Metformin Attenuates Neurological Deficit after Intracerebral Hemorrhage by Inhibiting Apoptosis, Oxidative Stress and Neuroinflammation in Rats

Abstract

Intracerebral hemorrhage (ICH) can lead to brain damage and even death, and there is lack of effective therapeutic methods for treating ICH. Although recent studies have focused on the administration of metformin in treating stroke, there is no literature to support whether it can be used to treat ICH. Therefore, the aim of this study was to evaluate the possible effects of metformin on ICH and the underlying mechanisms of those effects. An ICH model was established in adult male Sprague-Dawley rats. Rats were randomly divided into three groups: sham group, ICH group, and ICH+metformin group. The neurobehavioral deficit scoring method was used to examine neurological function in rats. The levels of lipid peroxidation antioxidant enzyme and 8-iso-PGF2α were detected to evaluate oxidative stress. Survival of striatal neurons was examined by TUNEL staining, immunohistochemistry and HE staining. The levels of p-JNK, p-c-Jun and cleaved caspase-3 in the striatum were measured by western blotting. The results demonstrated that metformin protected rats from neurological deficits induced by ICH. Moreover, metformin reduced oxidative stress and preserved the survival of striatal neurons under ICH conditions. Furthermore, metformin downregulated the levels of apoptotic factors (p-JNK3, p-c-Jun and cleaved caspase-3) as well as pro-inflammatory cytokines (IL-1β, IL-4 and IL-6 and TNF-α). Collectively, we speculate that metformin may be a potential clinical treatment for ICH patients.

The MC4 receptor agonist RO27‐3225 inhibits NLRP1‐dependent neuronal pyroptosis via the ASK1/JNK/p38 MAPK pathway in a mouse model of intracerebral haemorrhage

“…The apoptosis signalling‐regulating kinase 1 (ASK1) is known as a MAP3K that activates the JNK/p38 MAPK signalling pathway (Barros‐Minones et al, ; Tobiume et al, ). Previous studies have shown that the JNK/p38 MAPK signalling pathway was activated following ICH, leading to the release of pro‐inflammatory mediators and neuronal cell death (Ni et al, ; Qi et al, ). Interestingly, the JNK/p38 MAPK signalling pathway promoted NLRP1 inflammasome activation in neurons following ischaemic stroke in vivo and in vitro (Fann et al, , ).…”

Activation of melanocortin receptor 4 with RO27-3225 attenuates neuroinflammation through AMPK/JNK/p38 MAPK pathway after intracerebral hemorrhage in mice

“…c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) that belong to the MAPK family have already been widely investigated for their roles in response to various stress stimuli [ 19 ]. Several studies have demonstrated that JNK and p38 MAPK signaling pathways were activated after ICH, leading to the upregulation of proinflammatory mediators including TNF-α, IL-6, and IL-1β [ 20 , 21 ]. A previous study indicated that activation of MC4R could significantly decrease the expression levels of JNK and p38 MAPK [ 18 ].…”

Metformin Improves Neurologic Outcome Via AMP‐Activated Protein Kinase–Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation

“…Recent animal studies have further demonstrated that long‐term metformin pretreatment can obviously alleviate the damage of ischemic stroke to brain tissue 12, 13, 14. In addition, metformin is also effective in treating global cerebral ischemia,15 intracerebral hemorrhage,16 epilepsy,17 Parkinson disease,18, 19 and Huntington disease 20. However, whether and how metformin treatment is effective in reducing brain injury after CA remain uninvestigated.…”