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Intrastriatal grafting of a GDNF‐producing cell line protects striatonigral neurons from quinolinic acid excitotoxicity in vivo
Author(s) -
PérezNavarro E.,
Arenas E.,
Marco S.,
Alberch J.
Publication year - 1999
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.1999.00433.x
Subject(s) - glial cell line derived neurotrophic factor , quinolinic acid , excitotoxicity , in vivo , chemistry , neuroscience , microbiology and biotechnology , pharmacology , biology , biochemistry , programmed cell death , neurotrophic factors , apoptosis , amino acid , genetics , tryptophan , receptor
Glial cell line‐derived neurotrophic factor (GDNF) is a neurotrophic factor with a therapeutic potential in neurodegenerative disorders. GDNF is expressed in the adult striatum, but its signalling tyrosine kinase receptor, c‐ret, has not been detected in this structure by in situ hybridization. In the present work, we first examined c‐ret and GDNF receptor α1 (GFR‐α1) expression using an RNAse protection assay, and found that both receptors are expressed in the adult rat striatum. We then examined whether GDNF was able to regulate the phenotype and/or prevent the degeneration of striatal projection neurons in a well‐characterized model of excitotoxic damage. A fibroblast cell line, engineered to overexpress GDNF, was grafted in adult rats striatum 24 h before quinolinic acid (QUIN) injection. QUIN injection alone or in combination with the control cell line induced a loss of glutamic acid decarboxylase 67 (GAD)‐, preprotachykinin A (PPTA)‐, prodynorphin (DYN)‐ and preproenkephalin (PPE)‐positive neurons. GDNF selectively prevented: (i) the loss of a subpopulation of striatonigral neurons expressing GAD and PPTA; (ii) the atrophy of PPTA‐positive neurons; and (iii) the decrease in GAD, PPTA and DYN mRNA expression, after QUIN injection. Moreover, in unlesioned animals, GDNF increased the size of PPTA‐positive neurons and up‐regulated their mRNA levels. In contrast, GDNF showed no effect in intact or lesioned striatopallidal PPE‐positive neurons. Thus, our findings show that GDNF selectively regulates the phenotype and protects striatonigral neurons from QUIN‐induced excitotoxicity, suggesting that GDNF may be used for the treatment of striatonigral degenerative disorders, e.g. Huntington's disease and multiple system atrophy.