Rotenone impairs learning and memory in mice through microglia-mediated blood brain barrier disruption and neuronal apoptosis

Chemosphere. 2021 Nov 22:132982. doi: 10.1016/j.chemosphere.2021.132982. Online ahead of print.ABSTRACTRotenone is a neurotoxic pesticide widely used in agriculture. Dopaminergic neuron has long been considered as the target of rotenone. We recently reported that rotenone exposure also resulted in hippocampal and cortical neurodegeneration and cognitive dysfunction in mice. However, the mechanisms remain unknown. Here, we elucidated whether blood brain barrier (BBB) disruption and subsequent neuronal apoptosis mediated by microglial activation were involved in rotenone-elicited cognitive impairments. Results showed that rotenone dose-dependently elevated evens blue extravasation, fibrinogen accumulation and reduced expressions of tight junction proteins in the hippocampus and cortex of mice. Interestingly, microglial depletion and inactivation by PLX3397 and minocycline, respectively, markedly attenuated rotenone-elicited increase of BBB permeability, indicating a critical role of microglia. Furthermore, microglial depletion and inactivation were shown to abrogate rotenone-induced activation of matrix metalloproteinases 2 and 9 (MMP-2/-9), two important factors to regulate tight junction degradation and BBB permeability, in mice. Moreover, SB-3CT, a widely used MMP-2/-9 inhibitor, increased BBB integrity and simultaneously elevated expressions of tight junction proteins in rotenone-intoxicated mice. Finally, we found that SB-3CT significantly mitigated rotenone-induced neuron...
Source: Chemosphere - Category: Chemistry Authors: Source Type: research