2-Iminothiazolidine-4-carboxylic acid produces hippocampal CA1 lesions independent of seizure excitation and glutamate receptor activation.
We previously demonstrated that 2-iminothiazolidine-4-carboxylic acid (2-ICA), formed by cyanide reacting with cysteine, caused glutamate antagonist-sensitive seizures when injected i.c.v. (intracerebroventricular) in mice and produced hippocampal CA1 damage following i.c.v. infusion in rats. In this study, the ability of either 2-ICA, glutamate, proline or NMDA (N-methyl-D-aspartate) injected i.c.v. to produce hippocampal lesions sensitive to glutamate antagonists was compared in mice. Hippocampal CA1 damage was observed 5-days following either a seizure (3.2 mumol) or subseizure (1.0 mumol) dose of 2-ICA. Glutamate (3.2 mumol) or proline (10 mumol) also produced hippocampal damage; glutamate damage was primarily to the CA1 subfield, whereas proline damaged neurons throughout the entire hippocampal formation. NMDA (3.2 nmol) caused seizure activity in all animals with a 50% lethality. No hippocampal damage was observed in surviving mice. Neither MK-801 (dizocilpine maleate) nor CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) pretreatment prevented hippocampal lesions produced by 2-ICA. In contrast, MK-801 significantly reduced the frequency of mice displaying glutamate hippocampal lesions, but failed to block seizures produced by glutamate. MK-801 also protected neurons in the CA2-3 zone and the dentate gyrus, but not in the CA1 region of proline-injected mice. Finally, pretreatment with the mixed metabotropic glutamate receptor (mGluR)1/mGluR2 antagonist-agonist (S)-4-carboxy-3-hydroxyphenylglycine (CHPG) prevented hippocampal damage produced by the mGluR1 agonist (RS)-3,5-dihydroxyphenylglycine (DHPG), but did not protect against 2-ICA hippocampal lesions. These results show that 2-ICA hippocampal CA1 damage is not mediated through ionotropic or metabotropic glutamate receptors. 2-ICA hippocampal damage may represent a neurotoxicity that is distinct from excitotoxic-mediated cell death.
Bitner
R S
RS
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907-1334, USA.
Yim
G K
GK
Isom
G E
GE
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000627:therapeutic use; D000818:Animals; D002545:Brain Ischemia / Q000139:chemically induced / Q000503:physiopathology*; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D018690:Excitatory Amino Acid Agonists / Q000627:therapeutic use*; D018698:Glutamic Acid / Q000633:toxicity; D006624:Hippocampus / Q000098:blood supply / Q000187:drug effects*; D007276:Injections, Intraventricular; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009498:Neurotoxins / Q000633:toxicity*; D011392:Proline / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced*
D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D009498:Neurotoxins; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D011392:Proline