Debomoy K Lahiri

Indiana University-Purdue University School of Medicine, Indianapolis, Indiana, United States

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Publications (334)1461.04 Total impact

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    ABSTRACT: Stroke is the world’s leading cause of physiological disability, but there are currently no available agents that can be delivered early after stroke to enhance recovery. Daidzein, a soy isoflavone, is a clinically approved agent that has a neuroprotective effect in vitro, and it promotes axon growth in an animal model of optic nerve crush. The current study investigates the efficacy of daidzein on neuroprotection and functional recovery in a clinically relevant mouse model of stroke recovery. In light of the fact that cholesterols are essential lipid substrates in injury-induced synaptic remodeling, we found that daidzein enhanced the cholesterol homeostasis genetic program, including Lxr and downstream transporters, Apoe, Abca1, and Abcg1 genes in vitro. Daidzein also elevated the cholesterol homeostasis genes in the poststroke brain with Apoe, the highest expressing transporter, but did not affect infarct volume or hemispheric swelling. Despite the absence of neuroprotection, daidzein improved motor/gait function in chronic stroke and elevated synaptophysin expression. However, the daidzein-enhanced functional benefits and synaptophysin expression were abolished in Apoe-knock-out mice, suggesting the importance of daidzein-induced ApoE upregulation in fostering stroke recovery. Dissociation between daidzein-induced functional benefits and the absence of neuroprotection further suggest the presence of nonoverlapping mechanisms underlying recovery processes versus acute pathology. With its known safety in humans, early and chronic use of daidzein aimed at augmenting ApoE may serve as a novel, translatable strategy to promote functional recovery in stroke patients without adverse acute effect.
    Full-text · Article · Nov 2015 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the fourth leading cause of death in the United States and most common cause of adult-onset dementia. The major hallmarks of AD are the formation of senile amyloid plaques made of beta amyloid and neurofibrillary tangles (NFT) which are primarily composed of phosphorylated tau protein. Although numerous agents have been considered as providing protection against AD, identification of potential agents with neuroprotective ability is limited. Thioflavin T has been used in the past to stain amyloid beta plaques in brain. In this study, Thioflavin T (ThT) and vehicle (infant formula) were administered orally by gavage to transgenic (B6C3 APP PS1; AD-Tg) mice beginning at 4 months age and continuing until sacrifice at 9 months of age at 40mg/kg dose. The number of amyloid plaques was reduced dramatically by ThT treatment in both male and female transgenic mice compared to those in control mice. Additionally, GFAP and Amylo-Glo labeling suggest that astrocytic hypertrophy is minimized in ThT-treated animals. Similarly, CD68 labeling, which detects activated microglia, along with Amylo-Glo labeling, suggests that microglial activation is significantly less in ThT-treated mice. Both Aβ-40 and Aβ-42 concentrations in blood rose significantly in the ThT-treated animals suggesting that ThT may inhibit the deposition, degradation, and/or clearance of Aβ plaques in brain.
    No preview · Article · Oct 2015 · Current Alzheimer Research
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    ABSTRACT: Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to Alzheimer's disease (AD) appears to have retarded the pace of translation in the field, and there is much frustration in the public about the lack of an effective treatment. We critically reviewed past literature (1990-2014), analyzed numerous data, and discussed key issues at a consensus conference on Brain Ageing and Dementia to identify and overcome roadblocks in studies intended for translation. We highlight various factors that influence the translation of preclinical research and highlight specific preclinical strategies that have failed to demonstrate efficacy in clinical trials. The field has been hindered by the domination of the amyloid hypothesis in AD pathogenesis while the causative pathways in disease pathology are widely considered to be multifactorial. Understanding the causative events and mechanisms in the pathogenesis are equally important for translation. Greater efforts are necessary to fill in the gaps and overcome a variety of confounds in the generation, study design, testing, and evaluation of animal models and the application to future novel anti-dementia drug trials. A greater variety of potential disease mechanisms must be entertained to enhance progress.
    No preview · Article · Sep 2015 · Journal of Alzheimer's disease: JAD
  • D Sokol · D Lahiri · B Maloney · C Ho

