Oral post-lesion administration of 5-HT(1A) receptor agonist repinotan hydrochloride (BAY x 3702) attenuates NMDA-induced delayed neuronal death in rat magnocellular nucleus basalis.
Recent evidence indicates that stimulation of postsynaptic 5-HT(1A) receptors abates excitotoxic neuronal death. Here we investigated whether oral post-lesion administration of the 5-HT(1A) receptor agonist (-)-(R)-2-[4-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]butyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide monohydrochloride (Repinotan HCl) attenuates N-methyl-D-aspartate (NMDA) excitotoxicity (60 nmol/microl) in the rat magnocellular nucleus basalis. Repinotan HCl (1 mg/kg) was administered from day 1, 2, 3, or 6 post-surgery twice daily for five consecutive days. This delayed drug administration protocol was employed to investigate the initiation period during which 5-HT(1A) receptor agonists may significantly influence ongoing neurodegeneration processes. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 1 mg/kg) served as reference compound. Twenty-four hours after drug delivery a small open-field test, while on day 14 post-surgery a passive avoidance test was performed. Effects of Repinotan HCl treatment on the survival of cholinergic magnocellular nucleus basalis neurons and their cortical projections were determined by quantitative acetylcholinesterase (AChE) and choline-acetyltransferase (ChAT) histochemistry. Moreover, AChE and ChAT activities were biochemically measured both in the cerebral cortex and in the magnocellular nucleus basalis. Repinotan HCl treatment markedly increased spontaneous activities in the small open-field at any time-point investigated. Improved memory performance was only demonstrated when Repinotan HCl was administered from day 1 post-lesion on wards. Repinotan HCl treatment from day 2 and 3 post-lesion on markedly attenuated both histochemical and neurochemical characteristics of NMDA excitotoxicity on cholinergic magnocellular nucleus basalis neurons and on their cortical projections. Whereas the neuroprotective profile of Repinotan HCl was superior to that of 8-OH-DPAT, oral administration of both 5-HT(1A) receptor agonists yielded largely equivalent behavioral recovery after NMDA infusion in the magnocellular nucleus basalis. In conclusion, the present data indicate the potent neuroprotective action of the 5-HT(1A) receptor agonist Repinotan HCl with a peak efficacy of delayed (2-3 day) post-lesion drug treatment in vivo. Post-lesion treatment with 5-HT(1A) receptor agonists may therefore be of significance in the intervention of neuronal damage associated with acute excitotoxic conditions.
Harkany
T
T
Department of Animal Physiology, Graduate School of Behavioural and Cognitive Neurosciences, University of Groningen, Haren, The Netherlands. t.harkany@biol.rug.nl
Mulder
J
J
Horvath
K M
KM
Keijser
J
J
van der Meeberg
E K
EK
Nyakas
C
C
Luiten
P G
PG
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000109:Acetylcholine / Q000502:physiology; D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020532:Basal Nucleus of Meynert / Q000187:drug effects / Q000473:pathology*; D001522:Behavior, Animal / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology*; D002795:Choline O-Acetyltransferase / Q000032:analysis; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D008297:Male; D008568:Memory / Q000187:drug effects; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D010296:Parietal Lobe / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
D001578:Benzopyrans; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D013844:Thiazoles; C111221:repinotan hydrochloride; D016202:N-Methylaspartate; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine