Chronic
neuroinflammation has been considered to be involved in the progressive dopaminergic neurodegeneration in
Parkinson's disease (PD). However, the mechanisms remain unknown. Accumulating evidence indicated a key role of the blood-brain barrier (BBB) dysfunction in
neurological disorders. This study is designed to elucidate whether chronic
neuroinflammation damages dopaminergic neurons through BBB dysfunction by using a
rotenone-induced mouse PD model. Results showed that
rotenone dose-dependently induced nigral dopaminergic neurodegeneration, which was associated with increased
Evans blue content and
fibrinogen accumulation as well as reduced expressions of zonula occludens-1 (ZO-1),
claudin-5 and
occludin, three
tight junction proteins for maintaining BBB permeability, in mice, indicating BBB disruption.
Rotenone also induced nigral microglial activation. Depletion of microglia or inhibition of microglial activation by
PLX3397 or
minocycline, respectively, greatly attenuated BBB dysfunction in
rotenone-lesioned mice. Mechanistic inquiry revealed that microglia-mediated activation of matrix metalloproteinases-2 and 9 (
MMP-2/-9) contributed to
rotenone-induced BBB disruption and dopaminergic neurodegeneration.
Rotenone-induced activation of
MMP-2/-9 was significantly attenuated by microglial depletion and inactivation. Furthermore, inhibition of
MMP-2/-9 by a wide-range inhibitor,
SB-3CT, abrogated elevation of BBB permeability and simultaneously increased tight junctions expression. Finally, we found that microglial depletion and inactivation as well as inhibition of
MMP-2/-9 significantly ameliorated
rotenone-elicited nigrostriatal dopaminergic neurodegeneration and motor dysfunction in mice. Altogether, our findings suggested that microglial
MMP-2/-9 activation-mediated BBB dysfunction contributed to dopaminergic neurodegeneration in
rotenone-induced mouse PD model, providing a novel view for the mechanisms of
Parkinsonism.