Improved synthesis and in vitro/in vivo activities of natural product-inspired, artificial glutamate analogs

Here, we report our second-generation synthesis of 12 artificial glutamate analogs, starting from heterotricycle intermediates 3a-3d, readily prepared in three steps including tandem Ugi/Diels-Alder reactions. The new synthesis employs imidate intermediates for the deoxygenation of pyrrolidones (10a-10d to 6a-6d), and each advanced intermediate 6a-6d was diversified into three glutamate analogs (1a-1d, 5a-5d, 7a-7d) in 1-2 steps. In vitro electrophysiological assays revealed that the new piperidine-type analog 7c alters neuronal function with lower potency than 1a. Conversely, intracranial injection of 7c into mice produced a greater degree of hypoactivity than 1a. Our recent investigation has revealed that this series of compounds antagonizes AMPA-type glutamate receptor-mediated currents in a subtype selective manner. The more efficient syntheses of this novel set of neuroactive molecules will facilitate their pharmacological characterization

Effect of cardiac rehabilitation on the renal function in chronic kidney disease - Analysis using serum cystatin-C based glomerular filtration rate

Background: Whether an individually determined appropriate level of cardiac rehabilitation (CR) has a favorable effect on the renal function still remains unclarified. The aim of this study was to confirm the effect of CR on the estimated glomerular filtration rate (eGFR) using cystatin C, which is known to be unaffected by physical exercise. Methods: The study population was comprised of 86 patients (61 males; average age 74 y/o) with a lower-moderate level of chronic kidney disease (CKD) who was admitted to our hospital for treatment of cardiovascular disease (CVD) and who participated in our 3-month CR program. The exercise capacity was assessed by cardiopulmonary exercise testing (CPX) and the eGFR was measured by a formula based on the serum cystatin C concentration (eGFRcys) in each patient both at the beginning and end of the CR. Results: In the CVD patients with CKD, both the peak oxygen uptake (VO2) and peak work rate (WR) improved significantly after CR (15.0 ± 3 to 15.8 ± 3 ml/min/kg, p = 0.002. 65.5 ± 21 to 70.2 ± 25 W, p = 0.001). Regarding the renal function, the eGFRcys improved (45.2 ± 11 to 47.3 ± 13 ml/min/1.73 m2, p = 0.023), however, the eGFR assessed by the serum creatinine (eGFRcr) did not improve after CR (45.1 ± 12 to 44.9 ± 13 ml/min/1.73 m2, p = 0.834). Conclusions: In CVD patients, a novel CR program significantly improved the exercise capacity. Further, CR was shown to have a favorable effect on the renal function when it was estimated by the eGFRcys. Keywords: Cardiac rehabilitation, Chronic kidney disease, Cardiovascular disease, Cystatin C, Estimated glomerular filtration rate, Exercise capacit

Nerve growth factor activity detected in equine peripheral blood of horses with fever after truck transportation

application/pdfWe examined nerve growth factor (NGF) activity in sera obtained from 5 Anglo-Arab and 6 Thoroughbred horses after long-distance truck transportation. NGF activity was evaluated by neurite outgrowth from rat pheochromocytoma cells that respond to NGF. Five of 11 horses had mild or severe fever after the truck shipping; significant NGF activity was detected in serum samples collected from 4 of the fevered horses. The addition of polyclonal antibodies to murine 2.5S NGF completely abrogated the neurotrophic activity detected in the samples. These results suggested a possible role of NGF in the pathogenesis of equine shipping fever associated with continuous stress by truck transportation