Studies on the potential neurotoxic and convulsant effects of increased blood levels of quinolinic acid in rats with altered blood-brain barrier permeability.
Intravenous injection of 450 mg/kg quinolinic acid (Quin), an endogenous kynurenine metabolite with excitotoxic properties, induced only minor electroencephalographic (EEG) modifications and no neurotoxicity in rats with a mature blood-brain barrier (BBB). BBB permeability was altered in rats by focal unilateral irradiation of the cortex (7 mm in diameter and 5 mm in depth) with protons (60 Gy, 9 Gy/min). Three days after irradiation, Evans blue dye staining showed BBB breakdown in the dorsal hippocampus of the irradiated hemisphere. No neurotoxic or convulsant effects were observed as a consequence of the radiation itself. When BBB-lesioned rats were challenged with 225 mg/kg Quin iv, epileptiform activity was observed on EEG analysis. Tonic-clonic seizures were induced by 225-450 mg/kg Quin. Light microscopic analysis showed a dose-related excitotoxic type of lesion restricted to the hippocampus ipsilateral to the irradiated side. Neuro-degeneration was prevented by local injection of 120 nmol D(-)2-amino-7-phosphonoheptanoic acid, a selective N-methyl-D-aspartate receptor antagonist. No lesions or EEG or behavioral modifications occurred after 450 mg/kg nicotinic acid, an inactive analog of Quin. The potential neurotoxic and convulsant effects of increased blood levels of Quin under conditions of altered BBB permeability are discussed.
Vezzani
A
A
Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
Stasi
M A
MA
Wu
H Q
HQ
Castiglioni
M
M
Weckermann
B
B
Samanin
R
R
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives*; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants; D001812:Blood-Brain Barrier / Q000502:physiology*; D002540:Cerebral Cortex / Q000528:radiation effects; D004569:Electroencephalography; D006624:Hippocampus / Q000473:pathology; D008297:Male; D009043:Motor Activity / Q000502:physiology; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D011522:Protons; D011725:Pyridines / Q000097:blood*; D017378:Quinolinic Acid; D011805:Quinolinic Acids / Q000097:blood*; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology
D000596:Amino Acids; D000927:Anticonvulsants; D011522:Protons; D011725:Pyridines; D011805:Quinolinic Acids; D015763:2-Amino-5-phosphonovalerate; D017378:Quinolinic Acid; C031231:2-amino-7-phosphonoheptanoic acid