2-Iminothiazolidine-4-carboxylic acid produces hippocampal CA1 lesions independent of seizure excitation and glutamate receptor activation.

Abstract

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.

• Authors: R S Bitner, G K Yim, G E Isom
• Journal: Neurotoxicology (Neurotoxicology) Vol. 18 Issue 1 Pg. 191-200 ( 1997) ISSN: 0161-813X [Print] Netherlands
• PMID: 9216001 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Excitatory Amino Acid Agonists
• Neuroprotective Agents
• Neurotoxins
• Glutamic Acid
• Dizocilpine Maleate
• 6-Cyano-7-nitroquinoxaline-2,3-dione
• Proline

Topics

• 6-Cyano-7-nitroquinoxaline-2,3-dione (therapeutic use)
• Animals
• Brain Ischemia (chemically induced, physiopathology)
• Dizocilpine Maleate (therapeutic use)
• Excitatory Amino Acid Agonists (therapeutic use)
• Glutamic Acid (toxicity)
• Hippocampus (blood supply, drug effects)
• Injections, Intraventricular
• Male
• Neuroprotective Agents (therapeutic use)
• Neurotoxins (toxicity)
• Proline (toxicity)
• Rats
• Rats, Sprague-Dawley
• Seizures (chemically induced)