ABSTRACT
OBJECTIVE: This study was aimed at investigating whether sevoflurane inhalation induced cognitive impairment in rats with a possible mechanism involved in the event. METHODS: Thirty-two rats were randomly divided into four groups of normal saline (NS) + O2, NS + sevoflurane (sevo), amyloid-ß peptide (Aß) + O2, and Aß + sevo. The rats in the four groups received bilateral intrahippocampus injections of NS or Aß. The treated hippocampus was harvested after inhaling 30% O2 or 2.5% sevoflurane. Evaluation of cognitive function was performed by Morris water maze (MWZ) and an Aß 1-42 level was determined by ELISA. Protein and mRNA expressions were executed by immunohistochemical (IHC) staining, Western blotting, and qRT-PCR. RESULTS: Compared with the NS-treated group, sevoflurane only caused cognitive impairment and increased the level of Aß 1-42 of the brain in the Aß-treated group. Sevoflurane inhalation but not O2 significantly increased glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule (IBA)1 expression in Aß-treated hippocampus of rats. Expression levels for Bcl-xL, caspase-9, receptor for advanced glycation end products (RAGE) and brain-derived neurotrophic factor (BDNF) were significantly different in quantification of band intensity between the rats that inhaled O2 and sevoflurane in Aß-treated groups (all P < 0.05). Interleukin- (IL-) 1ß, nuclear factor-κB (NF-κB), and inducible nitric oxide synthase (iNOS) mRNA expression increased after the rats inhaled sevoflurane in the Aß-treated group (both P < 0.01). There were no significant differences in the change of GFAP, IBA1, Bcl-xL, caspase-9, RAGE, BDNF, IL-1ß, NF-κB, and iNOS in the NS + O2 and NS + sevo group (all P > 0.05). CONCLUSION: Sevoflurane exacerbates cognitive impairment induced by Aß 1-40 in rats through initiating neurotoxicity, neuroinflammation, and neuronal apoptosis in rat hippocampus.
Subject(s)
Amyloid beta-Peptides/toxicity , Cognitive Dysfunction/drug therapy , Hippocampus/metabolism , Sevoflurane/therapeutic use , Animals , Apoptosis/drug effects , Brain-Derived Neurotrophic Factor/metabolism , Calcium-Binding Proteins/metabolism , Caspase 9/metabolism , Enzyme-Linked Immunosorbent Assay , Hippocampus/drug effects , Male , Microfilament Proteins/metabolism , NF-kappa B/metabolism , Nitric Oxide Synthase Type II/metabolism , Peptide Fragments/metabolism , Rats , Rats, Sprague-Dawley , bcl-X Protein/metabolismABSTRACT
AIM: To develop a rapid and sensitive LC/MS/MS method for the analysis of levodropropizine in plasma and study the pharmacokinetics of levodropropizine in healthy Chinese volunteers. METHODS: Levodropropizine and zolmitriptan (internal standard, IS) were extracted from plasma samples and chromatographed on a C18 column and detected using a tandem mass spectrometer with a TurboIon Spray ionization interface. Quantitation was performed using multiple reaction monitoring (MRM) of the transitions of the m/z 237 --> m/z 120 for levodropropizine and m/z 288 --> m/z 58 for the IS. RESULTS: The limit of quantification of the method for levodropropizine was 0.25 microg x L(-1). The assay was linear over the concentration range from 0.25 to 500.0 microg x L(-1) and intra- and inter-day precision over this range were < 11.4% with good accuracy. CONCLUSION: The method is shown to be accurate, and suitable for clinical pharmacokinetic study of levodropropizine.