Neuroprotective effects of propofol on ER stress-mediated apoptosis in neuroblastoma SH-SY5Y cells.

Anesthetic treatment has been associated with widespread apoptotic neurodegeneration in the neonatal rodent brain. It has recently been suggested that propofol, a short-acting intravenous anesthetic agent, may have a potential as a neuroprotective agent. An apoptotic pathway mediated through endoplasmic reticulum (ER) stress has been attracting attention. ER stress is associated with accumulation of unfolded or misfolded proteins in ER, and ER stress-induced apoptosis is implicated in a wide range of diseases, including ischemia/reperfusion injury, neurodegeneration, and diabetes. We investigated whether thapsigargin-induced ER stress is prevented by propofol in human neuroblastoma SH-SY5Y cells. SH-SY5Y cells were pretreated with various concentrations of propofol (1-10 µM) for 3h before co-treatment with 0.5 µM thapsigargin and propofol for 20 h. Levels of ssDNA, specific evidence of apoptosis, and biomarkers of ER stress (mRNA expression of Chop and sXbp-1) were determined. We also assayed calpain and caspase-4 activities and intracellular Ca(2+) ([Ca(2+)]i) levels. Thapsigargin-induced increases in ssDNA levels, expressions of ER stress biomarkers, activities of caspase-4 and calpain, and level of [Ca(2+)]i were suppressed by co-incubation with propofol. Our data indicate the possibility that propofol inhibits the Ca(2+) release from ER at clinically employed dose levels. These results demonstrate that propofol suppresses the ER stress-induced apoptosis in this cell system, and may have the neuroprotective potency. It may also be a promising agent for preventing damage from cerebral ischemia or edema.

Virtual needle pain stimuli activates cortical representation of emotions in normal volunteers.

Psychological factors are known to play an extremely important role in the maintenance and development of chronic pain conditions. However, it is unclear how such factors relate to the central neural processing of nociceptive transmission in healthy individuals. To investigate this issue, the activation of the brain was studied in 30 healthy volunteers responding to virtual pain stimuli by fMRI. In the first series of the study (non-preconditioned study), 15 participants were shown a digital video demonstrating an injection needle puncturing the right palm. In the second series of the study (pre-conditioned study), same-task paradigms were used for another 15 participants. Prior to the fMRI session, real needle punctuate stimuli were applied to the right palm of participants for pre-conditioning. fMRI analysis revealed that bilateral activations in anterior insula (BA45), parietal operculum (S2: BA40), premotor area, medial globus pallidus, inferior occipital gyrus (BA18), left temporal association cortex, right fusiform gyrus, right parietal association cortex and cerebellum occurred due to the task in the preconditioned group. On the other hand, right parietal operculum (S2: BA40), premotor area, parietal association cortex, left inferior frontal gyrus and bilateral temporal association cortex were activated in the non-preconditioned group. In addition, activation of anterior insula, inferior frontal gyrus, precentral gyrus and cerebellum significantly increased in the preconditioned group compared with the non-preconditioned group. These results suggest that the virtual needle puncture task caused memory retrieval of unpleasant experiences which is possibly related to empathy for pain, resulting in the activation of specific brain areas.

Low-grade inflammation is a risk factor for clinical stroke events in addition to silent cerebral infarcts in Japanese older hypertensives: the Jichi Medical School ABPM Study, wave 1.

BACKGROUND AND PURPOSE: High-sensitivity C-reactive protein (hsCRP), a marker of inflammation, is associated with atherosclerosis, hypertensive target organ damage, and cardiovascular events. In the general Japanese population, the level of hsCRP is reported to be lower than that in Western countries, and the relationships among hsCRP, silent cerebral infarcts (SCIs), and clinical stroke events in older Japanese hypertensives remain unclear. METHODS: We conducted brain MRI and measured hsCRP at baseline in 514 older Japanese hypertensives (clinic blood pressure > or =140/90 mm Hg, age > or =50 years old) who were enrolled in the Jichi Medical School ABPM Study, wave 1. They were followed up for an average of 41 months (range: 1 to 68 months, 1751 person-years) and the incidence of subsequent clinical stroke events was evaluated. RESULTS: The subjects with SCIs at baseline (n=257) had a higher hsCRP level than those without SCIs (geometric mean hsCRP [SD range]; 0.19 [0.18 to 0.21] versus 0.14 [0.13 to 0.16] mg/L, P=0.007) after adjustment for confounding factors, and the OR for the presence of SCIs was increased with the quartile of hsCRP levels. In Cox regression analysis, the patients with above median hsCRP level (> or =0.21 mg/L) (hazard ratio [HR]: 2.50, 95% CI: 1.24 to 5.00, P=0.01) and those with SCIs (HR: 4.60, 95% CI: 1.91 to 11.03, P=0.001) at baseline had independently higher risks for clinical stroke events after adjustment for age, smoking status, antihypertensive medication use, and 24-hour systolic blood pressure level. Compared with the patients with below median hsCRP level without SCIs, those with above median hsCRP level and SCIs at baseline had a higher risk for clinical stroke events (HR: 7.32, 95% CI: 2.17 to 24.76, P=0.001), although those with below median hsCRP level and SCIs (HR: 2.46, 95% CI: 0.64 to 9.47, P=0.19) and those with above median hsCRP level without SCIs (HR: 1.11, 95% CI: 0.22 to 5.55, P=0.90) did not have significant risks. CONCLUSIONS: High-sensitivity C-reactive protein is a risk factor for clinical stroke events in addition to silent cerebral infarcts in Japanese older hypertensives, indicating that the risk for clinical stroke events increases with preexisting hypertensive target organ damage in the brain and additionally with ongoing low-grade inflammation.