Repeated administration of escalating high doses of dexfenfluramine does not produce morphological evidence for neurotoxicity in the cortex of rats.
Rats were treated for 28 days with increasing doses of dexfenfluramine (0.5, 1, 1.5, 2, 3, 4 and 5 mg/kg bid ip, each dose given for 4 days before being increased) and subsequently studied at intervals between 1 and 60 days following the cessation of treatment. Control rats received vehicle and were allowed food ad libitum or were pair fed with dexfenfluramine-treated animals. Immediately following drug treatment 5-HT immunoreactivity was increased in cortical areas compared to control animals. Subsequently, there was a persistent decrease in fine fibre density and the appearance of coarse truncated fibres. 5-HT levels in cortex were decreased 1 day following dexfenfluramine treatment but recovered to control values by 15 days. GFAP and GAP 43 immunoreactivity was unaffected by dexfenfluramine treatment compared to control animals, indicating a lack of evidence for neuronal degeneration and regeneration. Dexfenfluramine treatment decreased the density of 5-HT uptake sites in the cortex, labelled with [3H]-citalopram, but this partially recovered towards control values at 60 days. These alterations in 5-HT terminal networks conflict with the return of 5-HT levels to normal and the lack of evidence for degenerative changes or neuronal regrowth. On the basis of these results, it cannot be concluded that dexfenfluramine is neurotoxic.
Rose
S
S
Neurodegenerative Diseases Research Centre, King's College London.
Hunt
S
S
Collins
P
P
Hindmarsh
J G
JG
Jenner
P
P
D000818:Animals; D001067:Appetite Depressants / Q000633:toxicity*; D001665:Binding Sites; D015415:Biomarkers; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D015283:Citalopram / Q000378:metabolism; D005277:Fenfluramine / Q000633:toxicity*; D019922:GAP-43 Protein; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D009410:Nerve Degeneration; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D009416:Nerve Regeneration; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009498:Neurotoxins; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*
D001067:Appetite Depressants; D015415:Biomarkers; D019922:GAP-43 Protein; D005904:Glial Fibrillary Acidic Protein; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D015283:Citalopram; D005277:Fenfluramine; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid