Effects of metformin in an experimental chronic unpredictable mild stress model

Abstract

Prolonged interaction with challenging life situations is a well-recognised risk factor for depression, anxiety, and cognitive decline, particularly among menopausal women. This research aimed to assess the effects of metformin (MF) on anxiety-like behavioural changes, cognitive impairment, brain neuroplasticity, and apoptosis induced by chronic unpredictable mild stress (CUMS) in menopausal rats. To achieve this, we conducted the open field test (OFT) to measure anxiety- like behaviours and locomotor activity, the elevated plus- maze (EPM) to assess anxiety-like behaviour, and the novel object recognition test (NORT) to evaluate recognition memory. Additionally, we measured the levels of BDNF, SIRT 1, synaptophysin, and caspase-9 by ELISA in the hippocampus, prefrontal cortex (PFC), and amygdala. Our experimental groups were categorised into five groups, with six rats in each group, as follows: Control, ovariectomized (OVX), OVX+CUMS, OVX+MF, and OVX+CUMS+MF. Four weeks after the OVX, the CUMS protocol was implemented, and MF treatment commenced following CUMS and continued for 14 days. Chronic administration of MF improved recognition memory and anxiety levels in rats subjected to CUMS, as assessed by the NORT, OFT, and EPM. MF increased brain-derived neurotrophic factor, synaptophysin, and sirtuin1, key markers of neuroplasticity in specific brain regions. We also found that MF treatment reduced pro-apoptotic caspase-9 levels. Histopathological analysis of the hippocampal DG and prefrontal cortex indicated neurodegenerative changes such as pyknotic nuclei, cytoplasmic sparseness, widespread vacuolization, and perivascular and pericellular oedema in the OVX and OVX+CUMS groups. However, these pathological features were significantly diminished in the MF groups, resulting in better preservation of neuronal integrity, fewer pyknotic cells, and reduced vacuolization. In conclusion, metformin appears to be a beneficial therapeutic agent that enhances neural plasticity, decreases apoptosis, and improves recognition memory and anxiety- like behaviours induced by OVX+CUMS

Keywords

• CUMS
• BDNF
• SIRT1
• synaptophysin
• caspase-9
• metformin
• brain
• rat

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