    No preview · Article · Sep 2015 · Archives of Clinical Neuropsychology
  • Becker RE · Seeman MV · Nigel H Greig · Debomoy K Lahiri
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    ABSTRACT: 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. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Aug 2015 · The Lancet Psychiatry

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  • No preview · Article · Jul 2015
  • Debomoy K Lahiri

    No preview · Article · Jun 2015 · Current Aging Science
  • Debomoy K Lahiri

    No preview · Article · May 2015 · Current Alzheimer research
  • Yokesh Balaraman · Debomoy K. Lahiri · John I. Nurnberger
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    ABSTRACT: Recent advances in genome-wide association studies are pointing towards a major role for voltage-gated ion channels in neuropsychiatric disorders and, in particular, bipolar disorder (BD). The phenotype of BD is complex, with symptoms during mood episodes and deficits persisting between episodes. We have tried to elucidate the common neurobiological mechanisms associated with ion channel signaling in order to provide a new perspective on the clinical symptoms and possible endophenotypes seen in BD patients. We propose a model in which the multiple variants in genes coding for ion channel proteins would perturb motivational circuits, synaptic plasticity, myelination, hypothalamic-pituitary-adrenal axis function, circadian neuronal rhythms, and energy regulation. These changes in neurobiological mechanisms would manifest in endophenotypes of aberrant reward processing, white matter hyperintensities, deficits in executive function, altered frontolimbic connectivity, increased amygdala activity, increased melatonin suppression, decreased REM latency, and aberrant myo-inositol/ATP shuttling. The endophenotypes result in behaviors of poor impulse control, motivational changes, cognitive deficits, abnormal stress response, sleep disturbances, and energy changes involving different neurobiological process domains. The hypothesis is that these disturbances start with altered neural circuitry during development, following which multiple environmental triggers may disrupt the neuronal excitability balance through an activity-dependent molecular process, resulting in clinical mood episodes.
    No preview · Article · Apr 2015
  • Mythily Srinivasan · Debomoy K Lahiri
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    ABSTRACT: Introduction: Advances in molecular pathogenesis suggest that the chronic inflammation is a shared mechanism in the initiation and progression of multiple neurodegenerative diseases with diverse clinical manifestations such as Alzheimer's disease (AD) and Multiple sclerosis (MS). Restricted cell renewal and regenerative capacity make the neural tissues extremely vulnerable to the uncontrolled inflammatory process leading to irreversible tissue damage. Areas covered: A predominant consequence of increased inflammatory signaling is the upregulation of the transcription factor, NF-κB with subsequent neuroprotective or deleterious effects depending on the strength of the signal and the type of NF-κB dimers activated. We discuss the interplay between neuroinflammation and neurodegeneration keeping in focus NF-κB signaling as the point of convergence of multiple pathways associated with the development of the neurodegenerative pathologies, AD and MS. Expert opinion: Considerable interest exists in developing efficient NF-κB inhibitors for neurodegenerative diseases. The review includes an overview of natural compounds and rationally designed agents that inhibit NF-κB and mediate neuroprotection in AD and MS. The key chemical moieties of the natural and the synthetic compounds provide efficient leads for the development of effective small molecule inhibitors that selectively target NF-κB activation; this would result in the desired benefit to risk therapeutic effects.
    No preview · Article · Feb 2015 · Expert Opinion on Therapeutic Targets
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    ABSTRACT: Amyloid-β proteins(Aβ) of 42 (Aβ42)and 40 aa (Aβ40) accumulate as senile plaques (SP) and cerebrovascular amyloid protein deposits that are defining diagnostic features of Alzheimer's disease (AD). A number of rare mutations linked to familial AD (FAD) on the Aβ precursor protein (APP),Presenilin-1 (PS1), Presenilin-2 (PS2),Adamalysin10,and other genetic risk factors for sporadic AD such as the γ4 allele of Apolipoprotein E (ApoE-γ4) foster the accumulation of Aβ and also induce the entire spectrum of pathology associated with the disease. Aβ accumulation is therefore a key pathological event and a prime target for the prevention and treatment of AD. APP is sequentially processed by β -site APP cleaving enzyme (BACE1)and β-secretase, a multisubunit PS1/PS2-containing integral membrane protease, to generate Aβ. Although Aβ accumulates in all forms of AD, the only pathways known to be affected in FAD increase Aβ production by APP gene duplication or via base substitutions on APP and γ-secretase subunits PS1 and PS2 that either specifically increase the yield of the longer Aβ42 or both Aβ40 and Aβ42.However, the vast majority of AD patients accumulate Aβ without these known mutations. This led to proposals that impairment of Aβdegradation or clearance may play a key rolein AD pathogenesis. Several candidate enzymes, including Insulin-degrading enzyme (IDE), Neprilysin (NEP), Endothelin-converting enzyme (ECE), Angiotensin converting enzyme (ACE), Plasmin, and Matrix metalloproteinases (MMPs) have been identified and some have even been successfully evaluated in animal models. Several studies also have demonstrated the capacity of γ-secretase inhibitors to paradoxically increase the yield of Aβ and we have recently established that the mechanism is by skirting Aβ degradation. This review outlines major cellular pathways of Aβ degradation to provide a basis for future efforts to fully characterize the panel of pathways responsible for Aβturnover.
    No preview · Article · Dec 2014 · Current Alzheimer Research
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    Mythily Srinivasan · Corinne Blackburn · Debomoy K Lahiri
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    ABSTRACT: Glucocorticoid-induced leucine zipper (GILZ) is a glucocorticoid responsive protein that links the nuclear factor-kappa B (NFκB) and the glucocorticoid signaling pathways. Functional and binding studies suggest that the proline-rich region at the carboxy terminus of GILZ binds the p65 subunit of NFκB and suppresses the immunoinflammatory response. A widely-used strategy in the discovery of peptide drugs involves exploitation of the complementary surfaces of naturally occurring binding partners. Previously, we observed that a synthetic peptide (GILZ-P) derived from the proline-rich region of GILZ bound activated p65 and ameliorated experimental encephalomyelitis. Here we characterize the secondary structure of GILZ-P by circular dichroic analysis. GILZ-P adopts an extended polyproline type II helical conformation consistent with the structural conformation commonly observed in interfaces of transient intermolecular interactions. To determine the potential application of GILZ-P in humans, we evaluated the toxicity and efficacy of the peptide drug in mature human macrophage-like THP-1 cells. Treatment with GILZ-P at a wide range of concentrations commonly used for peptide drugs was nontoxic as determined by cell viability and apoptosis assays. Functionally, GILZ-P suppressed proliferation and glutamate secretion by activated macrophages by inhibiting nuclear translocation of p65. Collectively, our data suggest that the GILZ-P has therapeutic potential in chronic CNS diseases where persistent inflammation leads to neurodegeneration such as multiple sclerosis and Alzheimer's disease.
    Preview · Article · Dec 2014 · Drug Design, Development and Therapy
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    Full-text · Dataset · Nov 2014
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    Full-text · Dataset · Nov 2014
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    Full-text · Dataset · Nov 2014
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    Full-text · Dataset · Nov 2014
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    Nigel H. Greig · Kumar Sambamurti · Debomoy K. Lahiri · Robert E. Becker

