Browsing by Subject "Parkinson’s disease (PD)"

Now showing 1 - 4 of 4
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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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    EXPERIENCING POSITIVE ASPECTS IN BEING A SPOUSAL CAREGIVER IN PARKINSON’S AND ALZHEIMER’S DISEASE
    (Office of the Vice Chancellor for Research, 2010-04-09) Habermann, Barbara; Davis, Linda Lindsey
    Aim: A primary aim of this study was to describe caregiver appraisal and coping strategies in caregivers of family members with Parkinson’s (PD) or Alzheimer’s disease (AD). This study was part of a larger randomized clinical trial of a skill building intervention for caregivers. Method: To achieve this aim, 84 spousal caregivers who were consecutively enrolled in the study were interviewed at baseline. The interview focused on specific caregiving situations where the caregiver was asked to describe a positive or meaningful caregiving event. Interviews were semi-structured and included probes to elicit the full narrative of the events. Interviews were transcribed verbatim and analyzed by the research team utilizing a thematic analysis. Results: Of the 84 caregivers, 48% (N=44) were PD caregivers and 52% (N=40) were AD caregivers. Male caregivers comprised 17% (N=14) of the sample. The mean age of the caregivers was 63.7 years (SD ±26.8) with the mean age of their spouses being 75.5 years (SD ± 7.2). The core theme identified was “time spent together”. Within this core theme were several relational sub-themes including turning back the hands of time, being able to rely on the caregiver, and experiencing moments of joy when the family member can participate. Conclusions: Differences existed in both how easily caregivers could identify positive or meaningful aspects to caregiving and how many aspects they could identify. However, the majority of caregivers were able to identify a positive or a meaningful aspect to spousal caregiving. Future intervention studies with spousal caregivers might consider developing targeted interventions based on positive meaningful caregiving situations and building on this relational aspect.
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    Regeneration Through in vivo Cell Fate Reprogramming for Neural Repair
    (Frontiers Media, 2020-04-24) Tai, Wenjiao; Xu, Xiao-Ming; Zhang, Chun-Li; Neurological Surgery, School of Medicine
    The adult mammalian central nervous system (CNS) has very limited regenerative capacity upon neural injuries or under degenerative conditions. In recent years, however, significant progress has been made on in vivo cell fate reprogramming for neural regeneration. Resident glial cells can be reprogrammed into neuronal progenitors and mature neurons in the CNS of adult mammals. In this review article, we briefly summarize the current knowledge on innate adult neurogenesis under pathological conditions and then focus on induced neurogenesis through cell fate reprogramming. We discuss how the reprogramming process can be regulated and raise critical issues requiring careful considerations to move the field forward. With emerging evidence, we envision that fate reprogramming-based regenerative medicine will have a great potential for treating neurological conditions such as brain injury, spinal cord injury (SCI), Alzheimer's disease (AD), Parkinson's disease (PD), and retinopathy.
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    Synchronous neural oscillations in Parkinson’s disease: Variability and its potential network mechanisms
    (Office of the Vice Chancellor for Research, 2011-04-08) Rubchinsky, L.L.; Park, C.; Worth, R.M.
    Recent studies indicate that patterns of oscillatory synchronous activity in Basal Ganglia (BG) may be relevant to BG physiology and disorders, including Parkinson’s disease (PD). Oscillations in BG, in particular, in relation to motor control, are observed in different species, different conditions and different dopaminergic states (e.g., PD vs. normal). The rich membrane properties of BG neurons easily support oscillatory behavior. Correlations of oscillatory activity between different BG locations depend on the brain state and are dynamically organized. A general feature of BG oscillations is strong power and correlations of the β-band activity when no movement is performed and replacement of β with γ-band activity during movement. Dopamine-depleted state, such as PD, is marked by increase of oscillatory and synchronous activity, in particular in the β-band. This study explores the dynamical nature of these oscillations on short time-scales.