Dextromethorphan attenuates LPS-induced adhesion molecule expression in human endothelial cells.

OBJECTIVE: This study examines the effect of Dextromethorphan (d-3-methoxy-17-methylmorphinan; DXM), a commonly used cough-suppressing drug, on the expression of VCAM-1 and ICAM-1 in human umbilical vein endothelial cells (HUVECs) stimulated with lipopolysaccharide (LPS). METHODS: The effect of DXM on expression of cell adhesion molecules induced by LPS was evaluated by monocyte bindings in vitro and ex vivo and transmigration assays. The signaling pathways involved in the inflammation inhibitory effect of DXM were analyzed by Western blot and immunofluorescent stain. RESULTS: Pretreatment of HUVECs with DXM inhibited LPS-induced adhesion of THP-1 cells in vitro and ex vivo, and reduced transendothelial migration of these cells. Furthermore, treatment of HUVECs with DXM can significantly decrease LPS-induced expression of ICAM-1 and VCAM-1. DXM abrogated LPS-induced phosphorylation of ERK and Akt. The translocation of early growth response gene-1 (Egr-1), a downstream transcription factor involved in the mitogen-activated kinase (MEK)-ERK signaling pathway, was suppressed by DXM treatment. Furthermore, DXM inhibited LPS-induced IκBα degradation and nuclear translocation of p65. CONCLUSIONS: Dextromethorphan inhibits the adhesive capacity of HUVECs by reducing the LPS-induced ICAM-1 and VCAM-1 expression via the suppression of the ERK, Akt, and NF-κB signaling pathways. Thus, DXM is a potential anti-inflammatory therapeutic that may modulate atherogenesis.

The genesis and functional consequences of cortico-subthalamic beta augmentation and excessive subthalamic burst discharges after dopaminergic deprivation.

The cardinal electrophysiological signs in Parkinson's disease (PD) include augmented beta oscillations in the motor cortex-subthalamic nucleus (MC-STN) axis and excessive burst discharges in STN. We have shown that excessive STN burst discharges have a direct causal relation with the locomotor deficits in PD. To investigate the correlation between the two cardinal signs, we characterized the courses of development of the electrophysiological abnormalities in the hemiparkinsonian rat model. The loss of dopaminergic neurons develops fast, and is histologically completed within 4-7 days of the lesion. The increase in STN burst discharges is limited to the lesioned side, and follows a very similar course. In contrast, beta augmentation has a bilateral presentation, and requires 14-21 days for full development. Behaviorally, the gross locomotor deficits in open field test and limb akinesia in stepping test match the foregoing fast and slow time courses, respectively. A further look into the spike entrainment shows that the oscillations in local field potential (LFP) of the MC effectively entrain the multi-unit (MU) spikes of MC, STN and entopeduncular nucleus (EPN), a rat homolog of human globus pallidus interna (GPi), whereas the LFP of STN or EPN (GPi) cannot entrain the spikes in MC. We conclude that excessive STN burst discharges are a direct consequence, whereas beta augmentation is probably a secondary or adaptive changes in the cortico-subcortical re-entrant loops, to dopaminergic deprivation. Beta augmentation is therefore not so consistently present as excessive STN burst discharges, but could signal more delicate derangements at the level of cortical programming in PD.