Striatal ablation of GABAergic neurons prevents the in vivo neuroprotective effect of DCG-IV against the MPP+-induced neurotoxicity on dopaminergic nerve terminals.
In previous studies we found that intrastriatal DCG-IV administration, an agonist for group II metabotropic glutamate receptor: (i) protected striatal dopaminergic terminals against MPP(+)-induced neurotoxicity (Matarredona et al., 2001); (ii) selectively destroyed striatal GABAergic neurons (Venero et al., 2002) and (iii) induced early robust up-regulation of brain-derived neurotrophic factor (BDNF) in nigral dopaminergic neurons afferents in a target-dependent manner (Rite et al., 2005). Considering that BDNF protein is anterogradely transported to dopaminergic nerve endings, an autocrine role of BDNF could account for the neuroprotective effect of DCG-IV against the MPP(+)-induced toxicity of dopaminergic terminals. To test this possibility, we first performed a previous insult with quinolinic acid (QA) to specifically damage the striatal GABAergic neuronal cell bodies in order to remove the nigral BDNF target. Fourteen days later, we explored the potential in vivo neuroprotective action of DCG-IV against MPP(+)-induced toxicity on striatal dopaminergic nerve terminals by in vivo microdialysis. Integrity of GABAergic system was evaluated by glutamic acid decarboxylase (GAD) in situ hybridization. We demonstrate that previous striatal target ablation with QA prevented the neuroprotective effect of DCG-IV perfusion against the MPP(+)-induced neurotoxicity on dopaminergic terminals. Our results strongly suggest an important autocrine neuroprotective role of BDNF on striatal dopaminergic nerve terminals. In addition, we found an unexpected regulatory response of surviving striatal GABAergic neurons in terms of high levels of GAD mRNA expression.
Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, 41012-Sevilla, Spain.
José Luis
JL
Venero
Raquel
R
Mauriño
Alberto
A
Machado
Marti
M
Santiago
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003521:Cyclopropanes / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D003521:Cyclopropanes; D018696:Neuroprotective Agents; C082313:2-(2,3-dicarboxycyclopropyl)glycine; D005680:gamma-Aminobutyric Acid; D005998:Glycine; D004298:Dopamine