Activation of A(1) adenosine or mGlu3 metabotropic glutamate receptors enhances the release of nerve growth factor and S-100beta protein from cultured astrocytes.
Pharmacological activation of A(1) adenosine receptor with 2-chloro-N6-cyclopentyladenosine (CCPA) or mGlu3 metabotropic glutamate receptors with (2S,2'R,3'R)-2-(2', 3'-dicarboxycyclopropyl)glycine (DCG-IV) or aminopyrrolidine-2R, 4R-dicarboxylate (2R,4R-APDC) enhanced the release of nerve growth factor (NGF) or S-100beta protein from rat cultured astrocytes. Stimulation of release by CCPA and DCG-IV or 2R,4R-APDC was inhibited by the A(1) adenosine receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine and by the mGlu2/3 receptor antagonist (2S,1'S, 2'S,3'R)-2-(2'-carboxy-3'-phenylcyclopropyl)glycine (PCCG-4), respectively. Time-course studies revealed a profound difference between the release of S-100beta protein and the release of NGF in response to extracellular signals. Stimulation of S-100beta protein exhibited rapid kinetics, peaking after 1 h of drug treatment, whereas the enhancement of NGF release was much slower, requiring at least 6 h of A(1) adenosine or mGlu3 receptor activation. In addition, stimulation of NGF but not S-100beta release was substantially reduced in cultures treated with the protein synthesis inhibitor cycloheximide. In addition, a 6-8 h treatment of cultured astrocytes with A(1) or mGlu3 receptor agonists increased the levels of both NGF mRNA and NGF-like immunoreactive proteins, including NGF prohormone. We conclude that activation of A(1) adenosine or mGlu3 receptors produces pleiotropic effects in astrocytes, stimulating the synthesis and/or the release of protein factors. Astrocytes may therefore become targets for drugs that stimulate the local production of neurotrophic factors in the CNS, and this may provide the basis for a novel therapeutic strategy in chronic neurodegenerative disorders.
Ciccarelli
R
R
Department of Biomedical Sciences, University "G. D'Annunzio" of Chieti, School of Medicine, University of Chieti, Chieti, Italy.
Di Iorio
P
P
Bruno
V
V
Battaglia
G
G
D'Alimonte
I
I
D'Onofrio
M
M
Nicoletti
F
F
Caciagli
F
F
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology; D003521:Cyclopropanes / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007700:Kinetics; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology / Q000502:physiology*; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000502:physiology*; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
C097299:4-aminopyrrolidine-2,4-dicarboxylic acid; D003521:Cyclopropanes; D018690:Excitatory Amino Acid Agonists; D009414:Nerve Growth Factors; D018094:Receptors, Metabotropic Glutamate; D018047:Receptors, Purinergic P1; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C102718:metabotropic glutamate receptor 3; C082313:2-(2,3-dicarboxycyclopropyl)glycine; C058394:2-chloro-N(6)cyclopentyladenosine; D011392:Proline; D000241:Adenosine; D005998:Glycine