Neuroprotective effect of GYKI 52466 on AMPA-induced neurotoxicity in rat striatum.
The neuroprotective effect of intraperitonally administered GYKI 52466 (2,3-benzodiazepine derivate) was investigated on AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxalon-propionic acid)-induced neuronal degeneration in the striatum of adult rats. The dose-dependent neurotoxic effect of AMPA was evaluated by the decrease in the activity of choline acetyltransferase (ChAT), due to degeneration of cholinergic neurons. An injection of 25 mg/kg GYKI 52466 30 min prior to the striatal application of 50 nmol AMPA, followed by repeated application of GYKI 52466 (10 times 5 mg/kg at 10 min intervals, reaching a final dose of 75 mg/kg) was able to prevent neuronal damage monitored by ChAT activity. Conversely, co-injection of GYKI 52466 (50 and 75 mg/kg) with AMPA (50 and 100 nmol) did not elicit any significant protection against the neuronal loss as measured by the ChAT enzyme activity. Therefore, one dose of agonist decreasing ChAT activity by about 40% (50 nmol) was tested on [3H]girisopam binding sites and on the immunoreactivity of glial fibrillary acid protein. The lesions were measured on methylene blue-stained serial sections with a computer assisted image analysis program (NIH Image 1.60). As a result of the AMPA treatment [3H]girisopam binding sites became depleted, and the immunoreactivity of glial fibrillary acid protein increased and on the site of the injection in the striatum a lesion developed. In the presence of AMPA (50 nmol) administered intrastriatally, GYKI 52466 (75 mg/kg i.p.) was able to make the radioactive signal of [3H]girisopam reappear. The volume of AMPA induced neuronal damage in the striatum and the extent of gliosis was reduced. These data provide evidence for the neuroprotective effect of GYKI 52466, and suggest a potential therapeutic value in some neurological disorders.
Institute for Drug Research, Budapest, Hungary.
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Bartha
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Lovas
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Szentkuty
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EJ
Horváth
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Palkovits
D000818:Animals; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D001345:Autoradiography; D001569:Benzodiazepines; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D005911:Gliosis / Q000139:chemically induced; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009498:Neurotoxins / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity*
D014151:Anti-Anxiety Agents; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D009498:Neurotoxins; C061950:GYKI 52466; D001569:Benzodiazepines; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D002795:Choline O-Acetyltransferase