Metformin Mitigates Trimethyltin-Induced Cognition Impairment and Hippocampal Neurodegeneration

Cell Mol Neurobiol. 2024 Oct 23;44(1):70. doi: 10.1007/s10571-024-01502-4.

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.

MeSH terms

  • Animals
  • Cognitive Dysfunction* / drug therapy
  • Cognitive Dysfunction* / metabolism
  • Cognitive Dysfunction* / pathology
  • Hippocampus* / drug effects
  • Hippocampus* / metabolism
  • Hippocampus* / pathology
  • Male
  • Maze Learning / drug effects
  • Metformin* / pharmacology
  • Metformin* / therapeutic use
  • Nerve Degeneration / drug therapy
  • Nerve Degeneration / pathology
  • Neurodegenerative Diseases / drug therapy
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use
  • Oxidative Stress / drug effects
  • Trimethyltin Compounds* / toxicity

Substances

  • Metformin
  • trimethyltin
  • Trimethyltin Compounds
  • Neuroprotective Agents

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