Release of glutamate, noradrenaline and adenosine from rat parietal cortical slices.
Date
2000
Authors
Wang, Yushan.
Journal Title
Journal ISSN
Volume Title
Publisher
Dalhousie University
Abstract
Description
The roles of protein kinase C (PKC) and Li+ in N-methyl-D-aspartate (NMDA)-evoked releases of adenosine and noradrenaline (NA) were studied. In the absence of Mg2+, activation of PKC by phorbol 12-myristate 13-acetate (PMA) potentiated the release of adenosine evoked by 20muM NMDA and the release of [3H]NA evoked by 100muM NMDA. The potentiating effects of PMA on NMDA-evoked releases of adenosine and NA were reversed by inhibition of PKC with GF109,203X (GFX). GFX by itself had no effect on NMDA-evoked release of either adenosine or NA, suggesting that endogenous PKC does not play a role in NMDA-evoked releases. Li+, at concentrations of 1.5mM or 10mM, potentiated 300muM NMDA-evoked release of NA but had no effect on the release of adenosine. In the presence of Mg2+, NMDA-evoked release of NA was essentially abolished, whereas adenosine release persisted. Under these conditions, PMA or Li+ did not permit NMDA-evoked release of NA to occur, nor did they increase NMDA-evoked adenosine release. Taken together, these results indicate that PKC does not play an essential role in NMDA-evoked release of either adenosine or NA. However, activation of PKC potentiates the release of adenosine and NA evoked by submaximal concentrations of NMDA, but not by relieving the voltage-sensitive Mg 2+ block of NMDA receptors.
Inflammation may play an important role in various neurological disorders, including the central actions of bacterial and viral infections. Here we show that exposure of rat parietal cortical slices to lipopolysaccharide (LPS) triggers very rapid (<2.5 min) releases of glutamate, NA and adenosine. Detoxified LPS is ineffective. LPS-evoked release of NA appears to be partly due to the released glutamate acting at its ionotropic receptors. LPS-evoked release of glutamate does not require extracellular Ca2+ and is tetrodotoxin (TTX)-insensitive. The glutamate transport blocker L-trans-pyrrolidine-2,4-dicarboxylate (tPDC) decreases glutamate release, suggesting that release might occur via the reversal of glutamate transporter(s). These findings raise the possibility that LPS releases glutamate from non-neuronal cells rather than from neurons. It is not known exactly how LPS releases glutamate. Glutamate release is not mimicked by IL-1beta, IL-6, TNF-alpha, or a combination of IL-1beta and TNF-alpha, suggesting that it is not mediated by these cytokines. Inhibition of COX-1 with resveratrol, COX-2 with NS-398, or both COX-1 and COX-2 with indomethacin does not diminish LPS-evoked glutamate release. Thus prostaglandins do not appear to be involved in LPS-evoked glutamate release. Inhibition of eNOS with L-NIO, iNOS with L-NIL, nNOS with 7-NI, or non-selective inhibition of NOS with L-NAME has no effects on LPS-evoked glutamate release, indicating that NO is not involved. Finally, scavenging free radicals with SOD and catalase or with alpha-tocopherol does not prevent LPS from releasing glutamate. These findings raise the possibility that similar inappropriate excitations may participate in other neurological disorders such as AIDS dementia. Indeed, the HIV glycoproteins gp120 and gp41 also caused very rapid releases of glutamate, NA and adenosine from rat cortical slices. HIV gp41 is much more effective than gp120 at releasing glutamate and NA while both glycoproteins are equally effective at releasing adenosine.
Thesis (Ph.D.)--Dalhousie University (Canada), 2000.
Inflammation may play an important role in various neurological disorders, including the central actions of bacterial and viral infections. Here we show that exposure of rat parietal cortical slices to lipopolysaccharide (LPS) triggers very rapid (<2.5 min) releases of glutamate, NA and adenosine. Detoxified LPS is ineffective. LPS-evoked release of NA appears to be partly due to the released glutamate acting at its ionotropic receptors. LPS-evoked release of glutamate does not require extracellular Ca2+ and is tetrodotoxin (TTX)-insensitive. The glutamate transport blocker L-trans-pyrrolidine-2,4-dicarboxylate (tPDC) decreases glutamate release, suggesting that release might occur via the reversal of glutamate transporter(s). These findings raise the possibility that LPS releases glutamate from non-neuronal cells rather than from neurons. It is not known exactly how LPS releases glutamate. Glutamate release is not mimicked by IL-1beta, IL-6, TNF-alpha, or a combination of IL-1beta and TNF-alpha, suggesting that it is not mediated by these cytokines. Inhibition of COX-1 with resveratrol, COX-2 with NS-398, or both COX-1 and COX-2 with indomethacin does not diminish LPS-evoked glutamate release. Thus prostaglandins do not appear to be involved in LPS-evoked glutamate release. Inhibition of eNOS with L-NIO, iNOS with L-NIL, nNOS with 7-NI, or non-selective inhibition of NOS with L-NAME has no effects on LPS-evoked glutamate release, indicating that NO is not involved. Finally, scavenging free radicals with SOD and catalase or with alpha-tocopherol does not prevent LPS from releasing glutamate. These findings raise the possibility that similar inappropriate excitations may participate in other neurological disorders such as AIDS dementia. Indeed, the HIV glycoproteins gp120 and gp41 also caused very rapid releases of glutamate, NA and adenosine from rat cortical slices. HIV gp41 is much more effective than gp120 at releasing glutamate and NA while both glycoproteins are equally effective at releasing adenosine.
Thesis (Ph.D.)--Dalhousie University (Canada), 2000.
Keywords
Health Sciences, Pharmacology.