ABSTRACT
Studies have shown the ability of benzodiazepine drugs to cause memory loss in animals and humans. Midazolam is a benzodiazepine commonly administered intravenously during surgical procedures because it reacts rapidly, causes anterograde amnesia, and has few side effects. It has also been used in palliative medicine where, among others, an oral route has been employed for chronic administration of the drug. The current study evaluated the effects of chronic orally administered midazolam on spatial working memory and procedural memory in control and experimental female rats over a three-week experimental period utilizing the Morris water maze. Sample and test run times to a submerged platform in the maze were recorded daily. In addition, activity wheels attached to each cage were employed to monitor daily circadian activity of the animals. Spatial working memory was not impaired in either group. However, procedural memory amnesia occurred in animals receiving the drug indicative of a consolidation or retrieval problem. Concerning circadian rhythms, a phase-shift was noted in experimental animals possibly indicating that time of day of drug administration is important. The findings of the present study could shed insight into altered reactions observed in humans who have received midazolam as a component of treatment in palliative medicine.
Subject(s)
Benzodiazepines , Midazolam , Humans , Rats , Female , Animals , Amnesia , Administration, Oral , Circadian RhythmABSTRACT
Cyclophilin A (CypA), an 18 kDa multi-functional protein with cis-trans isomerase activity, is both a ligand for cyclosporine A and a proinflammatory factor. CypA is also a chemoattractant for hemopoietic stem cells and progenitors of different lineages, and can mediate regenerative processes in an organism. Accumulated experimental data have suggested there are practical applications for this protein in the treatment of several diseases (i.e. neutralization of cyclosporine A side effects, etc.). However, the range of CypA safe doses as well as its toxic effects remain unknown. The study here investigated the acute toxicity of a single intraperitoneal (IP) or subcutaneous (SC) dosing of recombinant human CypA (rhCypA) in both female and male mice and its effect on gene expression of acute phase proteins (APP) in the female mice after IP treatment. The results showed that toxicity of rhCypA was most evident in female and male mice dosed IP with 750 mg/kg, and manifested as kidney injury and increased granulocyte/lymphocyte ratios in the blood. Enhanced expression of Sаа1 and Sаа2 genes was induced with doses of 0.1-2 mg/mouse of rhCypA. Injection of the maximal dose (750 mg/kg) significantly stimulated expression of all the APP genes studied.
Subject(s)
Acute Kidney Injury/chemically induced , Acute-Phase Proteins/metabolism , Cyclophilin A/toxicity , Toxicity Tests, Acute , Acute Kidney Injury/blood , Acute Kidney Injury/immunology , Acute-Phase Proteins/immunology , Animals , Cyclophilin A/administration & dosage , Cyclophilin A/isolation & purification , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Gene Expression/drug effects , Gene Expression/immunology , Gene Expression Profiling , Granulocytes , Humans , Injections, Intraperitoneal , Injections, Subcutaneous , Kidney/drug effects , Kidney/immunology , Kidney/pathology , Lethal Dose 50 , Lymphocyte Count , Male , Mice , Recombinant Proteins/administration & dosage , Recombinant Proteins/isolation & purification , Recombinant Proteins/toxicityABSTRACT
Both TCRα and TCRß types of T-cell receptors contribute to antigen recognition. However, some TCRs have chain centricity, which means that either the α-chain or the ß-chain dictates the peptide-MHC complex specificity. Most earlier reports investigated the role of well-studied ß-chains in antigen recognition by TCRαß. In a previous study, we identified TCRs specific to the H-2Kb molecule. In the present work, we generated transgenic mice carrying the α-chain of this TCR. We found that these transgenic mice rejected EL-4 tumor cells bearing alloantigen H-2Kb more effectively than wild-type mice and similarly to mice with established specific memory T cells. Moreover, we found that T cells transduced with this TCRα can inhibit EL-4 cell growth in vitro and in vivo. We also found that transgenic mice recruit fewer CD8 T cells into the peritoneal cavity at the peak of the immune response and had a significantly higher number of central memory CD8 T cells in the spleen of intact transgenic mice compared to intact wild-type control. These results indicate the ability of a single transgenic α-chain of the H-2Kb-specific TCR to determine specific recognition of the H-2Kb molecule by a repertoire of T lymphocytes and to rapidly reject H-2Kb-bearing lymphoma cells.
