Objective: Literature shows that memory disturbances are accompanied by the activation of potassium channels, and the antagonists of these channels should be used for dementia treatment. What subtypes of the potassium channels are to be preferably blocked in patients with dementia is a question of great interest. One of the appropriate approaches to this question is the investigation of the potency of known nootropic agents to block different subtypes of voltage-gated potassium currents. The goal of the present work was to examine the effects of several cognitive enhancers on different types of voltage gated potassium current.
Design: The experiments were performed on isolated neurons of the land snail. We think that it is possible to study the mechanisms of the effects of nootropics in molluscan neurons because, as it is known from literature, ion channels are highly conserved across species.
Materials and Methods: The group of drugs included: vinpocetine (cavinton), piracetam (nootropil) and a peptide analogue of piracetam, an ethyl ester of N-phenyl-acetyl-L prolyl-glycine (GVS-111) (Seredenin et al., 1995). Two-microelectrode voltage clamp method was used to measure the voltage-gated potassium and calcium currents.
Results: Three subtypes of voltage-gated potassium current were recorded: calcium-dependent potassium current (I.K(Ca)), delayed rectifying current (I.DR), and fast-inactivating potassium current (I.A). A few similar features in the mode of action of nootropics tested were found. Firstly, voltage-gated potassium currents appeared to be much more sensitive to nootropics than voltage-gated inward calcium current. The suppression of the latter required one-two orders higher drugs concentrations than potassium currents reduction. Secondly, the effects of nootropics on different subtypes of potassium current were different. The slow-inactivating, TEA-sensitive subtypes of potassium current (I.K(Ca) and I.DR) were inhibited by low concentrations of the drugs. The I.K(Ca) was inhibited by about 50% and I.DR was diminished by about 20% in the presence of 30 mkM vinpocetine, 100 mkM piracetam or 10 nM GVS-111. In contrast, the fast-inactivating, 4-AP-sensitive I.A was not diminished at all by low concentrations of nootropics. Piracetam and GVS-111 did not affect this current, while vinpocetine even augmented it.
Conclusion: Our results allow to suggest that a desirable profile of action of nootropics should include a selective suppression of slow-inactivatng potassium currents without affecting (or with augmentation of) the fast-inactivating A-current. The results of our work are in line with findings that beta-amyloid, a peptide that is widely believed to play a critical role in the pathophysiology of Alzheimer's disease, blocks I.A (Good et al., 1996), but increases I.DR (Colom et al., 1998).
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