Browsing by Author "Becker, Robert E."

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    Amyloid-β precursor protein synthesis inhibitors for Alzheimer's disease treatment
    (Wiley, 2014-10) Greig, Nigel H.; Sambamurti, Kumar; Lahiri, Debomoy K.; Becker, Robert E.; Department of Psychiatry, IU School of Medicine
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    Incretin mimetics as pharmacological tools to elucidate and as a new drug strategy to treat traumatic brain injury
    (Elsevier, 2014-02) Greig, Nigel H.; Tweedie, David; Rachmany, Lital; Li, Yazhou; Rubovitch, Vardit; Schreiber, Shaul; Chiang, Yung-Hsiao; Hoffer, Barry J.; Miller, Jonathan; Lahiri, Debomoy K.; Sambamurti, Kumar; Becker, Robert E.; Pick, Chaim G.; Department of Psychiatry, IU School of Medicine
    Traumatic brain injury (TBI), either as an isolated injury or in conjunction with other injuries, is an increasingly common occurring event. An estimated 1.7 million injuries occur within the US each year and 10 million people are affected annually worldwide. Indeed, some one-third (30.5%) of all injury-related deaths in the U.S. are associated with TBI, which will soon outstrip many common diseases as the major cause of death and disability. Associated with a high morbidity and mortality, and no specific therapeutic treatment, TBI has become a pressing public health and medical problem. The highest incidence of TBI occurs among young adults (15 to 24 years age) as well as in the elderly (75 years and older) who are particularly vulnerable as injury, often associated with falls, carries an increased mortality and worse functional outcome following lower initial injury severity. Added to this, a new and growing form of TBI, blast injury, associated with the detonation of improvised explosive devices in the war theaters of Iraq and Afghanistan, are inflicting a wave of unique casualties of immediate impact to both military personnel and civilians, for which long-term consequences remain unknown and may potentially be catastrophic. The neuropathology underpinning head injury is becoming increasingly better understood. Depending on severity, TBI induces immediate neuropathological effects that for the mildest form may be transient but with increasing severity cause cumulative neural damage and degeneration. Even with mild TBI, which represents the majority of cases, a broad spectrum of neurological deficits, including cognitive impairments, can manifest that may significantly influence quality of life. In addition, TBI can act as a conduit to longer-term neurodegenerative disorders. Prior studies of glucagon-like peptide-1 (GLP-1) and long-acting GLP-1 receptor agonists have demonstrated neurotrophic/neuroprotective activities across a broad spectrum of cellular and animal models of chronic neurodegenerative (Alzheimer's and Parkinson's diseases) and acute cerebrovascular (stroke) disorders. In line with the commonality in mechanisms underpinning these disorders as well as TBI, the current article reviews this literature and recent studies assessing GLP-1 receptor agonists as a potential treatment strategy for mild to moderate TBI.
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    (-)-Phenserine and Inhibiting Pre-Programmed Cell Death: In Pursuit of a Novel Intervention for Alzheimer's Disease
    (Bentham Science Publishers, 2018) Becker, Robert E.; Greig, Nigel H.; Schneider, Lon S.; Ballard, Clive; Aarsland, Dag; Lahiri, Debomoy K.; Flanagan, Douglas; Govindarajan, Ramprakash; Sano, Mary; Kapogiannis, Dimitrios; Ferrucci, Luigi; Psychiatry, School of Medicine
    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.
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    What can triumphs and tribulations from drug research in Alzheimer's disease tell us about the development of psychotropic drugs in general?
    (Elsevier, 2015-08) Becker, Robert E.; Seeman, Mary V.; Greig, Nigel H.; Lahiri, Debomoy K.; Department of Psychiatry, IU School of Medicine
    Drug development for psychiatric disorders has almost ground to a halt. Some newer drugs are better tolerated or safer than older ones, but none is more effective. Years of failure in preventing or delaying the onset of illness, ameliorating symptoms, lowering suicide rates, or improving quality of life has put the commercial investments that had previously funded drug development at risk. To promote the development of psychiatric drugs with greater efficacy, we need to improve the way we bring potentially beneficial drugs to market. We need to acknowledge, as has been done in other specialties, that people differ in their response to drugs. Psychiatric drug research needs to be grounded in a better understanding of molecular brain mechanisms, neural circuits, and their relations to clinical disease. With this understanding, drugs need to be more precisely directed at specific brain targets. In psychiatric drug development, government, industry, regulatory bodies, and academia should realign to ensure medical science is used in the best interests of patients.