The attenuation of kainate-induced neurotoxicity by chlormethiazole and its enhancement by dizocilpine, muscimol, and adenosine receptor agonists.
Systemically administered kainate (10 mg.kg-1) caused neuronal loss in both the hippocampus and the entorhinal regions of the rat brain. This resulted in a loss of 68.3 +/- 13.8 and 53.3 +/- 12.8% of pyramidal neurones in the hippocampal CA1 and CA3a regions, respectively. Chlormethiazole attenuated the loss of neurones in the hippocampal cell layers CA1 (cell loss 10 +/- 3.2%) and CA3a (cell loss 10 +/- 7.7%). The neuroprotective activity of chlormethiazole was apparent in the presence or absence of a low dose of clonazepam (200 micrograms.kg-1 i.p.). The kainate-induced damage could also be measured by the increase in binding of the peripheral benzodiazepine ligand ([3H]PK11195) in the hippocampus. In kainate-treated rats there was a 350-500% increase in binding indicative of reactive gliosis. Chlormethiazole prevented this elevation in a dose- and time-dependent manner, with an ED50 of 10.64 mg.kg-1 and an effective therapeutic window from 1 to 4 h posttreatment. Dizocilpine also attenuated damage significantly. The GABAA agonist muscimol was also able to attenuate the increase in [3H]PK11195 binding in a dose-dependent manner, with an ED50 of approximately 0.1 mg.kg-1. If muscimol, dizocilpine, or the adenosine A1 receptor agonist R-N6-phenylisopropyl-adenosine were administered together with chlormethiazole at their respective ED25 doses, a potentiation was apparent in the degree of neuroprotection. It is concluded that the combination of neuroprotective agents with different mechanisms of action can lead to a synergistic protection against excitotoxicity.
MacGregor
D G
DG
Division of Neuroscience and Biomedical Systems, University of Glasgow, Scotland, United Kingdom.
Graham
D I
DI
Stone
T W
TW
D000241:Adenosine / Q000502:physiology*; D000818:Animals; D001831:Body Temperature; D002719:Chlormethiazole / Q000494:pharmacology* / Q000627:therapeutic use; D016291:Dizocilpine Maleate / Q000494:pharmacology* / Q000627:therapeutic use; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D018728:Entorhinal Cortex / Q000187:drug effects* / Q000473:pathology; D004830:Epilepsy, Tonic-Clonic / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D018755:GABA Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D005911:Gliosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D007546:Isoquinolines / Q000378:metabolism; D007608:Kainic Acid / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D009118:Muscimol / Q000494:pharmacology* / Q000627:therapeutic use; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D014970:Xanthines / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D007546:Isoquinolines; D018696:Neuroprotective Agents; D009498:Neurotoxins; D058915:Purinergic P1 Receptor Antagonists; D014970:Xanthines; D002719:Chlormethiazole; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D016291:Dizocilpine Maleate; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine; D007608:Kainic Acid; C037850:PK 11195