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bioRxiv · 10.1101/2023.07.11.548638

Moderate intensity aerobic exercise in 6-OHDA-lesioned rats alleviates established motor deficits and reduces neurofilament light and glial fibrillary acidic protein serum levels without increased striatal dopamine or tyrosine hydroxylase protein

Kasanga, E. A.·Soto, I.·Centner, A.·McManus, R.·Shifflet, M. K.·Navarrete, W.·Han, Y.·Lisk, J.·Wheeler, K.·Mhatre-Winters, I.·Richardson, J. R.·Bishop, C.·Nejtek, V. A.·Salvatore, M. F.
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Abstract

BackgroundAlleviation of motor impairment by aerobic exercise (AE) in Parkinsons disease (PD) points to a CNS response that could be targeted by therapeutic approaches, but recovery of striatal dopamine (DA) or tyrosine hydroxylase (TH) has been inconsistent in rodent studies. ObjectiveTo increase translation of AE, 3 components were implemented into AE design to determine if recovery of established motor impairment, concomitant with >80% striatal DA and TH loss, was possible. We also evaluated if serum levels of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP), blood-based biomarkers of disease severity in human PD, were affected. MethodsWe used a 6-OHDA hemiparkinson rat model featuring progressive nigrostriatal neuron loss over 28 days, with impaired forelimb use 7 days post-lesion, and hypokinesia onset 21 days post-lesion. After establishing forelimb use deficits, moderate intensity AE began 1-3 days later, 3x per week, for 40 min/session. Motor assessments were conducted weekly for 3 wks, followed by determination of striatal DA, TH protein and mRNA, and NfL and GFAP serum levels. ResultsSeven days after 6-OHDA lesion, recovery of depolarization-stimulated extracellular DA and DA tissue content was <10%, representing severity of DA loss in human PD, concomitant with 50% reduction in forelimb use. Despite severe DA loss, recovery of forelimb use deficits and alleviation of hypokinesia progression began after 2 weeks of AE and was maintained. Increased NfLand GFAP levels from lesion were reduced by AE. Despite these AE-driven changes, striatal DA tissue and TH protein levels were unaffected. ConclusionsThis proof-of-concept study shows AE, using exercise parameters within the capabilities most PD patients, promotes recovery of established motor deficits in a rodent PD model, concomitant with reduced levels of blood-based biomarkers associated with PD severity, without commensurate increase in striatal DA or TH protein.

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Kasanga, E. A., Soto, I., Centner, A., McManus, R., Shifflet, M. K., Navarrete, W., Han, Y., Lisk, J., Wheeler, K., Mhatre-Winters, I., Richardson, J. R., Bishop, C., Nejtek, V. A., Salvatore, M. F.. 2023-07-12. Moderate intensity aerobic exercise in 6-OHDA-lesioned rats alleviates established motor deficits and reduces neurofilament light and glial fibrillary acidic protein serum levels without increased striatal dopamine or tyrosine hydroxylase protein. https://doi.org/10.1101/2023.07.11.548638

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