    Full-text · Article · Oct 2014 · Annals of Neurology
  • Debomoy K. Lahiri · Bryan Maloney · Justin M. Long · Nigel H. Greig
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    ABSTRACT: Alzheimer's disease (AD) is characterized by formation of neuritic plaque primarily composed of a small filamentous protein called amyloid-β peptide (Aβ). The rate-limiting step in the production of Aβ is the processing of Aβ precursor protein (APP) by β-site APP-cleaving enzyme (BACE1). Hence, BACE1 activity plausibly plays a rate-limiting role in the generation of potentially toxic Aβ within brain and the development of AD, thereby making it an interesting drug target. A phase II trial of the promising LY2886721 inhibitor of BACE1 was suspended in June 2013 by Eli Lilly and Co., due to possible liver toxicity. This outcome was apparently a surprise to the study's team, particularly since BACE1 knockout mice and mice treated with the drug did not show such liver toxicity. Lilly proposed that the problem was not due to LY2886721 anti-BACE1 activity. We offer an alternative hypothesis, whereby anti-BACE1 activity may induce apparent hepatotoxicity through inhibiting BACE1's processing of β-galactoside α-2,6-sialyltransferase I (STGal6 I). In knockout mice, paralogues, such as BACE2 or cathepsin D, could partially compensate. Furthermore, the short duration of animal studies and short lifespan of study animals could mask effects that would require several decades to accumulate in humans. Inhibition of hepatic BACE1 activity in middle-aged humans would produce effects not detectable in mice. We present a testable model to explain the off-target effects of LY2886721 and highlight more broadly that so-called off-target drug effects might actually represent off-site effects that are not necessarily off-target. Consideration of this concept in forthcoming drug design, screening, and testing programs may prevent such failures in the future.
    No preview · Article · Oct 2014 · Alzheimer's & dementia: the journal of the Alzheimer's Association
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    Balmiki Ray · Nipun Chopra · Justin M Long · Debomoy K Lahiri
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    ABSTRACT: Background Culturing primary cortical neurons is an essential neuroscience technique. However, most cultures are derived from rodent brains and standard protocols for human brain cultures are sparse. Herein, we describe preparation, maintenance and major characteristics of a primary human mixed brain culture, including neurons, obtained from legally aborted fetal brain tissue. This approach employs standard materials and techniques used in the preparation of rodent neuron cultures, with critical modifications.ResultsThis culture has distinct differences from rodent cultures. Specifically, a significant numbers of cells in the human culture are derived from progenitor cells, and the yield and survival of the cells grossly depend on the presence of bFGF. In the presence of bFGF, this culture can be maintained for an extended period. Abundant productions of amyloid-ß, tau and proteins make this a powerful model for Alzheimer¿s research. The culture also produces glia and different sub-types of neurons.Conclusion We provide a well-characterized methodology for human mixed brain cultures useful to test therapeutic agents under various conditions, and to carry forward mechanistic and translational studies for several brain disorders.
    Preview · Article · Sep 2014 · Molecular Brain

