title: The effects of physical exercise on nonmotor symptoms and on neuroimmune RAGE network in experimental parkinsonism.
abstract: Parkinson's disease (PD) prodromal stages comprise neuropsychiatric perturbations that critically compromise a patient's quality of life. These nonmotor symptoms (NMS) are associated with exacerbated innate immunity, a hallmark of overt PD. Physical exercise (PE) has the potential to improve neuropsychiatric deficits and to modulate immune network including receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs) in distinct pathological settings. Accordingly, the present study aimed to test the hypothesis that PE1) alleviates PD NMS and2) modulates neuroimmune RAGE network in experimental PD. Adult Wistar rats subjected to long-term mild treadmill were administered intranasally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probed for PD NMS before the onset of motor abnormalities. Twelve days after MPTP, neuroimmune RAGE network transcriptomics (real-time quantitative PCR) was analyzed in frontal cortex, hippocampus, and striatum. Untrained MPTP animals displayed habit-learning and motivational deficits without gross motor impairments (cued version of water-maze, splash, and open-field tests, respectively). A suppression of RAGE and neuroimmune-related genes was observed in frontal cortex on chemical and physical stressors (untrained MPTP: RAGE, TLR5 and -7, and p22 NADPH oxidase; saline-trained animals: RAGE, TLR1 and -5 to -11, TNF-α, IL-1β, and p22 NADPH oxidase), suggesting the recruitment of compensatory mechanisms to restrain innate inflammation. Notably, trained MPTP animals displayed normal cognitive/motivational performances. Additionally, these animals showed normal RAGE expression and neuroprotective PD-relatedDJ-1gene upregulation in frontal cortex when compared with untrained MPTP animals. These findings corroborate PE efficacy in improving PD NMS and newly identify RAGE network as a neural substrate for exercise intervention. Additional research is warranted to unveil functional consequences of PE-induced modulation of RAGE/DJ-1 transcriptomics in PD premotor stages.NEW & NOTEWORTHYThis study newly shows that physical exercise (PE) corrects nonmotor symptoms of the intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of experimental parkinsonism. Additionally, we show that suppression of neuroimmune receptor for advanced glycation end products (RAGE) network occurs in frontal cortex on chemical (MPTP) and physical (PE) interventions. Finally, PE normalizes frontal cortical RAGE transcriptomics and upregulates the neuroprotectiveDJ-1gene in the intranasal MPTP model of experimental parkinsonism.
authors.affiliation: Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|Center for Neuroscience and Cell Biology-Institute for Biomedical Imaging and Life Sciences, University of Coimbra, Coimbra, Portugal.|Polytechnic Institute of Coimbra, Escola Superior de Tecnologia da Saúde de Coimbra-Coimbra Health School, Pharmacy, Coimbra, Portugal.
authors.forename: Sofia D
authors.initials: SD
authors.lastname: Viana
authors.affiliation: Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|Center for Neuroscience and Cell Biology-Institute for Biomedical Imaging and Life Sciences, University of Coimbra, Coimbra, Portugal.
authors.forename: Inês R
authors.initials: IR
authors.lastname: Pita
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Lemos
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.|Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rial
authors.affiliation: Immunology and Oncology Laboratory, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Couceiro
authors.affiliation: Immunology and Oncology Laboratory, Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.|Institute of Immunology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|Center of Investigation in Environment, Genetics and Oncobiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Paulo
authors.initials: P
authors.lastname: Rodrigues-Santos
authors.affiliation: Laboratory of Biostatistics and Medical Informatics, Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Francisco
authors.initials: F
authors.lastname: Caramelo
authors.affiliation: Research Unit on Applied Molecular Biosciences, Rede de Química e Tecnologia, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal; and.
authors.forename: Félix
authors.initials: F
authors.lastname: Carvalho
authors.affiliation: Neurochemistry Laboratory, Division of Neurotoxicology, National Center of Toxicological Research, Food and Drug Administration, Jefferson, Arkansas.
authors.forename: Syed F
authors.initials: SF
authors.lastname: Ali
authors.affiliation: Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil.
authors.forename: Rui D
authors.initials: RD
authors.lastname: Prediger
authors.affiliation: Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.|Center for Neuroscience and Cell Biology-Institute for Biomedical Imaging and Life Sciences, University of Coimbra, Coimbra, Portugal.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Fontes Ribeiro
authors.affiliation: Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; fredcp@ci.uc.pt.|Center for Neuroscience and Cell Biology-Institute for Biomedical Imaging and Life Sciences, University of Coimbra, Coimbra, Portugal.
authors.forename: Frederico C
authors.initials: FC
authors.lastname: Pereira
mesh_terms: D000818:Animals; D001921:Brain / Q000276:immunology / Q000378:metabolism; D005080:Exercise Test / Q000379:methods; D008297:Male; D015213:Neuroimmunomodulation / Q000502:physiology*; D020734:Parkinsonian Disorders / Q000276:immunology* / Q000534:rehabilitation*; D010805:Physical Conditioning, Animal / Q000379:methods / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D000067759:Receptor for Advanced Glycation End Products / Q000096:biosynthesis* / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: C000593874:Ager protein, rat; D000067759:Receptor for Advanced Glycation End Products
keywords: Parkinson’s disease; intranasal MPTP; neuroimmune RAGE network; nonmotor symptoms; physical exercise