Metformin Mitigates Trimethyltin-Induced Cognition Impairment and Hippocampal Neurodegeneration

Abstract

The neurotoxicant trimethyltin (TMT) triggers cognitive impairment and hippocampal neurodegeneration. TMT is a useful research tool for the study of Alzheimer's disease (AD) pathogenesis and treatment. Although the antidiabetic agent metformin has shown promising neuroprotective effects, however, its precise modes of action in neurodegenerative disorders need to be further elucidated. In this study, we investigated whether metformin can mitigate TMT cognition impairment and hippocampal neurodegeneration. To induce an AD-like phenotype, TMT was injected i.p. (8 mg/kg) and metformin was administered daily p.o. for 3 weeks at 200 mg/kg. Our results showed that metformin administration to the TMT group mitigated learning and memory impairment in Barnes maze, novel object recognition (NOR) task, and Y maze, attenuated hippocampal oxidative, inflammatory, and cell death/pyroptotic factors, and also reversed neurodegeneration-related proteins such as presenilin 1 and p-Tau. Hippocampal level of AMP-activated protein kinase (AMPK) as a key regulator of energy homeostasis was also improved following metformin treatment. Additionally, metformin reduced hippocampal acetylcholinesterase (AChE) activity, glial fibrillary acidic protein (GFAP)-positive reactivity, and prevented the loss of CA1 pyramidal neurons. This study showed that metformin mitigated TMT-induced neurodegeneration and this may pave the way to develop new therapeutics to combat against cognitive deficits under neurotoxic conditions.

Keywords: AMP-activated protein kinase; Alzheimer’s; Metformin; Neurodegeneration; Neuroprotection; Trimethyltin.

Fig. 1

Design of the study. Trimethyltin (TMT) was intraperitoneally given to generate model of cognitive dysfunction and neuronal degeneration. Metformin was orally given at 200 mg/kg for 3 weeks

Fig. 2

Data of behavioral tests comprising Y maze (pane A), novel object discrimination (pane B), and Barnes maze (panes C and D). Metformin mitigated TMT behavioral deficits in these tasks, as analyzed by two-way ANOVA and Tukey tests. (means ± SD, n = 8/group)

Fig. 3

Data of oxidative stress factors comprising MDA (pane A), catalase activity (pane B), and SOD activity (pane C). Metformin properly attenuated TMT oxidative burden and improved antioxidants, as analyzed by two-way ANOVA and Tukey tests. (means ± SD, n = 7/group)

Fig. 4

Data of inflammation-associated factors including TNF (pane A) and IL-10 (pane B) in addition to AD pathology markers consisting of presenilin 1 (pane C) and p-Tau (pane D), as analyzed by two-way ANOVA and Tukey tests. Metformin reversed TMT-induced changes regarding these factors. (means ± SD, n = 7/group)

Fig. 5

Data for hippocampal level of caspase 1 (pane A), caspase 3 (pane B), AMPK (pane C), and AChE activity (pane D), as analyzed by two-way ANOVA and Tukey tests. Metformin was capable to reverse TMT-induced changes regarding these factors. (means ± SD, n = 7/group)

Fig. 6

Density of CA1 Nissl-stained neurons (pane A) and immunoreactivity for GFAP as a marker of astrocytes (pane B) and related photomicrograph. Metformin at 200 mg/kg was able to attenuate CA1 neurodegeneration and astrogliosis. Dotted-border rectangle shows stratum radiatum area for assessment of GFAP immunoreactivity. Two-way ANOVA and Tukey tests. (means ± SD, n = 6/group)