Haloperidol Abrogates Matrix Metalloproteinase-9 Expression by Inhibition of NF-κB Activation in Stimulated Human Monocytic Cells

Abstract

Much evidence has indicated that matrix metalloproteinases (MMPs) participate in the progression of neuroinflammatory disorders. The present study was undertaken to investigate the inhibitory effect and mechanism of the antipsychotic haloperidol on MMP activation in the stimulated THP-1 monocytic cells. Haloperidol exerted a strong inhibition on tumor necrosis factor- (TNF-) α-induced MMP-9 gelatinolysis of THP-1 cells. A concentration-dependent inhibitory effect of haloperidol was observed in TNF-α-induced protein and mRNA expression of MMP-9. On the other hand, haloperidol slightly affected cell viability and tissue inhibition of metalloproteinase-1 levels. It significantly inhibited the degradation of inhibitor-κB-α (IκBα) in activated cells. Moreover, it suppressed activated nuclear factor-κB (NF-κB) detected by a mobility shift assay, NF-κB reporter gene, and chromatin immunoprecipitation analyses. Consistent with NF-κB inhibition, haloperidol exerted a strong inhibition of lipopolysaccharide- (LPS-) induced MMP-9 gelatinolysis but not of transforming growth factor-β1-induced MMP-2. In in vivo studies, administration of haloperidol significantly attenuated LPS-induced intracerebral MMP-9 activation of the brain homogenate and the in situ in C57BL/6 mice. In conclusion, the selective anti-MMP-9 activation of haloperidol could possibly involve the inhibition of the NF-κB signal pathway. Hence, it was found that haloperidol treatment may represent a bystander of anti-MMP actions for its conventional psychotherapy.

HDAC8 Inhibitor WK2-16 Therapeutically Targets Lipopolysaccharide-Induced Mouse Model of Neuroinflammation and Microglial Activation

“…C57BL/6 mice were processed for intrastriatal LPS injection as previously described [57]. LPS was dissolved in sterilized normal saline and 3 μL (equivalent to 4 μg LPS) was injected.…”

Proteome Analysis of PC12 Cells Reveals Alterations in Translation Regulation and Actin Signaling Induced by Clozapine

“…Metalloproteinases play an important role in schizophrenia and other neuropsychiatric disorders probable by abnormal synaptic plasticity and functional reorganization of excitatory synapses that are located on dendritic spines [ 41 ]. Moreover, metalloproteinases influence learning and memory processes and are linked to progression of neuroinflammatory disorders [ 42 ].…”

Activity of selected metalloproteinases in neurodegenerative diseases of the central nervous system as exemplified by dementia and schizophrenia

“…Despite the scarcity of data concerning the studied issue, it is worth noting that pharmacotherapy of neurodegenerative diseases of the central nervous system (typical neuroleptics medication, memantine) also has an impact on the expression of metalloproteinase genes and their inhibitors. A correlation has been found between the dose of haloperidol and expression of mRNA MMP-9 and TIMP-1, with no effect on MMP-2 within the range of monocytes [45]. It has been observed that the MMP-9 polymorphism and severity of traumatic events in childhood have an effect on the response to flupentixol treatment in the population of patients with the first episode of schizophrenia [46].…”