Elsevier

Neuroscience

Volume 197, 1 December 2011, Pages 280-292
Neuroscience

Cognitive, Behavioral, and Systems Neuroscience
Research Paper
The coumarin scopoletin potentiates acetylcholine release from synaptosomes, amplifies hippocampal long-term potentiation and ameliorates anticholinergic- and age-impaired memory

https://doi.org/10.1016/j.neuroscience.2011.09.006Get rights and content
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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 (Emax: 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 (Emax: 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.

Highlights

▶The coumarin scopoletin has been described as AChE inhibitor. ▶Now we show it exerts promising procognitive properties via nAChRs. ▶It enhances release of ACh and potentiates hippocampal LTP. ▶It improves novel object recognition and T-maze alternation in scopolamine-amnestic mice and ameliorates object memory in age-impaired mice.

Key words

ACh release
long-term potentiation
hippocampus slice
nicotinic acetylcholine receptor
T-maze
object recognition

Abbreviations

ACh
acetylcholine
AChE
acetylcholinesterase
AD
Alzheimer's dementia
AP-5
d,l-2-amino-5-phosphonopentanoic acid
CSF
cerebrospinal fluid
DHE
dihydro-β-erythroidine
DMSO
dimethyl sulfoxide
fEPSPs
field excitatory postsynaptic potentials
HFS
high-frequency stimulation
LTP
long-term potentiation
MAO
monoamino oxidase
MEC
mecamylamine
nAChR
nicotinic acetylcholine receptor
NMDA
N-methyl-D-aspartate
SCOP
scopolamine
SCT
scopoletin

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These authors contributed equally to this work.