Antiplatelet effect by p-cresol, a uremic and environmental toxicant, is related to inhibition of reactive oxygen species, ERK/p38 signaling and thromboxane A2 production.
ABSTRACT P-cresol is a well-known uremic toxin and environmental toxicant that may affect platelet functions. In this study, p-cresol (1-5 μM) inhibited the arachidonic acid (AA)-induced platelet aggregation, with 47% and 82% of inhibition at concentrations of 2 and 5 μM, respectively. Under similar experimental condition, p-cresol showed little effect on the U46619-induced platelet aggregation. p-cresol (<500 μM) revealed no discernable cytotoxicity to platelets as analyzed by quantification of lactate dehydrogenase release. Antiplatelet effect of p-cresol was related to inhibition of thromboxane A(2) (TXA(2)) and prostaglandin D(2) (PGD(2)) formation. P-cresol (2-100 μM) partly inhibited the AA-induced reactive oxygen species (ROS) production as well as the extracellular signal-regulated kinase (ERK1/2) and p38 phosphorylation in platelets. P-cresol further inhibited the AA-induced aggregation of rabbit platelet-rich plasma (PRP) with an IC50 of 2 μM and aggregation of human PRP (IC50 = 13.6 μM). Intravenous administration of p-cresol (250-1000 nmole) into mice effectively suppressed the ex vivo platelet aggregation, whereas showed little effect on the value of RBC, hemoglobin (HGB), hematocrit, MCV, MCH, MCHC, platelets and lymphocyte counts. These results indicate that in acute p-cresol-poisoning and long-term exposure to cresol as in severe uremic patients, p-cresol may potentially inhibit blood clot formation and lead to hemorrhagic disorders via inhibition of platelet aggregation, ROS production, ERK/p38 activation and TXA(2) production.
- Journal of Neurophysiology 04/1964; 27:152-71. · 3.30 Impact Factor
- The Journal of Comparative Neurology 05/1981; 197(4):579-603. · 3.66 Impact Factor
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ABSTRACT: The significance of oscillations that characterize the subthalamic nucleus in Parkinson's disease is still under debate. Here, we analysed the spectral and spatial characteristics of 314 microelectrode trajectories from 128 patients undergoing subthalamic nucleus deep brain stimulation surgery for Parkinson's disease. We correlated the subthalamic nucleus pathophysiology with the outcome of surgery, as evaluated by the third section of the Unified Parkinson's Disease Rating Scale (motor score), which was subdivided into tremor, rigidity, limb-bradykinesia and axial-bradykinesia subscores. beta-oscillatory activity (13-30 Hz) comprised a continuous stretch within the subthalamic nucleus, and was limited to a distinctly-bounded dorsolateral oscillatory region. Although less consistent and more sporadic, low-frequency (3-7 Hz) power was also increased in the dorsolateral oscillatory region. In contrast, the more ventral subthalamic nucleus was characterized by consistently reduced beta and increased gamma (30-100 Hz) activity. Neuronal responses to passive arm movement (analysed by their alignment to goniometer tracing of the joints' angular displacement) were significantly more common in the dorsolateral oscillatory region than the ventral subthalamic nucleus region (62 versus 25% of sites tested respectively, P<0.01). The length of the dorsolateral oscillatory region recorded in the macroelectrode-implanted trajectory predicted a favourable response to subthalamic nucleus deep brain stimulation (R=0.67, P<0.0001). This correlation was also evident for improvement in the specific symptom subscores of rigidity, limb-bradykinesia and axial-bradykinesia (P<0.05). Similarly, increased subthalamic nucleus beta power was associated with postoperative improvement. In contrast, the preoperative response to levodopa did not correlate with dorsolateral oscillatory region length (P=0.33), however, it did tend to be associated with increased beta (and decreased low frequency) subthalamic nucleus power. Finally, the active macroelectrode contact, independently selected by optimal clinical outcome, coincided with the dorsolateral oscillatory region centre. On average, the location of the active contact was not significantly different from the dorsolateral oscillatory region centre (P=0.10), but was significantly different from the subthalamic nucleus centre (P<0.0001). We conclude that the spatial extent of the dorsolateral oscillatory region, which overlaps the motor territories of the subthalamic nucleus, predicts the outcome of subthalamic nucleus deep brain stimulation. Thus the frequency and spatial characteristics of the subthalamic nucleus trajectory may be used for deep brain stimulation outcome optimization.Brain 07/2010; 133(Pt 7):2007-21. · 9.92 Impact Factor