Peripheral and central routes of administration of quaternary ammonium compound IEM-1460 are equally potent in reducing the severity of nicotine-induced seizures in mice

• Published in: Bulletin of experimental biology and medicine Vol. 146; no. 1; pp. 18 - 21
• Main Authors: Gmiro, V. E, Serdyuk, S. E, Efremov, O. M
• Format: Journal Article
• Language: English
• Published: Boston Boston : Springer US 01-07-2008; Springer US; Springer Nature B.V
• Subjects: Adamantane - administration & dosage; Adamantane - analogs & derivatives; Adamantane - therapeutic use; Animals; arcaine; Biguanides - administration & dosage; Biguanides - therapeutic use; Biomedical and Life Sciences; Biomedicine; blood-brain barrier; Cell Biology; IEM-1460; Internal Medicine; Laboratory Medicine; Male; Mice; nicotine; Nicotine - pharmacology; Pathology; Physiology; Receptors, AMPA - metabolism; Receptors, Nicotinic - metabolism; seizures; Seizures - chemically induced; Seizures - drug therapy; Seizures - mortality; blood-brain barrier; seizures; nicotine; IEM-1460; arcaine
• ISSN: 0007-4888; 1573-8221
• DOI: 10.1007/s10517-008-0229-9

Peripheral administration of nicotinic receptor antagonists with a quaternary ammonium group (hexamethonium and chlorisondamine) did not prevent the development of seizures induced by systemic treatment with nicotine in the toxic dose. The Me₃N⁺ group with stable positive charge inhibits transport of these compounds into the brain through the blood-brain barrier. Intracerebral and peripheral (intraperitoneal) administration of compound IEM-1460 with the Me₃N⁺ group was equally potent in reducing the severity of nicotine-induced seizures in mice. This phenomenon is related to the fact that IEM-1460 acts as a nicotinic receptor antagonist and polyamine agonist, which increases blood-brain barrier permeability for polar compounds. These features contribute to IEM-1460 transport into the brain. High anticonvulsant activity of IEM-1460 on the model of nicotine-induced seizures is associated with combined blockade of nicotinic receptors (α3β4 receptors) and glutamate receptors (GluR1 AMPA receptors).