Inhibition of Synaptic Glutamate Exocytosis and Prevention of Glutamate Neurotoxicity by Eupatilin from Artemisia argyi in the Rat Cortex.

The inhibition of synaptic glutamate release to maintain glutamate homeostasis contributes to the alleviation of neuronal cell injury, and accumulating evidence suggests that natural products can repress glutamate levels and associated excitotoxicity. In this study, we investigated whether eupatilin, a constituent of Artemisia argyi, affected glutamate release in rat cortical nerve terminals (synaptosomes). Additionally, we evaluated the effect of eupatilin in an animal model of kainic acid (KA) excitotoxicity, particularly on the levels of glutamate and N-methyl-D-aspartate (NMDA) receptor subunits (GluN2A and GluN2B). We found that eupatilin decreased depolarization-evoked glutamate release from rat cortical synaptosomes and that this effect was accompanied by a reduction in cytosolic Ca2+ elevation, inhibition of P/Q-type Ca2+ channels, decreased synapsin I Ca2+-dependent phosphorylation and no detectable effect on the membrane potential. In a KA-induced glutamate excitotoxicity rat model, the administration of eupatilin before KA administration prevented neuronal cell degeneration, glutamate elevation, glutamate-generating enzyme glutaminase increase, excitatory amino acid transporter (EAAT) decrease, GluN2A protein decrease and GluN2B protein increase in the rat cortex. Taken together, the results suggest that eupatilin depresses glutamate exocytosis from cerebrocortical synaptosomes by decreasing P/Q-type Ca2+ channels and synapsin I phosphorylation and alleviates glutamate excitotoxicity caused by KA by preventing glutamatergic alterations in the rat cortex. Thus, this study suggests that eupatilin can be considered a potential therapeutic agent in the treatment of brain impairment associated with glutamate excitotoxicity.

Acacetin inhibits glutamate release and prevents kainic acid-induced neurotoxicity in rats.

An excessive release of glutamate is considered to be a molecular mechanism associated with several neurological diseases that causes neuronal damage. Therefore, searching for compounds that reduce glutamate neurotoxicity is necessary. In this study, the possibility that the natural flavone acacetin derived from the traditional Chinese medicine Clerodendrum inerme (L.) Gaertn is a neuroprotective agent was investigated. The effect of acacetin on endogenous glutamate release in rat hippocampal nerve terminals (synaptosomes) was also investigated. The results indicated that acacetin inhibited depolarization-evoked glutamate release and cytosolic free Ca(2+) concentration ([Ca(2+)]C) in the hippocampal nerve terminals. However, acacetin did not alter synaptosomal membrane potential. Furthermore, the inhibitory effect of acacetin on evoked glutamate release was prevented by the Cav2.2 (N-type) and Cav2.1 (P/Q-type) channel blocker known as ω-conotoxin MVIIC. In a kainic acid (KA) rat model, an animal model used for excitotoxic neurodegeneration experiments, acacetin (10 or 50 mg/kg) was administrated intraperitoneally to the rats 30 min before the KA (15 mg/kg) intraperitoneal injection, and subsequently induced the attenuation of KA-induced neuronal cell death and microglia activation in the CA3 region of the hippocampus. The present study demonstrates that the natural compound, acacetin, inhibits glutamate release from hippocampal synaptosomes by attenuating voltage-dependent Ca(2+) entry and effectively prevents KA-induced in vivo excitotoxicity. Collectively, these data suggest that acacetin has the therapeutic potential for treating neurological diseases associated with excitotoxicity.

Tetrandrine ameliorated reperfusion injury of small bowel transplantation.

PURPOSE: In small bowel transplantation, the bowel graft is susceptible to reperfusion injury. This study investigated the effects of tetrandrine, a bisbenzylisoquinoline alkaloid, on the development of intestinal reperfusion injury in small bowel transplantation in pigs. MATERIALS AND METHODS: Pigs underwent small bowel transplantation and were treated with tetrandrine or a vehicle. Blood and small bowel specimens were harvested at 1, 3, and 24 hours after reperfusion. Histopathologic analysis of the small bowel was assessed for tissue damage. Serum levels of tumor necrosis factor-alpha, interleukin-1beta (IL-1beta), and IL-6 were measured by enzyme-linked immunosorbent assay. Reverse-transcriptase polymerase chain reaction analysis was performed to analyze the expression of proinflammatory cytokines, and immunohistochemical analysis was used to study the expression of intercellular adhesion molecule-1 (ICAM-1) in the small bowel. Myeloperoxidase staining detected neutrophil infiltration in the small bowel and the number of myeloperoxidase positively stained cells was counted. RESULTS: Pigs receiving small bowel transplantation had elevated serum proinflammatory cytokine levels. The transplanted small bowel showed mucosal damage, increased expression of proinflammatory cytokines and ICAM-1, and prominent neutrophil infiltration. Tetrandrine administration reduced mucosal damage, serum and tissue proinflammatory cytokine levels, ICAM-1 expression, and neutrophil accumulation in the transplanted small bowel. CONCLUSIONS: Tetrandrine reduced the reperfusion injury in porcine intestinal transplantation during the first 24 hours after the procedure.

Local infusion of bupivacaine combined with intravenous patient-controlled analgesia provides better pain relief than intravenous patient-controlled analgesia alone in patients undergoing minimally invasive cardiac surgery.

OBJECTIVE: This prospective randomized double-blind study examined the effect of local wound infusion of anesthetics on pain control in the thoracotomy wound of patients undergoing minimally invasive cardiac surgery. METHODS: Patients who underwent coronary artery bypass grafting or cardiac valvular procedures via a minimally invasive thoracotomy were studied. Patients were enrolled and randomly allocated to two groups with different modalities of postoperative analgesia. The thoracotomy wound infusion group received 0.15% bupivacaine infused continuously at 2 mL/h through a catheter embedded in the wound, as well as intravenous patient-controlled analgesia. The control group had patient-controlled analgesia alone with a sham thoracotomy wound infusion of normal saline. Verbal analog pain scores (0-10 points) and recovery profiles were investigated. RESULTS: There were 19 patients in each group for complete data analysis. On the first day after the operation, infusion of local anesthetics significantly reduced the verbal analog pain scores both at rest and during motion (thoracotomy wound infusion vs control). The improved pain relief with thoracotomy wound infusion persisted at day 3 and even at 3 months after the operation. No difference was noted about time to extubation, length of intensive care unit stay, or hospital stay. CONCLUSION: In this controlled double-blind study, thoracotomy wound infusion and patient-controlled analgesia were superior to patient-controlled analgesia alone in reducing pain at 1, 3, and 90 days after minimally invasive cardiac surgery.