Microglial Activation Damages Dopaminergic Neurons through MMP-2/-9-Mediated Increase of Blood-Brain Barrier Permeability in a Parkinson’s Disease Mouse Model

Abstract

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.

The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment

“…Thanks to the ability to efficiently cross the BBB, minocycline is considered neuroprotective for a variety of neurological conditions, including PD [ 251 , 252 , 253 , 254 , 255 , 256 , 257 ]. This effect is mainly ascribable to the minocycline-dependent suppression of microglia activation, which has been reported by several in vivo studies [ 251 , 258 , 259 , 260 , 261 , 262 , 263 ]. In this respect, microglial inactivation by minocycline correlates with decreased IL-1β formation, as well as reduced NADPH-oxidase and inducible nitric oxide synthase (iNOS) activity, suggesting that both anti-inflammatory and antioxidant pathways are involved [ 262 , 264 ].…”

Role of Glial Cell-Derived Oxidative Stress in Blood-Brain Barrier Damage after Acute Ischemic Stroke

“…BBB disruption also plays an important role in the pathogenesis of PD, which is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra (SN) [45]. For example, the expression of TJPs decreased, along with increased vascular permeability and accumulation of oligomeric α-syn in activated astrocytes of mice brain [46]. In addition, astrocytic VEGFA has been shown to be an essential mediator in BBB disruption in PD [47].…”

Zinc Homeostasis: An Emerging Therapeutic Target for Neuroinflammation Related Diseases

“…Treatment with the Zn 2+ chelator clioquinol (CQ) significantly inhibited MMP-2 and MMP-9 activity in hippocampal neurons, indicating that Zn 2+ is critical for MMP activation [ 29 ]. Treatment of mice with minocycline, an inhibitor of microglial activation, inhibits rotenone-induced MMP-2 and MMP-9 activation, indicating that microglial activation is a key factor mediating MMP activation [ 30 ]. Zinc chloride (ZnCl 2 ) treatment enhanced the effect of LPS-induced microglia to release proinflammatory factors, but ROS scavenger inhibited the effect of ZnCl 2 , suggesting that Zn 2+ promoted microglial expression and release of proinflammatory factors by mediating ROS generation [ 31 ].…”