Abstract
Neurological and psychiatric disorders are frequently associated with disruption of various cognitive functions, but development of effective drug treatments for these conditions has proven challenging. One of the main obstacles is the poor predictive validity of our preclinical animal models. In the present study the effects of the γ-secretase inhibitor semagacestat was evaluated in preclinical in vivo electrophysiological models. Recently disclosed Phase III findings on semagacestat indicated that Alzheimer’s disease (AD) patients on this drug showed significantly worsened cognitive function compared to those treated with placebo. Since previous studies have shown that drugs impairing cognitive function (including scopolamine, NMDA (N-methyl-D-aspartate) receptor antagonists, and nociceptin receptor agonists) disrupt or decrease power of elicited theta oscillation in the hippocampus, we tested the effects of acute and sub-chronic administration of semagacestat in this assay. Field potentials were recorded across the hippocampal formation with NeuroNexus multi-site silicon probes in urethane anesthetized male C57BL/6 mice; hippocampal CA1 theta oscillation was elicited by electrical stimulation of the brainstem nucleus pontis oralis. Sub-chronic administration of semagacestat twice daily over 12 days at a dose known to reduce beta-amyloid peptide (Aβ) level [100 mg/kg, p.o. (per oral)] diminished power of elicited hippocampal theta oscillation. Acute, subcutaneous administration of semagacestat (100 mg/kg) produced a similar effect on hippocampal activity. We propose that the disruptive effect of semagacestat on hippocampal function could be one of the contributing mechanisms to its worsening of cognition in patients with AD. As it has been expected, both acute and sub-chronic administrations of semagacestat significantly decreased Aβ40 and Aβ42 levels but the current findings do not reveal the mode of action of semagacestat in disrupting hippocampal oscillignificantly reduced braination.
Highlights
Neurological and psychiatric disorders are frequently associated with disruption of various cognitive functions, but development of effective drug treatments for these conditions has proven challenging
ACUTE ADMINISTRATION OF SEMAGACESTAT REDUCES POWER OF ELICITED HIPPOCAMPAL THETA OSCILLATION Effects of acutely administered semagacestat were evaluated on stimulation-induced hippocampal theta oscillation
Time-frequency decomposition of representative hippocampal recordings indicated that power of spontaneous hippocampal field potential shifted to lower (
Summary
Neurological and psychiatric disorders are frequently associated with disruption of various cognitive functions, but development of effective drug treatments for these conditions has proven challenging. In transgenic mice capturing some pathology of a neurological or psychiatric disease and showing cognitive impairment power of elicited hippocampal theta is significantly reduced, including the beta-amyloid peptide (Aβ) overproducing amyloid precursor protein (APP)/PS1transgenic mice, tau-transgenic mice and NMDA receptor hypomorphic mice (Scott et al, 2011, 2012; Kiss et al, 2013). Those few drugs which improve cognitive function in patients, including acetylcholine esterase inhibitors and memantine increase the power of elicited theta oscillation in this assay (Kinney et al, 1999; Guadagna et al, 2012). Semagacestat, by inhibiting γsecretase reduces level of Aβ in Alzheimer’s patients (Bateman et al, 2009; Mancuso et al, 2011), it was predicted that www.frontiersin.org
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