Impaired learning and memory in male mice induced by sodium arsenite was associated with MMP-2/MMP-9-mediated blood-brain barrier disruption and neuronal apoptosis

Abstract

Arsenic is a widespread environmental contaminant known to accumulate in the brain, leading to cognitive impairment. However, the exact mechanisms by which arsenic causes cognitive deficits remain unclear. The present study aims to discover whether the destruction of the blood-brain barrier (BBB) mediated by matrix metalloproteinases 2 and matrix metalloproteinases 9 (MMP-2 and MMP-9) and subsequent neuronal apoptosis are involved in arsenic-induced cognitive impairment. Ninety male mice were given 0, 25, and 50 mg/L NaAsO2 in drinking water and 30 mg/kg doxycycline hyclate (DOX, an inhibitor of MMPs) gavage for 12 weeks to observe the alterations in learning and memory of mice, the morphology of hippocampal neurons, as well as the BBB permeability and ultrastructure, the localization and expression of tight junction proteins, MMP-2, and MMP-9. Our findings indicated that arsenic exposure induced learning and memory impairment in mice, accompanied by neuronal loss and apoptosis. Furthermore, arsenic exposure increased hematogenous IgG leakage into the brain, disrupted the tight junctions, reduced the expression of Claudin5, Occludin, and ZO1 in the endothelial cells, and increased the expression of MMP-2 and MMP-9 in the endothelial cells and astrocytes. Finally, DOX intervention preserved BBB integrity, alleviated hippocampal neuronal apoptosis, and improved cognitive impairment in mice caused by arsenic exposure. Our research demonstrates that cognitive disfunction in mice induced by arsenic exposure is associated with MMP-2 and MMP-9-mediated BBB destruction and neuronal apoptosis. The current investigation provides new insights into mechanisms of arsenic neurotoxicity and suggests that MMP-2 and MMP-9 may serve as potential therapeutic targets for treating arsenic-induced cognitive dysfunction in the future.