Neuroprotection against hypoxic/hypoglycaemic injury after the insult by the group III metabotropic glutamate receptor agonist (R, S)-4-phosphonophenylglycine

Abstract

The role of group III metabotropic glutamate receptors (mGluR) in ischaemic neurodegeneration is still unsettled. In order to examine a possible modulatory effect of these receptors on ischaemia-induced damage we tested the novel selective agonist (R, S)-4-phosphonophenylglycine [(R,S)-PPG] after an hypoxic/hypoglycaemic insult in rat hippocampal slices. The recovery of population spike amplitudes in the CA1-region was used as parameter for neuronal viability. (R,S)-PPG significantly improved the recovery of synaptic transmission in the CA1-region even when applied only during the recovery period. The results imply that presynaptic glutamate release after an insult contributes to neurodegeneration. Since agonists of group III mGluR reduce neurotransmitter release - probably via presynaptic autoreceptors - we interpret the results obtained in our in vitro model of hypoxia/hypoglycaemia as support of the hypothesis that group III mGluR agonists might be beneficial drugs against diseases where excitotoxicity is one of the dominant pathological mechanisms.

Figure 1

Effect of the novel selective group III agonist (R,S)-4-phosphonophenylglycine ((R,S)-PPG, 30 μM) on the recovery of PS in area CA1 of rat hippocampal slices after a 4 min hypoxia/hypoglycaemia. (a) The representative traces show evoked PS recorded immediately before, during and at different time points after hypoxia/hypoglycaemia. In the second column (R,S)-PPG was present from the time of re-establishment of oxygen and glucose supply for throughout the recovery period. (b) Time course of PS recovery in untreated control slices (n=6) and in slices treated with 30 μM (R,S)-PPG (n=6). Asterisks indicate significant differences from control slices, calculated with Mann-Whitney's U-test (^*P<0.05; ^**P<0.01). Data are expressed as the mean±standard error.