Abstract
Many neurodegenerative diseases are associated with severe memory loss and cognitive impairment, highlighting a critical demand for the development of neuroprotectants and nootropics. It has been shown that certain compounds can trigger lasting neuroprotective mechanisms. This phenomenon is called ‘pharmacological preconditioning,’ and it has recently been suggested that preconditioning may also enhance cognitive function. Indeed, preconditioning with GYKI-52466 and domoic acid (DOM) has prophylactic neuroprotective efficacy in vivo and in vitro, and preliminary in vitro results demonstrate their ability to enhance long term synaptic potentiation (LTP) and long term depression (LTD), thus denoting nootropic potential. The aim of the present study was develop an effective in vitro preconditioning strategy using GYKI-52466 or DOM, and clarify their effects on LTP and LTD induction in the rat hippocampus.
Hippocampal slices from male Sprague Dawley rats were subject to acute or chronic preconditioning with 6 μM GYKI-52466, or acute preconditioning with 50 nM DOM. Control slices were not preconditioned. Slices subsequently underwent LTP or LTD induction, and electrophysiological techniques were used to assess the response to this. Orthodromic Schaffer collateral-evoked CA1 population spikes and field excitatory postsynaptic potentials (fEPSP) were monitored before and after LTP or LTD induction. Data were expressed as mean percentage change from baseline (± SEM) and group differences compared to controls at a 30 minute time-point post LTP or LTD induction was determined by an unpaired student’s t-test at a confidence level of P<0.05.
GYKI-52466 and DOM preconditioning failed to enhance LTP and LTD induction. Both control and preconditioned slices exhibited comparable magnitudes of LTP and LTD for population spike amplitude, area and fEPSP slope, with no significant differences between control and preconditioned slices evident at a 30 minute time-point. These findings suggest that preconditioning with GYKI-52466 and DOM would not confer nootropic potential.