Browsing by Author "Tweedie, David"

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    Design, synthesis and biological assessment of novel N-substituted 3-(phthalimidin-2-yl)-2,6-dioxopiperidines and 3-substituted 2,6-dioxopiperidines for TNF-α inhibitory activity
    (Elsevier, 2011-07-01) Luo, Weiming; Yu, Qian-sheng; Salcedo, Isidro; Holloway, Harold W.; Lahiri, Debomoy K.; Brossi, Arnold; Tweedie, David; Greig, Nigel H.; Department of Psychiatry, IU School of Medicine
    Eight novel 2-(2,6-dioxopiperidin-3-yl)phthalimidine EM-12 dithiocarbamates 9 and 10, N-substituted 3-(phthalimidin-2-yl)-2,6-dioxopiperidines 11-14 and 3-substituted 2,6-dioxopiperidines 16 and 18 were synthesized as tumor necrosis factor-α (TNF-α) synthesis inhibitors. Synthesis involved utilization of a novel condensation approach, a one-pot reaction involving addition, iminium rearrangement and elimination, to generate the phthalimidine ring required for the creation of compounds 9-14. Agents were, thereafter, quantitatively assessed for their ability to suppress the synthesis on TNF-α in a lipopolysaccharide (LPS)-challenged mouse macrophage-like cellular screen, utilizing cultured RAW 264.7 cells. Whereas compounds 9, 14 and 16 exhibited potent TNF-α lowering activity, reducing TNF-α by up to 48% at 30 μM, compounds 12, 17 and 18 presented moderate TNF-α inhibitory action. The TNF-α lowering properties of these analogs proved more potent than that of revlimid (3) and thalidomide (1). In particular, N-dithiophthalimidomethyl-3-(phthalimidin-2-yl)-2,6-dioxopiperidine 14 not only possessed the greatest potency of the analogs to reduce TNF-α synthesis, but achieved this with minor cellular toxicity at 30 μM. The pharmacological focus of the presented compounds is towards the development of well-tolerated agents to ameliorate the neuroinflammation, that is, commonly associated with neurodegenerative disorders, epitomized by Alzheimer's disease and Parkinson's disease.
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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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    Sitagliptin elevates plasma and CSF incretin levels following oral administration to nonhuman primates: relevance for neurodegenerative disorders
    (Springer, 2024) Li, Yazhou; Vaughan, Kelli L.; Wang, Yun; Yu, Seong‑Jin; Bae, Eun‑Kyung; Tamargo, Ian A.; Kopp, Katherine O.; Tweedie, David; Chiang, Cheng‑Chuan; Schmidt, Keith T.; Lahiri, Debomoy K.; Tones, Michael A.; Zaleska, Margaret M.; Hoffer, Barry J.; Mattison, Julie A.; Greig, Nigel H.; Psychiatry, School of Medicine
    The endogenous incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) possess neurotrophic, neuroprotective, and anti-neuroinflammatory actions. The dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin reduces degradation of endogenous GLP-1 and GIP, and, thereby, extends the circulation of these protective peptides. The current nonhuman primate (NHP) study evaluates whether human translational sitagliptin doses can elevate systemic and central nervous system (CNS) levels of GLP-1/GIP in naive, non-lesioned NHPs, in line with our prior rodent studies that demonstrated sitagliptin efficacy in preclinical models of Parkinson's disease (PD). PD is an age-associated neurodegenerative disorder whose current treatment is inadequate. Repositioning of the well-tolerated and efficacious diabetes drug sitagliptin provides a rapid approach to add to the therapeutic armamentarium for PD. The pharmacokinetics and pharmacodynamics of 3 oral sitagliptin doses (5, 20, and 100 mg/kg), equivalent to the routine clinical dose, a tolerated higher clinical dose and a maximal dose in monkey, were evaluated. Peak plasma sitagliptin levels were aligned both with prior reports in humans administered equivalent doses and with those in rodents demonstrating reduction of PD associated neurodegeneration. Although CNS uptake of sitagliptin was low (cerebrospinal fluid (CSF)/plasma ratio 0.01), both plasma and CSF concentrations of GLP-1/GIP were elevated in line with efficacy in prior rodent PD studies. Additional cellular studies evaluating human SH-SY5Y and primary rat ventral mesencephalic cultures challenged with 6-hydroxydopamine, established cellular models of PD, demonstrated that joint treatment with GLP-1 + GIP mitigated cell death, particularly when combined with DPP-4 inhibition to maintain incretin levels. In conclusion, this study provides a supportive translational step towards the clinical evaluation of sitagliptin in PD and other neurodegenerative disorders for which aging, similarly, is the greatest risk factor.