Oral post-lesion administration of 5-HT1A receptor agonist repinotan hydrochloride (Bay X 3702) attenuates NMDA-induced delayed neuronal death in rat magnocellular nucleus basalis

T. Harkany, Jan Mulder, K.M. Horvath, Johannes Keijser, E.K. van der Meeberg, C. Nyakas, P.G.M. Luiten

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    Abstract

    Recent evidence indicates that stimulation of postsynaptic 5-HT1A receptors abates excitotoxic neuronal death. Here we investigated whether oral post-lesion administration of the 5-HT1A 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/mul) 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-HT1A 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 I 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-HT1A 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-HT1A receptor agonist Repinotan HCl with a peak efficacy of delayed (2-3 day) post-lesion drug treatment in vivo. Post-lesion treatment with 5-HT1A receptor agonists may therefore be of significance in the intervention of neuronal damage associated with acute excitotoxic conditions. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.

    Original languageEnglish
    Pages (from-to)629-642
    Number of pages14
    JournalNeuroscience
    Volume108
    Issue number4
    DOIs
    Publication statusPublished - 2001

    Keywords

    • apoptosis
    • cholinergic system
    • excitotoxicity
    • learning and memory
    • neuroprotection
    • METHYL-D-ASPARTATE
    • CORTICAL CHOLINERGIC INNERVATION
    • X 3702
    • ALZHEIMERS-DISEASE
    • IN-VIVO
    • INDUCED EXCITOTOXICITY
    • CULTURED NEURONS
    • FOREBRAIN NUCLEI
    • AMINO-ACIDS
    • BRAIN

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