OBJECTIVETo investigate the features of glutamate activity in the limbic system and the effects of glutamate on the activation of the hypothalamus-pituitary-adrenal (HPA) axis throughout both acute cerebral ischemia and reperfusion.

METHODSThe changes in glutamate content in the nervous cell gap, in corticotrophin releasing hormone (CHR) mRNA expression level in brain tissue, and in adrenocorticotropic hormone in blood plasma at different time-points after middle cerebral artery occlusion (MCAO) in rats were determined respectively with high-performance liquid chomatography (HPLC) and in situ hybridization.

RESULTSGlutamate content in the hippocampus and the hypothalamus increased rapidly at ischemia 15 minutes, and reached peak value (the averages were 21.05 mg/g +/- 2.88 mg/g and 14.20 mg/g +/- 2.58 mg/g, respectively) at 1 hour after middle cerebral artery occlusion. During recirculation, it returned rapidly to the baseline level. At 24 hours after reperfusion, it went up once more, and remained at a relative high level until 48 hours after reperfusion, and then declined gradually. CRH mRNA expression levels in the temporal cortex, hippocampus and hypothalamus were enhanced markedly at 1 hour ischemia and were maintained until 96 hours after reperfusion. At the same time, adrenocorticotropic hormone level in plasma was relatively increased. In the peak stage of reperfusion injury, there was a significantly positive correlation (n = 15, r = 0.566, P < 0.05) of the glutamate contents in the hypothalamus with the number of cells positive for CRH mRNA expression level in the hypothalamus.

CONCLUSIONIt is probable that the CRH system in the central nervous system is mainly distributed in the limbic system, and glutamate might be one of the trigger factors to induce excessive stress response in the HPA axis.

Animals ; Glutamic Acid ; analysis ; Hypothalamo-Hypophyseal System ; chemistry ; Infarction, Middle Cerebral Artery ; metabolism ; physiopathology ; Limbic System ; chemistry ; Male ; Pituitary-Adrenal System ; chemistry ; Rats ; Rats, Wistar ; Reperfusion Injury ; metabolism ; physiopathology

Objective To mine adverse drug event(ADE)signals of doxycycline using the U.S.Food and Drug Administration Adverse Event Reporting System(FAERS)database,and provide scientific evidence for clinical medication safety.Methods The data from the FAERS database between the first quarter of 2004 and the first quarter of 2024 were extracted.After data cleaning and standardization,ADE reports with doxycycline as the main suspected drug were screened.The system organ class(SOC)of ADE was performed using MedDRA,and the reporting odds ratio method and Medicines and Healthcare products Regulatory Agency method were used to mine ADE signals.The information component method was also used to evaluate signal strength.Results A total of 43 126 ADE reports with doxycycline as the primary suspected drug were collected,involving 14 642 patients,with a higher proportion of female patients(57.32％).There were 555 related ADE signals involving 26 SOC,with the top 5 SOC being gastrointestinal disorders,skin and subcutaneous tissue disorders,injuries,poisonings,and procedural complications,psychiatric disorders,and infections and infestations.The top 5 ADE signals with the highest signal intensity were Hatch reaction,sclerosing cholangitis,esophageal ulcer,gastrointestinal mucosal necrosis,and gastrointestinal injury.Among the ADE signals with the strongest signal strength not listed in the package insert,the top five were sclerosing cholangitis,nephrogenic diabetes insipidus,minimal change glomerular nephritis,diabetes insipidus and Sixth cranial nerve paralysis.Conclusion In clinical practice,particular attention should be paid to the frequent ADEs caused by doxycycline,as well as those not yet documented in the package insert,which involve multiple SOC such as renal and urinary disorders,hepatobiliary diseases,blood and lymphatic system disorders,and endocrine disorders.Therefore,clinical pharmacists should play a key role in assisting clinicians to develop and implement prevention plans for ADEs,thereby improving the safety of doxycycline in clinical use.