Browsing by Author "Hoffer, Barry J."

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    Elevating brain GLP‐1 and GIP levels as a treatment strategy for neurodegenerative disorders
    (Wiley, 2025-01-09) Greig, Nigel H.; Wang, Yun; Hoffer, Barry J.; Sambamurti, Kumar; Lahiri, Debomoy K.; Tones, Michael A.; Zaleska, Margaret M.; Mattison, Julie A.; Psychiatry, School of Medicine
    Background: Epidemiological studies report an elevated risk of neurodegenerative disorders, particularly Parkinson’s disease (PD), in patients with type 2 diabetes mellitus (T2DM) that is mitigated in those prescribed incretin mimetics or dipeptidyl peptidase 4 inhibitors (DPP‐4Is). Incretin mimetic repurposing appears promising in human PD and Alzheimer’s disease (AD) clinical trials. DPP‐4Is are yet to be evaluated in PD or AD human studies. Methods: Incretin mimetics have been evaluated in multiple cellular/animal PD models, including in 6‐hdroxydopamine (6‐OHDA) rats, and have demonstrated efficacy. The clinically approved DPP‐4Is, sitagliptin (Januvia) and PF‐00734200 (gosogliptin/Saterex) were hence evaluated in the classic 6‐OHDA unilateral medial forebrain bundle rat PD model to evaluate their repurposing potential when administered as human equivalent oral doses. Equivalent doses then were administered to naive nonhuman primates (NHPs) to evaluate whether biomarkers of efficacy in rat could be reproduced in NHPs as a further translational step towards human studies. Pharmacokinetics, DPP‐4 inhibition, GLP‐1/GIP and dopamine levels, together with dopaminergic and neuroinflammatory markers, and GLP‐1/GIP receptor levels were quantified. Results: Sitagliptin/PF‐00734,200 pre‐ or post‐treatment mitigated 6‐OHDA‐induced dopaminergic neurodegeneration, dopamine level loss and neuroinflammation, and augmented neurogenesis in lesioned substantia nigra pars compacta and in striatum, and reduced classical methamphetamine‐induced rotation in rats. This efficacy associated with 70‐80% plasma and 20‐30% brain DPP‐4 inhibition, and with elevated plasma and brain GLP‐1/GIP levels. Alike plasma/CSF DPP‐4 inhibition and elevated GLP‐1/GIP levels were determined in NHPs administered rat equivalent (human translational) sitagliptin doses. In relation to the drug targets, brain GLP‐1/GIP receptor protein levels were age‐dependently maintained in rodents, preserved in rats challenged with 6‐OHDA, and in humans with PD. Combined GLP‐1+GIP receptor activation in neuronal cultures resulted in neurotrophic/neuroprotective actions superior to single agonists alone – particularly when combined with a DPP‐4I Conclusions: These studies support further evaluation of repurposing clinically approved drugs that elevate plasma/brain/CSF GLP‐1/GIP as a treatment strategy for neurodegenerative disorders. Incretin mimetics are already in clinical evaluation in PD and AD. Similarly, the repurposing of gliptins warrants evaluation both alone and in combination with an effective incretin mimetic.
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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.