Document Detail

Adenosinergic protection of dopaminergic and GABAergic neurons against mitochondrial inhibition through receptors located in the substantia nigra and striatum, respectively.
MedLine Citation:
PMID:  14645494     Owner:  NLM     Status:  MEDLINE    
Mitochondrial dysfunction may contribute to dopaminergic (DAergic) cell death in Parkinson's disease and GABAergic cell death in Huntington's disease. In the present work, we tested whether blocking A1 receptors could enhance the damage to DAergic and GABAergic neurons caused by mitochondrial inhibition, and whether blocking A2a receptors could protect against damage in this model. Animals received an intraperitoneal injection of 8-cyclopentyl-1,3-dipropylxanthine (CPX) (A1 antagonist) or 3,7-dimethyl-1-propargylxanthine (DMPX) (A2a antagonist) 30 min before intrastriatal infusion of malonate (mitochondrial complex II inhibitor). Damage was assessed 1 week later by measuring striatal dopamine, tyrosine hydroxylase (TH), and GABA content. In mice and rats, malonate-induced depletion of striatal dopamine, TH, or GABA was potentiated by pretreatment with 1 mg/kg CPX and attenuated by pretreatment with 5 mg/kg DMPX. To determine the location of the A1 and A2a receptors mediating these effects, CPX or DMPX was infused directly into the striatum or substantia nigra of rats 30 min before intrastriatal infusion of malonate. When infused into the striatum, CPX (20 ng) potentiated, whereas DMPX (50 ng) prevented malonate-induced GABA loss, but up to 100 ng of CPX or 500 ng of DMPX did not alter malonate-induced striatal dopamine loss. Intranigral infusion of CPX (100 ng) or DMPX (500 ng), however, did exacerbate and protect, respectively, against malonate-induced striatal dopamine loss. Thus, A1 receptor blockade enhances and A2a receptor blockade protects against damage to DAergic and GABAergic neurons caused by mitochondrial inhibition. Interestingly, these effects are mediated by A1 and A2a receptors located in the substantia nigra for DAergic neurons and in the striatum for GABAergic neurons.
Peter D Alfinito; Sheng-Ping Wang; Lawrence Manzino; Sonia Rijhsinghani; Gail D Zeevalk; Patricia K Sonsalla
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  23     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2003 Nov 
Date Detail:
Created Date:  2003-12-03     Completed Date:  2003-12-16     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  10982-7     Citation Subset:  IM    
Levine Neuroscience Laboratory, Department of Neurology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
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MeSH Terms
Adenosine / metabolism*
Corpus Striatum / drug effects,  metabolism*
Dopamine / metabolism*
Drug Administration Routes
Drug Synergism
Electron Transport Complex II / antagonists & inhibitors
Huntington Disease / metabolism
Malonates / pharmacology
Mitochondria / drug effects,  metabolism*
Neurons / drug effects,  metabolism
Neuroprotective Agents / pharmacology
Parkinsonian Disorders / metabolism
Rats, Sprague-Dawley
Receptor, Adenosine A1 / antagonists & inhibitors
Receptor, Adenosine A2A / antagonists & inhibitors
Substantia Nigra / drug effects,  metabolism*
Theobromine / analogs & derivatives*,  pharmacology
Tyrosine 3-Monooxygenase / metabolism
Xanthines / pharmacology
gamma-Aminobutyric Acid / metabolism*
Grant Support
Reg. No./Substance:
0/Malonates; 0/Neuroprotective Agents; 0/Receptor, Adenosine A1; 0/Receptor, Adenosine A2A; 0/Xanthines; 102146-07-6/1,3-dipropyl-8-cyclopentylxanthine; 141-82-2/malonic acid; 14114-46-6/3,7-dimethyl-1-propargylxanthine; 56-12-2/gamma-Aminobutyric Acid; 58-61-7/Adenosine; 83-67-0/Theobromine; EC 3-Monooxygenase; EC Transport Complex II

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