Tetrahydrohyperforin (IDN5706) is a semi-synthetic compound derived from hyperforin (IDN5522) and is the
main active principle of St. John’s Wort. IDN5706 has shown numerous beneficial effects when administered to wild-type
and double transgenic (APPswe/PSEN1ΔE9) mice that model Alzheimer’s disease. However, its mechanism of action is
currently unknown. Toward this end, we analysed field excitatory postsynaptic potentials (fEPSPs) in mouse hippocampal
slices incubated with IDN5706 and in the presence of the TRPC3/6/7 activator 1-oleoyl-2-acetyl-sn-glycerol (OAG), the
TRPC channel blocker SKF96365, and neurotoxic amyloid β-protein (Aβ) oligomers. To study spatial memory, Morris
water maze (MWM) behavioural tests were conducted on wild-type mice treated with IDN5706 and SKF96365. In silico
studies were conducted to predict a potential pharmacophore. IDN5706 and OAG had a similar stimulating effect on
fEPSPs, which was inhibited by SKF96365. IDN5706 protected from reduced fEPSPs induced by Aβ oligomers.
IDN5706 improved spatial memory in wild-type mice, an effect that was counteracted by co-administration of SKF96365.
Our in silico studies suggest strong pharmacophore similarity of IDN5706 and other reported TRPC6 activators
(IDN5522, OAG and Hyp9). We propose that the effect of IDN5706 is mediated through activation of the TRPC3/6/7
channel subfamily. The unveiling of the drug’s mechanism of action is a necessary step toward the clinical use of
IDN5706 in Alzheimer’s disease.
Keywords: Aβ oligomers, Alzheimer's Disease, neuroprotection, hippocampus, tetrahydrohyperforin, TRPC channels.
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