midazolam brands

Molecular formula: C18H13ClFN3

The actions of benzodiazepines such as midazolam are mediated through the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), which is one of the major inhibitory neurotransmitters in the central nervous system. Benzodiazepines increase the activity of GABA, thereby producing a sedating effect, relaxing skeletal muscles, and inducing sleep, anesthesia, and amnesia. Benzodiazepines bind to the benzodiazepine site on GABA-A receptors, which potentiates the effects of GABA by increasing the frequency of chloride channel opening. These receptors have been identified in different body tissues including the heart and skeletal muscle, although mainly appear to be present in the central nervous system. Midazolam has neurotoxic properties when administered neuraxially in vivo. Furthermore, midazolam induces neurodegeneration in neonatal animal models in combination with other general anesthetics. Therefore, this study focuses on the mechanism of neurotoxicity by midazolam in neuronal and nonneuronal cells. The study aims to evaluate the apoptotic pathway and to investigate the protective effects of the benzodiazepine antagonist flumazenil and the caspase inhibitor N-(2-quinolyl)valyl-aspartyl-(2,6-difluorophenoxy)-methylketone. The apoptosis-inducing effect of preservative-free midazolam on human lymphoma and neuroblastoma cell lines was evaluated using flow cytometric analysis of early apoptotic stages (annexin V/7AAD) and caspase 3 activation. B-cell lymphoma (Bcl2) protein overexpressing and caspase 9-deficient lymphoma cells were used to determine the role of the mitochondrial (intrinsic) pathway. Caspase 8-deficient and Fas-associated protein with death domain (FADD)-deficient cells were used to evaluate the death receptor (extrinsic) pathway. The protective effects of flumazenil and the caspase inhibitor N-(2-quinolyl)valyl-aspartyl-(2,6-difluorophenoxy)-methylketone were investigated in neuroblastoma cells and primary rat neurons using metabolic activity assays (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) and immunofluorescence microscopy. Midazolam induced apoptosis in all investigated cell types in a concentration-dependent manner, indicated by flow cytometry. Bcl2-overexpression and caspase 9 deficiency protected against toxicity, whereas caspase 8 or FADD deficiency had no effect. Pancaspase inhibition had a strong protective effect, whereas flumazenil did not inhibit midazolam-induced apoptosis. Midazolam induces apoptosis via activation of the mitochondrial pathway in a concentration-dependent manner. The mechanism of midazolam toxicity switches from caspase-dependent apoptosis to necrosis with increasing concentrations. The induction of apoptosis and necrosis by midazolam is presumably unrelated to GABAA receptor pathway signaling. A consummatory conflict procedure that involves an abrupt reduction in magnitude of an expected reward (negative contrast) has been shown to be particularly sensitive to the effects of anxiolytic agents. Midazolam released suppressed consummatory performance in a dose-dependent manner. This effect was not due to a general appetite stimulation effect of the drug. The effects of three 5-HT antagonists on negative contrast were examined to evaluate the role serotonin may play in the anxiolytic action of benzodiazepine. Methysergide was found to be ineffective, cinanserin tended to reduce contrast at two intermediate doses, and cyproheptadine eliminated the contrast effect in a similar fashion as midazolam. The effectiveness of cyproheptadine may not be attributed to its anticholinergic or antihistaminergic actions since scopolamine and pyrilamine did not produce similar efects. The results are discussed in terms of the role serotonin may play in the anti-conflict action of benzodiaepine, as well as possible interactional effects of gamma-aminobutyric acid. The exact sites and mode of action of the benzodiazepines have not been fully elucidated, but the effects

Source: PubChem (NCBI) · compound 4192