Intracerebroventricular administration of quinolinic acid induces a selective decrease of inositol(1,4,5)-trisphosphate receptor in rat brain.
[3H]inositol(1,4,5)-trisphosphate (IP3) binding studies have shown decreased [3H]IP3 binding to brain tissue in several neurodegenerative diseases, including Alzheimer's and Huntington's diseases. In addition, previous results obtained from brains of Alzheimer patients indicated a reduction of IP3-receptor protein correlated to neuronal loss. The neurotoxic effect of the glutamate receptor agonist quinolinic acid (QUIN) was therefore examined with respect to the level of IP3-receptor immunoreactivity in rat brain. Neuronal lesions were estimated with antibodies to marker proteins for striatal medium-sized spiny neurons (dopamine- and cyclic AMP-regulated phosphoprotein, Mr 32,000; DARPP-32), synaptic vesicles (synaptophysin), mitochondria (phosphate-activated glutaminase; PAG) and glial cells (glial fibrillary acidic protein; GFAP). Injection of QUIN into rat neostriatum induced a massive loss of striatal medium-sized spiny neurons, and led to a comparable loss of IP3-receptor and PAG immunoreactivity, suggesting a neuronal localisation of both these proteins. In an effort to induce less pronounced excitotoxic damage, intracerebroventricular infusion of QUIN was performed. Following this lesion, the neostriatum showed a negligible loss of DARPP-32 immunoreactivity (-11+/-5%), but contained only 43+/-3% of IP3-receptor immunoreactivity levels compared to controls. In the hippocampus, cerebellum and entorhinal cortex, the IP3-receptor loss was less pronounced. The decrease in the level of IP3-receptor immunoreactivity appears to be selective with respect to the other proteins studied, and the IP3-receptor thus shows extreme sensitivity to QUIN neurotoxicity in the neostriatum.
Neurochemical Laboratory, University of Oslo, Norway.
L S
LS
Haug
A C
AC
Ostvold
I
I
Torgner
B
B
Roberg
L
L
Dvoráková
F
F
St'astný
S I
SI
Walaas
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D015220:Calcium Channels / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D005972:Glutaminase / Q000032:analysis; D007276:Injections, Intraventricular; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008297:Male; D009419:Nerve Tissue Proteins / Q000032:analysis; D009474:Neurons / Q000187:drug effects; D010750:Phosphoproteins; D017378:Quinolinic Acid / Q000008:administration & dosage* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D016708:Synaptophysin / Q000032:analysis; D014316:Tritium
D015415:Biomarkers; D015220:Calcium Channels; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D005904:Glial Fibrillary Acidic Protein; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D016708:Synaptophysin; D014316:Tritium; D015544:Inositol 1,4,5-Trisphosphate; D005972:Glutaminase; D017378:Quinolinic Acid