ABSTRACT
Meloxicam is a non-steroidal anti-inflammatory drug which has been reported to lessen the ischemic transcriptional effects in some of the glutamatergic system genes as well as to decrease the infarct volume in in vivo assays. In this study, we show how the presence of meloxicam decreases cell mortality in assays of oxygen-glucose deprivation (OGD) in rat organotypic hippocampal slices culture. Mortality was measured using propidium iodide. Transcript levels of some glutamatergic system genes, including vesicular and membrane glutamate transporters (VGLUT1, VGLUT2, GLAST-1A, GLT-1, and EAAC-1) and some glutamatergic receptor subunits (NMDA receptor, GluN1, GluN2A and GluN2B subunits and AMPA receptor, GluA1 and GluA2 subunits) were measured by real-time PCR (qPCR). The transcription of vesicular glutamate transporters and glutamatergic receptor subunits, but not membrane glutamate transporters, was modified by the presence of meloxicam. The study demonstrates the neuroprotective role of meloxicam in organotypic hippocampal slice cultures and shows how meloxicam is able to selectively increase or decrease the OGD-induced changes in the expression of the different glutamatergic system genes studied here. We suggest that the neuroprotective role of meloxicam could be due to a modification in the balance of the expression of some glutamatergic receptor subunits, leading to a different stoichiometry of receptors such as NMDA or AMPA. Thus, meloxicam would decrease the excitotoxicity induced by OGD.
Subject(s)
CA1 Region, Hippocampal/metabolism , Cyclooxygenase 2/metabolism , Glucose/deficiency , Hypoxia, Brain/metabolism , Receptors, Glutamate/metabolism , Vesicular Glutamate Transport Proteins/metabolism , Animals , CA1 Region, Hippocampal/drug effects , Cyclooxygenase Inhibitors/pharmacology , Excitatory Amino Acid Transporter 2/metabolism , Hypoxia, Brain/drug therapy , Meloxicam , Neuroprotective Agents/pharmacology , RNA, Messenger/metabolism , Rats, Wistar , Thiazines/pharmacology , Thiazoles/pharmacology , Tissue Culture Techniques , Vesicular Glutamate Transport Protein 1/metabolism , Vesicular Glutamate Transport Protein 2/metabolismABSTRACT
AIMS: This study has investigated how global brain ischaemia/reperfusion (I/R) modifies levels of mRNAs encoding γ-aminobutyric acid type A (GABA(A)) receptor α1, ß2 and γ2 subunits and glutamic acid decarboxylase 65 (GAD65) in an age- and structure-dependent manner. Gene expression in response to treatment with the anti-inflammatory agent meloxicam was also investigated. METHODS: Global ischaemia was induced in 3- and 18-month-old male Sprague-Dawley rats. CA1, CA3, and dentate gyrus (DG) hippocampal areas, cerebral cortex (CC) and caudate putamen (C-Pu) from sham-operated and I/R-injured animals were excised 48 h after the insult and prepared for quantitative polymerase chain reaction assays. Following I/R, meloxicam treatment was also carried out on young animals. RESULTS: Data revealed significant decreases in the levels of all GABA(A) receptor subunit transcripts in the hippocampus of both young and older injured animals compared with sham-operated ones. In contrast, there was either an increase or no change in GAD65 mRNA levels. GABA(A) receptor subunit transcript decreases were also observed in the CC and C-Pu in young injured animals but not in the CC of the older injured ones; interestingly, significant increases were observed in the C-Pu of older injured animals compared with controls. Meloxicam treatment following the insult resulted in a diminution of the previously described I/R response. CONCLUSIONS: The data indicate that I/R results in the modification of the levels of several gene transcripts involved in GABAergic signalling in both the pre- and postsynaptic components, of this neurotransmitter system, in an age- and structure-dependent manner.
