PMID- 12182892
OWN - NLM
STAT- MEDLINE
DCOM- 20021127
LR  - 20210105
IS  - 0306-4522 (Print)
IS  - 0306-4522 (Linking)
VI  - 113
IP  - 4
DP  - 2002
TI  - DCG-IV but not other group-II metabotropic receptor agonists induces microglial 
      BDNF mRNA expression in the rat striatum. Correlation with neuronal injury.
PG  - 857-69
AB  - We have previously described a neuroprotective action of 
      (2S,2'R,3'R)-2-(2'3'-dicarboxycyclopropyl)glycine (DCG-IV), an agonist for 
      group-II metabotropic receptors, on dopaminergic nerve terminals against the 
      degeneration induced by 1-methyl-4-phenylpyridinium (MPP+). This effect was 
      accompanied by an up-regulation of brain-derived neurotrophic factor (BDNF) mRNA 
      expression in the rat striatum. We have now analyzed the phenotypic nature of the 
      BDNF mRNA-expressing cells in response to intrastriatal injection of DCG-IV. Dual 
      in situ hybridization and immunohistochemistry revealed that microglial cells but 
      not astrocytes were responsible for this induction. Subsequent analysis 
      demonstrated that this effect was accompanied by striking loss of striatal 
      glutamic acid decarboxylase (GAD) mRNA and massive appearance of internucleosomal 
      DNA fragmentation, a hallmark of apoptosis. A dose-response study demonstrated 
      that doses of DCG-IV as low as 5 nmol was very toxic in terms GAD mRNA and 
      apoptosis. 0.5 nmol of DCG-IV did not induce toxicity at all in terms of GAD mRNA 
      and apoptosis. Activation of group-II metabotropic receptors in striatum with 
      N-Acetyl-Asp-Glu (NAAG; a mGlu3 agonist) and 
      (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (a mGlu2 and mGlu3 agonist) did not 
      induce neither loss of GAD mRNA nor appearance of apoptosis (doses up to 20 
      nmol). In additional experiments, NAAG, in contrast to DCG-IV, failed to protect 
      the striatal dopaminergic system against the degeneration induced by MPP+ as 
      studied by microdialysis. Finally, we studied the mechanism by which DCG-IV is 
      highly toxic. For that, selective antagonists of either 
      metabotropic--(R,S)-alpha-methyl-4-carboxyphenylglycine and LY 341495--or 
      ionotropic (N-methyl-D-aspartate, NMDA)--DL-2-amino-5-phosphonovaleric acid 
      (AP-5) glutamate receptors --were co-administered with DCG-IV. Only AP-5 highly 
      protected the striatum against the degeneration induced by DCG-IV. Since DCG-IV 
      also activates the NMDA receptor at concentrations higher than 3 microM, it is 
      conceivable that a intrastriatal concentration equal or higher than 3 microM 
      after a single striatal injection of 5-20 nmol of DCG-IV. Our findings suggest 
      that much caution must be exerted when testing the numerous neuroprotective 
      effects ascribed to group-II metabotropic receptor activation, in particular when 
      using DCG-IV. We conclude that the neuroprotectant capability of a given compound 
      on a specific system does not exclude the possibility of inducing toxicity on a 
      different one.
CI  - Copyright 2002 IBRO
FAU - Venero, J L
AU  - Venero JL
AD  - Departamento de Bioquimica, Bromatologia y Toxicologia, Facultad de Farmacia, 
      Universidad de Sevilla, C/Prof. Garcia Gonzalez s/n, 41012 Sevilla, Spain.
FAU - Santiago, M
AU  - Santiago M
FAU - Tomas-Camardiel, M
AU  - Tomas-Camardiel M
FAU - Matarredona, E R
AU  - Matarredona ER
FAU - Cano, J
AU  - Cano J
FAU - Machado, A
AU  - Machado A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Neuroscience
JT  - Neuroscience
JID - 7605074
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Cyclopropanes)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Metabotropic Glutamate)
RN  - 0 (metabotropic glutamate receptor 2)
RN  - 147782-19-2 (2-(2,3-dicarboxycyclopropyl)glycine)
RN  - TE7660XO1C (Glycine)
SB  - IM
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/*biosynthesis
MH  - Corpus Striatum/*drug effects/metabolism
MH  - Cyclopropanes/*pharmacology
MH  - DNA Fragmentation/drug effects/physiology
MH  - Dose-Response Relationship, Drug
MH  - Glycine/*analogs & derivatives/*pharmacology
MH  - Male
MH  - Microglia/*drug effects/metabolism
MH  - Nerve Degeneration/*metabolism
MH  - RNA, Messenger/biosynthesis
MH  - Rats
MH  - Rats, Wistar
MH  - Receptors, Metabotropic Glutamate/*agonists/metabolism
EDAT- 2002/08/17 10:00
MHDA- 2002/11/28 04:00
CRDT- 2002/08/17 10:00
PHST- 2002/08/17 10:00 [pubmed]
PHST- 2002/11/28 04:00 [medline]
PHST- 2002/08/17 10:00 [entrez]
AID - S0306452202002324 [pii]
AID - 10.1016/s0306-4522(02)00232-4 [doi]
PST - ppublish
SO  - Neuroscience. 2002;113(4):857-69. doi: 10.1016/s0306-4522(02)00232-4.