Inhibition of vascular adhesion protein 1 protects dopamine neurons from the effects of acute inflammation and restores habit learning in the striatum

Abstract

Background Changes in dopaminergic neural function can be induced by an acute inflammatory state that, by altering the integrity of the neurovasculature, induces neuronal stress, cell death and causes functional deficits. Effectively blocking these effects of inflammation could, therefore, reduce both neuronal and functional decline. To test this hypothesis, we inhibited vascular adhesion protein 1 (VAP-1), a membrane-bound protein expressed on the endothelial cell surface, that mediates leukocyte extravasation and induces oxidative stress. Method We induced dopaminergic neuronal loss by infusing lipopolysaccharide (LPS) directly into the substantia nigra (SN) in rats and administered the VAP-1 inhibitor, PXS-4681A, daily. Results LPS produced: an acute inflammatory response, the loss of dopaminergic neurons in the SN, reduced the dopaminergic projection to SN target regions, particularly the dorsolateral striatum (DLS), and a deficit in habit learning, a key function of the DLS. In an attempt to protect SN neurons from this inflammatory response we found that VAP-1 inhibition not only reduced neutrophil infiltration in the SN and striatum, but also reduced the associated striatal microglia and astrocyte response. We found VAP-1 inhibition protected dopamine neurons in the SN, their projections to the striatum and promoted the functional recovery of habit learning. Thus, we reversed the loss of habitual actions, a function usually dependent on dopamine release in DLS and sensitive to striatal dysfunction. Conclusions We establish, therefore, that VAP-1 inhibition has an anti-inflammatory profile that may be beneficial in the treatment of dopamine neuron dysfunction caused by an acute inflammatory state in the brain.

Cognitive effects of thalamostriatal degeneration are ameliorated by normalizing striatal cholinergic activity

“…We then investigated the influence of neuroinflammation in the Pf, induced by the infusion of LPS, on AO encoding. We found that LPS caused considerable changes in Pf and degeneration of the thalamostriatal pathway, similar to that we found in the case of dopamine neurons when infused into the substantia nigra (47). However, it did not affect initial AO encoding and only abolished the ability of rats to encode AO associations after AO associations changed during outcome identity reversal, as we found previously after NMDA lesions of the Pf (6,7).…”

Cognitive effects of thalamostriatal degeneration are ameliorated by normalizing striatal cholinergic activity

“…We then investigated the influence of neuroinflammation in the Pf, induced by the infusion of LPS, on AO encoding. We found that LPS caused considerable changes in Pf and degeneration of the thalamostriatal pathway, similar to that we found in the case of dopamine neurons when infused into the substantia nigra (46). However, it did not affect initial AO encoding and only abolished the ability of rats to encode AO associations after AO associations changed during outcome identity reversal, as we found previously after NMDA lesions of the Pf (4,5).…”

Engineered macrophage-biomimetic versatile nanoantidotes for inflammation-targeted therapy against Alzheimer's disease by neurotoxin neutralization and immune recognition suppression

“…It has been reported that stereotactic injection of LPS into the brain can induce microglial activation, the release of a variety of pro-inflammatory mediators, and cognition dysfunction, which has become the common approach for modeling neuroinflammation in vivo [ 49 , 50 ]. To further verify the inflammation-tropism efficiency in AD characteristic lesions, an in vivo local inflammation model was established by stereotactic injection of LPS into the right hippocampus of C57BL/6J mice, followed by intranasal administration of DiL-labeled OT-Lipo@M and OT-Lipo, respectively ( Fig.…”