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Systemically administered D-glucose conjugates of 7-chlorokynurenic acid are centrally available and exert anticonvulsant activity in rodents.
- Source :
-
Brain research [Brain Res] 2000 Mar 31; Vol. 860 (1-2), pp. 149-56. - Publication Year :
- 2000
-
Abstract
- We have synthesized D-glucose or D-galactose esters of 7-chlorokynurenic acid (7ClKynA) as prodrugs to facilitate the transport of 7ClKynA across the blood-brain barrier. Intraperitoneal (i.p.) administration of either 7ClKynA-D-glucopyranos-6'-ylester (7ClKynA/Glu6) or 7ClKynA-D-glucopyranos-3'-yl ester (7ClKynA/Glu3) was protective against seizures induced by N-methyl-D-aspartate (NMDA) in mice, with the former drug showing the highest anticonvulsive activity. Systemic injection of equal amounts of 7ClKynA-D-galactopyranos-6'-yl ester (7ClKynA/Gal6) or free 7ClKynA did not protect against NMDA seizures. Microdialysis in freely moving rats showed the presence of significant amounts of 7ClKynA/Glu6, as well as of 7ClKynA or KynA, in cortical perfusates after i.p. injections of 7ClKynA/Glu6. In contrast, only small amounts of 7ClKynA or KynA were detected after i.p. injection of unconjugated 7ClKynA. Prodrug metabolism has also been examined in mouse cortical cultures containing both neurons and astrocytes. 7ClKynA/Glu6 and 7ClKynA/Gal6 were rapidly metabolized into 7ClKynA and KynA, whereas 7ClKynA/Glu3 was metabolized with a slower kinetics. As a result of its conversion into 7ClKynA and KynA, 7ClKynA/Glu6 protected cortical neurons against NMDA toxicity. We conclude that sugar conjugates of 7ClKynA (and perhaps of other excitatory amino acid receptor antagonists) are prodrugs of potential interest in the experimental therapy of epilepsy and acute or chronic neurodegenerative disorders.
- Subjects :
- Animals
Anticonvulsants administration & dosage
Anticonvulsants chemical synthesis
Anticonvulsants therapeutic use
Astrocytes drug effects
Biotransformation
Blood-Brain Barrier
Cells, Cultured
Cerebral Cortex cytology
Culture Media, Conditioned
Epilepsies, Partial chemically induced
Epilepsy, Tonic-Clonic chemically induced
Excitatory Amino Acid Antagonists administration & dosage
Excitatory Amino Acid Antagonists chemical synthesis
Excitatory Amino Acid Antagonists therapeutic use
Galactose chemistry
Injections, Intraperitoneal
Kynurenic Acid administration & dosage
Kynurenic Acid chemistry
Kynurenic Acid pharmacokinetics
Kynurenic Acid therapeutic use
Male
Mice
Microdialysis
Molecular Structure
N-Methylaspartate toxicity
Neurons drug effects
Neuroprotective Agents administration & dosage
Neuroprotective Agents chemical synthesis
Neuroprotective Agents therapeutic use
Prodrugs chemical synthesis
Prodrugs chemistry
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Anticonvulsants pharmacokinetics
Epilepsies, Partial drug therapy
Epilepsy, Tonic-Clonic drug therapy
Excitatory Amino Acid Antagonists pharmacokinetics
Glucose chemistry
Kynurenic Acid analogs & derivatives
Kynurenic Acid metabolism
Neuroprotective Agents pharmacokinetics
Prodrugs pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 0006-8993
- Volume :
- 860
- Issue :
- 1-2
- Database :
- MEDLINE
- Journal :
- Brain research
- Publication Type :
- Academic Journal
- Accession number :
- 10727634
- Full Text :
- https://doi.org/10.1016/s0006-8993(00)01962-4