the current study, chronic d‐galactose treatment (d‐gal, 150 mg/kg/day; i.p., 6 weeks) induced a model of accelerated aging in male mice and was used to study the behavioral, anti‐oxidative, and neuroprotective effects of GFZ (100 mg/kg/day; p.o.). Anxiety‐like behaviors were assessed using the elevated plus‐maze while working memory was measured by spontaneous alternation in a Y‐maze. Brain oxidative stress was determined by measuring malondialdehyde (MDA) levels, superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities. Neuropathological evaluation of the brain with hematoxylin–eosin and Masson's trichrome staining was also performed. The results demonstrated that the anxious‐like phenotype and the cognitive impairments observed in d‐gal‐treated mice could be prevented in those animals coadministered with GFZ. Besides, the decrease in SOD and GPx antioxidant enzymatic activities and increase of MDA levels were also prevented in the brains of d‐gal plus GFZ treated mice. Preliminary hematoxylin–eosin staining also suggested neuroprotective effects of GFZ. The results of Masson's trichrome staining showed no evidence of fibrosis in brain sections of different experimental groups. The current data provide novel insights into GFZ in the d‐galactose‐induced aging mouse model that open promising future research lines to determine inflammatory mediators and cell signaling underlying these effects.

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Section: Discussionmentioning

confidence: 99%

Gemfibrozil, a lipid‐lowering drug, reduces anxiety, enhances memory, and improves brain oxidative stress in d‐galactose‐induced aging mice

Hakimizadeh

Zamanian

Борисов

et al. 2022

Fundamemntal Clinical Pharma

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“…The working memory was measured using the Y-maze test [ 23 ]. The apparatus consisted of three identical arms (90 × 90 × 70 cm; A, B, C) positioned 120 apart and made of black Plexiglas.…”

Section: Methodsmentioning

confidence: 99%

Naringenin alleviates cognitive dysfunction in rats with cerebral ischemia/reperfusion injury through up-regulating hippocampal BDNF-TrkB signaling: involving suppression in neuroinflammation and oxidative stress

Zhu,

Gao

2023

NeuroReport

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Cognitive dysfunction is one of the common complications of cerebral ischemia-reperfusion (CI/R) injury after ischemic stroke. Neuroinflammation and oxidative stress are the core pathological mechanism of CI/R injury. The activation of brain derived neurotrophic factor (BDNF)-tyrosine receptor kinase B (TrkB) signaling antagonize cognitive dysfunction in a series of neuropathy. Naringenin (NAR) improves cognitive function in many diseases, but the role of NAR in CI/R injury-induced cognitive dysfunction remains unexplored. The study aimed to explore the potential protective effects of NAR in CI/R injury-induced cognitive dysfunction and underlying mechanism. The rats were exposed to transient middle cerebral artery occlusion (MCAO) and then treated with distilled water or NAR (50 or 100 mg/kg/day, p.o.) for 30 days. The Y-maze test, Novel object recognition test and Morris water maze test were performed to assess cognitive function. The levels of oxidative stress and inflammatory cytokines were measured by ELISA. The expressions of BDNF/TrkB signaling were detected by Western blot. NAR prevented cognitive impairment in MCAO-induced CI/R injury rats. Moreover, NAR inhibited oxidative stress (reduced levels of malondialdehyde and 4-hydroxynonenal, increased activities of superoxide dismutase and Glutathione peroxidase) and inflammatory cytokines (reduced levels of tumor necrosis factor-α, Interleukin-1β and Interleukin-6), up-regulated the expressions of BDNF and p-TrkB in hippocampus of MCAO-induced CI/R rats. NAR ameliorated cognitive dysfunction of CI/R rats via inhibiting oxidative stress, reducing inflammatory response, and up-regulating BDNF/TrkB signaling pathways in the hippocampus.

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“…Metformin (Met) is a dimethyl biguanide that is widely used to treat diabetes mellitus (DM) but has also demonstrated pleiotropic effects. It has been reported that Met improved anxiety-like and depressive-like behaviors in addition to antioxidative activity in rats with cerebral ischemia-induced injury [ 13 ]. Additionally, Met has been known to reverse dyslipidemia and non-alcoholic fatty liver diseases by thought-provoking several antioxidant pathways and inhibiting inflammatory gene expression [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Gallic acid and metformin co-administration reduce oxidative stress, apoptosis and inflammation via Fas/caspase-3 and NF-κB signaling pathways in thioacetamide-induced acute hepatic encephalopathy in rats

Mohamed

Hafez

2023

BMC Complement Med Ther

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Background Hepatic encephalopathy (HE) is a consequence of chronic or acute liver diseases. This study evaluates the combined effect of gallic acid (GA), and metformin (Met) on the liver and brain damage associated with HE. Methods Acute HE was induced by a single dose of thioacetamide (TAA) (300 mg/kg) as an I.P. injection. Treated groups received GA group (100 mg/kg/day, p.o), Met (200 mg/kg/day, p.o), or their combination for 25 consecutive days before TAA injection. Results The administration of TAA induced various biochemical and histopathological alterations. In contrast, treatment with GA either alone or combined with Met resulted in improved liver functions by the significant reduction in serum ALT, AST, and ALP activities, and ammonia levels. Inflammatory mediators; TNF-α, IL-6, and NFkβ levels were decreased by these treatments as well as apoptotic cascade via down-regulation of FAS and caspase-3 (CASP-3) expression in hepatic tissues. Furthermore, GA and Met either alone or combined protected the liver and brain tissues from damage by increased glutathione concentration while decreasing malondialdehyde. In addition, it was accompanied by the improvement of the brain neurotransmitter profile via the restoration of norepinephrine, dopamine, and serotonin levels. Based on our data, this is the first study to report a novel combined hepatoprotective and cognitive enhancing effect of GA and Met against TAA-induced acute liver and brain injury. Conclusion GA and Met combination resulted in a prominent improvement in HE complications, relative to monotherapy. Both agents potentiated the antioxidant, anti-inflammatory, and anti-apoptotic effects of each other.

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Long-term metformin therapy improves neurobehavioral functions and antioxidative activity after cerebral ischemia/reperfusion injury in rats

Cited by 9 publications

References 43 publications

Gemfibrozil, a lipid‐lowering drug, reduces anxiety, enhances memory, and improves brain oxidative stress in d‐galactose‐induced aging mice

Gemfibrozil, a lipid‐lowering drug, reduces anxiety, enhances memory, and improves brain oxidative stress in d‐galactose‐induced aging mice

Naringenin alleviates cognitive dysfunction in rats with cerebral ischemia/reperfusion injury through up-regulating hippocampal BDNF-TrkB signaling: involving suppression in neuroinflammation and oxidative stress

Gallic acid and metformin co-administration reduce oxidative stress, apoptosis and inflammation via Fas/caspase-3 and NF-κB signaling pathways in thioacetamide-induced acute hepatic encephalopathy in rats

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