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.
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).
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
SCT (2 μg, i.c.v.) increased T-maze alternation and ameliorated
novel object recognition of mice with scopolamine-induced
It also reduced age-associated deficits in object memory of
15–18-month-old mice (2 mg/kg sc).
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.