ATH434 Rescues Pre-motor Hyposmia in a Mouse Model of Parkinsonism.

Autor: Beauchamp LC; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia.; Melbourne Dementia Research Centre, 30 Royal Parade, Parkville, VIC, 3052, Australia., Liu XM; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia., Vella LJ; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia.; Melbourne Dementia Research Centre, 30 Royal Parade, Parkville, VIC, 3052, Australia.; Department of Surgery, The Royal Melbourne Hospital, The University of Melbourne, 300 Grattan Street, Parkville, VIC, 3050, Australia., Adlard PA; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia.; Melbourne Dementia Research Centre, 30 Royal Parade, Parkville, VIC, 3052, Australia., Bush AI; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia.; Melbourne Dementia Research Centre, 30 Royal Parade, Parkville, VIC, 3052, Australia., Finkelstein DI; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia.; Melbourne Dementia Research Centre, 30 Royal Parade, Parkville, VIC, 3052, Australia., Barnham KJ; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia. kbarnham@unimelb.edu.au.; Melbourne Dementia Research Centre, 30 Royal Parade, Parkville, VIC, 3052, Australia. kbarnham@unimelb.edu.au.
Jazyk: angličtina
Zdroj: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics [Neurotherapeutics] 2022 Oct; Vol. 19 (6), pp. 1966-1975. Date of Electronic Publication: 2022 Sep 29.
DOI: 10.1007/s13311-022-01300-0
Abstrakt: Hyposmia is a prevalent prodromal feature of Parkinson's disease (PD), though the neuropathology that underlies this symptom is poorly understood. Unlike the substantia nigra, the status of metal homeostasis in the olfactory bulbs has not been characterized in PD. Given the increasing interest in metal modulation as a therapeutic avenue in PD, we sought to investigate bulbar metals and the effect of AT434 (formerly PBT434) an orally bioavailable, small molecule modulator of metal homeostasis on hyposmia in a mouse model of parkinsonism (the tau knockout (tau -/- ) mouse). 5.5 (pre-hyposmia) and 13.5-month-old (pre-motor) mice were dosed with ATH434 (30 mg/kg/day, oral gavage) for 6 weeks. Animals then underwent behavioral analysis for olfactory and motor phenotypes. The olfactory bulbs and the substantia nigra were then collected and analyzed for metal content, synaptic markers, and dopaminergic cell number. ATH434 was able to prevent the development of hyposmia in young tau -/- mice, which coincided with a reduction in bulbar iron and copper levels, an increase in synaptophysin, and a reduction in soluble α-synuclein. ATH434 was able to prevent the development of motor impairment in aged tau -/- mice, which coincided with a reduction in iron levels and reduced neurodegeneration in the substantia nigra. These data implicate metal dyshomeostasis in parkinsonian olfactory deficits, and champion a potential clinical benefit of ATH434 in both prodromal and clinical stages of PD.
(© 2022. The Author(s).)
Databáze: MEDLINE
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