The effects of physical exercise on nonmotor symptoms and on neuroimmune RAGE network in experimental parkinsonism

Sofia D Viana, Inês R Pita, Cristina Lemos, Daniel Rial, Patrícia Couceiro, Paulo Rodrigues-Santos, Francisco Caramelo, Félix Carvalho, Syed F Ali, Rui D Prediger, Carlos A Fontes Ribeiro, Frederico C Pereira

Parkinson's disease (PD) prodromic stages comprise neuropsychiatric perturbations that critically compromise patient's quality of life. These non-motor 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 receptors for advanced glycation endproducts (RAGE) and Toll-like receptors (TLRs) in distinct pathological settings. Accordingly, the present study aimed to test the hypothesis that PE i) alleviates PD NMS and ii) modulates neuroimmune RAGE-network in experimental PD. Adult Wistar rats subjected to long-term mild-treadmill were administered intranasally with 1-methyl-4-phenyl-tetrahydropyridine (MPTP) and probed for PD NMS prior to the onset of motor abnormalities. Twelve days post-MPTP, neuroimmune RAGE-network transcriptomics (RT-qPCR) 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 upon chemical and physical stressors (untrained-MPTP: RAGE, TLR5,7, p22-NADPH oxidase; trained-saline animals: RAGE, TLR1,5-11, TNF-α, IL-1β, 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-related DJ-1 gene upregulation in frontal cortex when compared to 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 pre-motor stages.