Neuroprotective effects of the mGlu5R antagonist MPEP towards quinolinic acid‐induced striatal toxicity: involvement of pre‐ and post‐synaptic mechanisms and lack of direct NMDA blocking activity

Abstract

The aim of this work was to investigate the potential neuroprotective effects of the metabotropic glutamate receptor 5 (mGlu5R) antagonist 2-Methyl-6-(phenylethynyl)-pyridine (MPEP) towards quinolinic acid (QA)-induced striatal excitoxicity. Intrastriatal MPEP (5 nmol/0.5 lL) significantly attenuated the body weight loss, the electroencephalographic alterations, the impairment in spatial memory and the striatal damage induced by bilateral striatal injection of QA (210 nmol/ 0.7 lL). In a second set of experiments, we aimed to elucidate the mechanisms underlying the neuroprotective effects of MPEP. In microdialysis studies in naive rats MPEP (80-250 lM through the dialysis probe) significantly reduced the increase in glutamate levels induced by 5 mM QA. In primary cultures of striatal neurons MPEP (50 lM) reduced the toxicity induced by direct application of glutamate [measured as release of lactate dehydrogenase [LDH]). Finally, we found that 50 lM MPEP was unable to directly block NMDA-induced effects (namely field potential reduction in corticostriatal slices, as well as LDH release and intracellular calcium increase in striatal neurons). We conclude that: (i) MPEP has neuroprotective effects towards QA-induced striatal excitotoxicity; (ii) both pre-and post-synaptic mechanisms are involved; (iii) the neuroprotective effects of MPEP do not appear to involve a direct blockade of NMDA receptors.

The cannabinoid receptor agonist WIN 55,212-2 attenuates the effects induced by quinolinic acid in the rat striatum

“…3C) was used. Consistently with previous observations from our group Popoli et al, 2004), the application of QA (1 mM over 10 min, N ¼ 12) to corticostriatal slices induced a strong reduction of FP amplitude (À91.28 AE 2.15%), followed by a partial recovery after washout (À54.1 AE 6.39%; P < 0.001 vs control, Figs. 3A, B).…”

“…Specifically, we took advantage of the model of QA-induced striatal damage, in which a chronic and progressive phenotype is thought to be triggered by early excitotoxic events Scattoni et al, 2004). Although such experiments were performed in a limited number of animals, at the dose used here WIN 55,212-2 significantly, though modestly, reduced the amount of QA-induced ventricular enlargement (an established index of the lesion, see Popoli et al, 2004). Such a protective activity was however not paralleled by a clear functional effect.…”

Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice

“…Others have shown that MPEP can target NMDA receptors at high concentrations (Lea et al, 2005;Popoli et al, 2004). However, it is unlikely that the rescue effect in this study is mediated by NMDA receptors, as we also see the rescue effect with the structurally different, more specific mGluR5 antagonist fenobam.…”

Ciliary Neurotrophic Factor Activates Astrocytes, Redistributes Their Glutamate Transporters GLAST and GLT-1 to Raft Microdomains, and Improves Glutamate HandlingIn Vivo

“…The effects of QA on the extracellular levels of glutamate and other amino acids were assessed in vivo with a microdialysis study according to the protocol of Popoli et al (2004) with some modifications. Lenti-CNTF/lenti-LacZ rats (n ϭ 5) or Veh/lenti-LacZ rats (n ϭ 4) were anesthetized with isoflurane and placed in a stereotaxic frame.…”