PMID- 29318971 OWN - NLM STAT- MEDLINE DCOM- 20190815 LR - 20190815 IS - 1875-5828 (Electronic) IS - 1567-2050 (Print) IS - 1567-2050 (Linking) VI - 15 IP - 9 DP - 2018 TI - (-)-Phenserine and Inhibiting Pre-Programmed Cell Death: In Pursuit of a Novel Intervention for Alzheimer's Disease. PG - 883-891 LID - 10.2174/1567205015666180110120026 [doi] AB - BACKGROUND: Concussion (mild) and other moderate traumatic brain injury (TBI) and Alzheimer's disease (AD) share overlapping neuropathologies, including neuronal pre-programmed cell death (PPCD), and clinical impairments and disabilities. Multiple clinical trials targeting mechanisms based on the Amyloid Hypothesis of AD have so far failed, indicating that it is prudent for new drug developments to also pursue mechanisms independent of the Amyloid Hypothesis. To address these issues, we have proposed the use of an animal model of concussion/TBI as a supplement to AD transgenic mice to provide an indication of an AD drug candidate's potential for preventing PPCD and resulting progression towards dementia in AD. METHODS: We searched PubMed/Medline and the references of identified articles for background on the neuropathological progression of AD and its implications for drug target identification, for AD clinical trial criteria used to assess disease modification outcomes, for plasma biomarkers associated with AD and concussion/TBI, neuropathologies and especially PPCD, and for methodological critiques of AD and other neuropsychiatric clinical trial methods. RESULTS: We identified and address seven issues and highlight the Thal-Sano AD 'Time to Onset of Impairment' Design for possible applications in our clinical trials. Diverse and significant pathological cascades and indications of self-induced neuronal PPCD were found in concussion/TBI, anoxia, and AD animal models. To address the dearth of peripheral markers of AD and concussion/TBI brain pathologies and PPCD we evaluated Extracellular Vesicles (EVs) enriched for neuronal origin, including exosomes. In our concussion/TBI, anoxia and AD animal models we found evidence consistent with the presence of time-dependent PPCD and (-)-phenserine suppression of neuronal self-induced PPCD. We hence developed an extended controlled release formulation of (-)-phenserine to provide individualized dosing and stable therapeutic brain concentrations, to pharmacologically interrogate PPCD as a drug development target. To address the identified problems potentially putting any clinical trial at risk of failure, we developed exploratory AD and concussion/TBI clinical trial designs. CONCLUSIONS: Our findings inform the biomarker indication of progression of pathological targets in neurodegenerations and propose a novel approach to these conditions through neuronal protection against self-induced PPCD. CI - Copyright(c) Bentham Science Publishers; For any queries, please email at epub@benthamscience.org. FAU - Becker, Robert E AU - Becker RE AD - Aristea Translational Medicine Corporation, Park City, UT 84098, United States. AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, Baltimore, MD 21224, United States. FAU - Greig, Nigel H AU - Greig NH AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, Baltimore, MD 21224, United States. FAU - Lahiri, Debomoy K AU - Lahiri DK AD - Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, United States. FAU - Bledsoe, Joseph AU - Bledsoe J AD - Surgery-Emergency Medicine, Stanford Medicine and Department of Emergency Medicine, Intermountain Medical Center, Murray, UT 84157, United States. FAU - Majercik, Sarah AU - Majercik S AD - Trauma and Surgical Critical Care, Intermountain Medical Center, Salt Lake City, UT 84107, United States. FAU - Ballard, Clive AU - Ballard C AD - Medical School, University of Exeter, Exeter, EX1 2LU, United Kingdom. FAU - Aarsland, Dag AU - Aarsland D AD - Department of Old Age Psychiatry, Institute of Psychiatry, Psychology, & Neuroscience, King's College London, London SE5 8AF, United Kingdom. FAU - Schneider, Lon S AU - Schneider LS AD - Departments of Psychiatry, Neurology, and Gerontology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, United States. FAU - Flanagan, Douglas AU - Flanagan D AD - College of Pharmacy, University of Iowa, Iowa City, IA 52242, United States. FAU - Govindarajan, Ramprakash AU - Govindarajan R AD - College of Pharmacy, University of Iowa, Iowa City, IA 52242, United States. FAU - Sano, Mary AU - Sano M AD - Department of Psychiatry and Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, United States. FAU - Ferrucci, Luigi AU - Ferrucci L AD - Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, Baltimore, MD 21224, United States. FAU - Kapogiannis, Dimitrios AU - Kapogiannis D AD - Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, Baltimore MD, 21224, United States. LA - eng GR - P50 AG005142/AG/NIA NIH HHS/United States GR - R01 AG051086/AG/NIA NIH HHS/United States GR - R41 AG053117/AG/NIA NIH HHS/United States GR - P30 AG010133/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural PT - Review PL - United Arab Emirates TA - Curr Alzheimer Res JT - Current Alzheimer research JID - 101208441 RN - 0 (Cholinesterase Inhibitors) RN - 9U1VM840SP (Physostigmine) RN - SUE285UG3S (phenserine) MH - Alzheimer Disease/*drug therapy MH - Animals MH - Cell Death/*drug effects MH - Cholinesterase Inhibitors/*therapeutic use MH - Humans MH - Physostigmine/*analogs & derivatives/therapeutic use PMC - PMC6039273 MID - NIHMS953146 OTO - NOTNLM OT - (-)-phenserine OT - Alzheimer's disease OT - apoptosis OT - concussion OT - exosomes OT - extracellular vesicle biomarkers OT - neurodegeneration OT - neurodegenerative disorder clinical trial design OT - pre-programmed cell death OT - traumatic brain injury. COIS- Authors other than REB have no conflicts of interest. EDAT- 2018/01/11 06:00 MHDA- 2019/08/16 06:00 PMCR- 2018/07/27 CRDT- 2018/01/11 06:00 PHST- 2017/11/14 00:00 [received] PHST- 2018/01/08 00:00 [accepted] PHST- 2018/01/11 06:00 [pubmed] PHST- 2019/08/16 06:00 [medline] PHST- 2018/01/11 06:00 [entrez] PHST- 2018/07/27 00:00 [pmc-release] AID - CAR-EPUB-87805 [pii] AID - 10.2174/1567205015666180110120026 [doi] PST - ppublish SO - Curr Alzheimer Res. 2018;15(9):883-891. doi: 10.2174/1567205015666180110120026.