The coumarin scopoletin potentiates acetylcholine release from synaptosomes, amplifies hippocampal long-term potentiation and ameliorates anticholinergic- and age-impaired memory.

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    • Source:
      Publisher: Elsevier Science Country of Publication: United States NLM ID: 7605074 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-7544 (Electronic) Linking ISSN: 03064522 NLM ISO Abbreviation: Neuroscience Subsets: MEDLINE
    • Publication Information:
      Publication: [New York?] : Elsevier Science
      Original Publication: Oxford, Elmsford, N. Y., Pergamon Press
    • Subject Terms:
      Acetylcholine/*metabolism ; Aging/*physiology ; Hippocampus/*drug effects ; Long-Term Potentiation/*physiology ; Memory/*physiology ; Scopoletin/*pharmacology ; Synaptosomes/*metabolism; Animals ; Excitatory Postsynaptic Potentials/drug effects ; Excitatory Postsynaptic Potentials/physiology ; Hippocampus/metabolism ; Long-Term Potentiation/drug effects ; Male ; Memory/drug effects ; Memory Disorders/prevention & control ; Mice ; Mice, Inbred C57BL ; Rats ; Rats, Sprague-Dawley ; Synaptosomes/drug effects
    • Abstract:
      In a previous study the simple, naturally derived coumarin scopoletin (SCT) was identified as an inhibitor of acetylcholinesterase (AChE), using a pharmacophore-based virtual screening approach. In this study the potential of SCT as procholinergic and cognition-enhancing therapeutic was investigated in a more detailed way, using different experimental approaches like measuring newly synthesized acetylcholine (ACh) in synaptosomes, long-term potentiation (LTP) experiments in hippocampal slices, and behavior studies. SCT enhanced the K+-stimulated release of ACh from rat frontal cortex synaptosomes, showing a bell-shaped dose effect curve (E(max): 4 μM). This effect was blocked by the nicotinic ACh receptor (nAChR) antagonists mecamylamine (MEC) and dihydro-β-erythroidine (DHE). The nAChR agonist (and AChE inhibitor) galantamine induced a similar increase in ACh release (E(max): 1 μM). SCT potentiated LTP in hippocampal slices of rat brain. The high-frequency stimulation (HFS)-induced, N-methyl-D-aspartate (NMDA) receptor dependent LTP of field excitatory postsynaptic potentials at CA3-CA1 synapses was greatly enhanced by pre-HFS application of SCT (4 μM for 4 min). This effect was mimicked by nicotine (2 μM) and abolished by MEC, suggesting an effect on nAChRs. SCT did not restore the total inhibition of LTP by NMDA receptor antagonist D, L-2-amino-5-phosphonopentanoic acid (AP-5). SCT (2 μg, i.c.v.) increased T-maze alternation and ameliorated novel object recognition of mice with scopolamine-induced cholinergic deficit. It also reduced age-associated deficits in object memory of 15-18-month-old mice (2 mg/kg sc). Our findings suggest that SCT possesses memory-improving properties, which are based on its direct nAChR agonistic activity. Therefore, SCT might be able to rescue impaired cholinergic functions by enhancing nAChR-mediated release of neurotransmitters and promoting neural plasticity in hippocampus.
      (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)
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    • Accession Number:
      KLF1HS0SXJ (Scopoletin)
      N9YNS0M02X (Acetylcholine)
    • Publication Date:
      Date Created: 20110928 Date Completed: 20120227 Latest Revision: 20211020
    • Publication Date:
      20240829
    • Accession Number:
      PMC3212650
    • Accession Number:
      10.1016/j.neuroscience.2011.09.006
    • Accession Number:
      21945033