Publication Stats

12k Citations
1,461.04 Total Impact Points


  • 1993-2015
    • Indiana University-Purdue University School of Medicine
      • • Institute of Psychiatric Research
      • • Psychiatry
      • • Medical and Molecular Genetics
      Indianapolis, Indiana, United States
  • 1991-2015
    • Indiana University-Purdue University Indianapolis
      • • Department of Psychiatry
      • • Department of Medical and Molecular Genetics
      • • Institute of Psychiatric Research
      • • Department of Medicine
      Indianapolis, Indiana, United States
    • CUNY Graduate Center
      New York, New York, United States
  • 2006-2014
    • University of Indianapolis
      Indianapolis, Indiana, United States
  • 2009
    • University of Rhode Island
      • Department of Biomedical and Pharmaceutical Sciences
      Kingston, RI, United States
  • 2008
    • Universidad Autónoma de Madrid
      • Department of Medicine
      Madrid, Madrid, Spain
  • 2002-2005
    • National Institute on Aging
      • • Drug Design and Development Section
      • • Laboratory of Neurosciences (LNS)
      Baltimore, Maryland, United States
  • 2003-2004
    • Medical University of South Carolina
      • Department of Neurosciences (College of Medicine)
      Charleston, South Carolina, United States
  • 2000
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1999
    • University of Louisville
      • Department of Microbiology and Immunology
      Louisville, Kentucky, United States
  • 1989
    • Icahn School of Medicine at Mount Sinai
      • Department of Psychiatry
      Borough of Manhattan, New York, United States