Brain Selective Estrogen Treatment Protects Dopaminergic Neurons and Preserves Behavioral Function in MPTP-induced Mouse
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ORIGINAL ARTICLE
Brain Selective Estrogen Treatment Protects Dopaminergic Neurons and Preserves Behavioral Function in MPTP-induced Mouse Model of Parkinson’s Disease Nidheesh Thadathil 1 & Jianfeng Xiao 1 & Roderick Hori 2 & Stephen E. Alway 3,4,5 & Mohammad Moshahid Khan 1,5 Received: 27 August 2020 / Accepted: 16 November 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra and loss of both motor and non-motor features. Several clinical and preclinical studies have provided evidence that estrogen therapy reduces the risk of PD but have limitations in terms of adverse peripheral effects. Therefore, we examined the potential beneficial effects of the brain-selective estrogen prodrug, 10β, 17β-dihydroxyestra-1,4-dien-3-one (DHED) on nigrostriatal dopaminergic neurodegeneration and behavioral abnormalities in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Wildtype mice were treated with daily subcutaneous injections of DHED (50 and 100 µg/kg) or vehicle for four weeks. To produce PD-like symptoms, mice were injected with MPTP (18 mg/kg in saline; intraperitoneally) four times at 2-hr intervals for one day. After behavioral examination, mice were sacrificed, and the brains were isolated for neurochemical and morphological examinations. MPTP injected mice exhibited loss of dopaminergic neurons and fibers in substantia nigra and striatum respectively, along with impaired motor function at day 7 post MPTP injection. These phenotypes were associated with significantly increased oxidative stress and inflammatory responses in the striatum regions. DHED treatments significantly mitigated behavioral impairments and dopaminergic neurodegeneration induced by MPTP. We further observed that DHED treatment suppressed oxidative stress and inflammation in the striatum of MPTP treated mice when compared to vehicle treated mice. In conclusions, our findings suggest that DHED protects dopaminergic neurons from MPTP toxicity in mouse model of PD and support a beneficial effect of brain-selective estrogen in attenuating neurodegeneration and motor symptoms in PD-related neurological disorders. Keywords Parkinson’s disease . DHED . Oxidative stress . Inflammation . MPTP . Behavioral function
Introduction * Mohammad Moshahid Khan [email protected] 1
Department of Neurology, College of Medicine, University of Tennessee Health Science Center, 855 Monroe Avenue, 415 Link Building, Memphis, TN 38163, USA
2
Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA
3
Laboratory of Muscle Biology and Sarcopenia, Department of Physical Therapy, College of Health Professions, University of Tennessee Health Science Center, Memphis, TN, USA
4
Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
5
Center for Muscle, Metabolism and Neuropathology, Divi
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