Metformin ameliorates sepsis-induced brain injury by inhibiting apoptosis, oxidative stress and neuroinflammation via the PI3K/Akt signaling pathway

Abstract

Sepsis-induced brain injuries increase mortality, morbidity, cognitive impairment and lack of effective therapeutic treatment. Previous studies have suggested that metformin provides neuroprotective effects against ischemia, brain trauma and other brain damage, but whether metformin protects a septic brain remains unknown. Thus, the aim of this study is to investigate the possible effects and the mechanism of metformin against septic brain damage using the cecal ligation and puncture (CLP) model. Mice were randomly divided into five groups: the Sham group, CLP group, CLP+ Met group, CLP+ vehicle group and CLP+ Met+ LY group. The survival percentage and brain water content were examined, and the Morris water maze was conducted to determine the protective effect of metformin. Neuronal apoptosis in the cerebral cortex, striatum and hippocampus was examined using TUNEL assay and immunohistochemistry, and western blot was applied to measure the expression of p-Akt. The results indicate that metformin can increase survival percentage, decrease brain edema, preserve the blood-brain barrier (BBB) and improve cognitive function. Metformin also reduced the neuronal apoptosis induced by sepsis and increased the phosphorylation of Akt. However, the protective effect of metformin can be reversed by LY294002, a PI3K inhibitor. In summary, our results demonstrate that metformin can exert a neuroprotective effect by activating the PI3K/Akt signaling pathway.

Metformin and its anti-inflammatory and anti-oxidative effects; new concepts

“…Likewise, in another research, it was revealed that metformin could reduce the concentration of inflammatory marker YKL-40 (33). Metformin also reduces the production of sepsis inflammatory cytokines, produced by neutrophils and monocytes, including IL-6, IL-1β, and TNF-α (34). In an investigation on obese children aged 6 to 12 years, it was found that metformin reduced the level of inflammatory factors such as TNF-α, IL-8 and insulin resistance (35).…”

“…Investigations have indicated that metformin leads to AKT phosphorylation by phosphatidylinositol-3-kinase (PI3K) activation, which this process is involved in maintaining mitochondrial integrity and increasing the ability to cope with damage induced by inflammation and oxidative stress. By inducing the production and increasing the activity of the antioxidant system, such as SOD, metformin cleans the ROS from brain tissue (34,66,67). During the brain ischemia, ROS production increases in tissue.…”

Prevention and treatment of brain damage in streptozotocin induced diabetic rats with Metformin, Nigella sativa, Zingiber officinale, and Punica granatum

“…Treatment with different substances containing antioxidants prevented the harmful effects of diabetes mellitus on neurological tissues. In the previous studies [38][39][40] , it has been found that metformin prevents the brain damage by reducing oxidative stress. The results of our study are in line with these studies, and significant prevention of the neuronal tissue damage was found in all areas of the brain of the animals.…”

Sepsis therapies: learning from 30 years of failure of translational research to propose new leads

“…Minimization or avoidance of iatrogenic factors related to treatment (e.g., prolonged use of benzodiazepine sedation, and adequate pain treatment) and non‐pharmacological modalities (e.g., physiological light cycle, cognitive stimulation, and early mobilization) may prove useful (Souza‐Dantas et al , ). Existing drugs such as metformin (Tang et al , ) and minocycline (Adembri et al , ) show brain protective effects in experimental sepsis. The natural antioxidant berberine improved survival in a rat CLP model but also motor and cognitive functions (Shi et al , ).…”