Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder that is the major cause of dementia in the elderly. There is no cure against AD. We have recently discovered a novel transient receptor potential canonical 6 (TRPC6)–mediated intracellular signaling pathway that regulates the stability of dendritic spines and plays a role in memory formation. We have previously shown that TRPC6 agonists exert beneficial effects in models of AD and may serve as lead compounds for development of AD therapeutic agents. In the current study, we used the Clarivate Analytics Integrity database to search for additional TRPC6 agonists. We selected four compounds to study as potential neuroprotective agents. We applied bioinformatics analyses to test the basic pharmacological properties of the selected compounds. We performed in vitro screening of these compounds to validate their ability to protect mushroom spines from amyloid toxicity and determined that two of these compounds exert neuroprotective effects in the nanomolar concentration range. We have chosen one of these compounds [piperazine (PPZ)] for further testing. In agreement with previously published data, we have shown that PPZ potentiates TRPC6 channels. We demonstrated that the neuroprotective mechanism of the investigated PPZ is based on activation of neuronal store-operated calcium entry in spines. We have shown that PPZ restores long-term potentiation induction in 6-month-old 5xFAD mouse hippocampal slices. The obtained results suggest that PPZ and its derivatives are potential lead molecules for development of AD therapeutic agents.
Footnotes
- Received September 7, 2018.
- Accepted January 6, 2019.
This work was supported by the National Institutes of Health [Grant R01NS080152] (to I.B.) (results depicted in Figure 5); the Russian Science Foundation [Grant 14-25-00024-П] (to I.B.) (results depicted in Figures 2–4); a State Grant [17.991.2017/4.6] (to I.B.) (results depicted in Figure 1 and Figure 6), in part by a grant from the Russian Foundation for Basic Research [Project No. 17-00-00408] (to A.V.Z.) (results depicted in Figure 7); the President of Russian Federation [Grant 14.Y30.17.1043-MK] (to E.P.) (results depicted in Table 1 and Table 2); and the Russian State Academies of Sciences Fundamental Research Program for 2013–2020 (to V.P.) (Integrity search and PASS Online support).
I.B. is a holder of the Carl J. and Hortense M. Thomsen Chair in Alzheimer’s Disease Research.
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This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics
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Piperazines as Potential Neuroprotective Agents
