Neuroprotective efficacy of the glucocorticoid receptor modulator PT150 in the rotenone mouse model of Parkinson's disease

Authors

• Amanda S. Latham, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, United States.
• Savannah M. Rocha, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, United States.
• Casey P. McDermott, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, United States.
• Philip Reigan, Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
• Richard A. Slayden, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, United States.
• Ronald B. Tjalkens, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, United States. Electronic address: ron.tjalkens@colostate.edu.

Document Type

Article

Abstract

Parkinson's disease (PD) is the most common neurodegenerative movement disorder worldwide. Current treatments for PD largely center around dopamine replacement therapies and fail to prevent the progression of pathology, underscoring the need for neuroprotective interventions. Approaches that target neuroinflammation, which occurs prior to dopaminergic neuron (DAn) loss in the substantia nigra (SN), represent a promising therapeutic strategy. The glucocorticoid receptor (GR) has been implicated in the neuropathology of PD and modulates numerous neuroinflammatory signaling pathways in the brain. Therefore, we investigated the neuroprotective effects of the novel GR modulator, PT150, in the rotenone mouse model of PD, postulating that inhibition of glial inflammation would protect DAn and reduce accumulation of neurotoxic misfolded ⍺-synuclein protein. C57Bl/6 mice were exposed to 2.5 mg/kg/day rotenone by intraperitoneal injection for 14 days. Upon completion of rotenone dosing, mice were orally treated at day 15 with 30 mg/kg/day or 100 mg/kg/day PT150 in the 14-day post-lesioning incubation period, during which the majority of DAn loss and α-synuclein (α-syn) accumulation occurs. Our results indicate that treatment with PT150 reduced both loss of DAn and microgliosis in the nigrostriatal pathway. Although morphologic features of astrogliosis were not attenuated, PT150 treatment promoted potentially neuroprotective activity in these cells, including increased phagocytosis of hyperphosphorylated α-syn. Ultimately, PT150 treatment reduced the loss of DAn cell bodies in the SN, but not the striatum, and prohibited intra-neuronal accumulation of α-syn. Together, these data indicate that PT150 effectively reduced SN pathology in the rotenone mouse model of PD.

Keywords

Astrocyte, Microglia, Molecular modeling, Neurodegeneration, Neuroinflammation, Neuroprotection, Parkinson's disease

Medical Subject Headings

Animals; Rotenone (toxicity); Neuroprotective Agents (pharmacology); Mice, Inbred C57BL; Mice; Male; Dopaminergic Neurons (drug effects, pathology, metabolism); Receptors, Glucocorticoid (metabolism); alpha-Synuclein (metabolism); Substantia Nigra (drug effects, pathology, metabolism); Parkinsonian Disorders (drug therapy, chemically induced, metabolism, pathology); Disease Models, Animal; Phenanthrenes

Publication Date

7-1-2024

Publication Title

Neurotoxicology

E-ISSN

1872-9711

Volume

103

First Page

320

Last Page

334

PubMed ID

38960072

Digital Object Identifier (DOI)

10.1016/j.neuro.2024.06.017

Recommended Citation

Latham, Amanda S.; Rocha, Savannah M.; McDermott, Casey P.; Reigan, Philip; Slayden, Richard A.; and Tjalkens, Ronald B., "Neuroprotective efficacy of the glucocorticoid receptor modulator PT150 in the rotenone mouse model of Parkinson's disease" (2024). Translational Neuroscience. 2546.
https://scholar.barrowneuro.org/neurobiology/2546