Continuous Real-Time in vivo Measurement of Cerebral Nitric Oxide Supports Theoretical Predictions of an Irreversible Switching in Cerebral ROS after Sufficient Exposure to External Toxins
Affiliations: Sensors Development Unit and Neurochemistry Research Unit, BioAnalytics Laboratory, Department of Chemistry, National University of Ireland Maynooth, Co. Kildare, Ireland | Institute GERAD and University of Montreal, Montreal, Canada | Hamilton Institute, National University of Ireland Maynooth, Co. Kildare, Ireland
Abstract: Background: Mathematical models of the interactions between alphasynuclein (αS) and reactive oxygen species (ROS) predict a systematic and irreversible switching to damagingly high levels of ROS after sufficient exposure to risk factors associated with Parkinson's disease (PD). Objectives: We tested this prediction by continuously monitoring real-time changes in neurochemical levels over periods of several days in animals exposed to a toxin known to cause Parkinsonian symptoms. Methods: Nitric oxide (NO) sensors were implanted in the brains of freely moving rats and the NO levels continuously recorded while the animals were exposed to paraquat (PQ) injections of various amounts and frequencies. Results: Long-term, real-time measurement of NO in a cohort of animals showed systematic switching in levels when PQ injections of sufficient size and frequency were administered. The experimental observations of changes in NO imply a corresponding switching in endogenous ROS levels and support theoretical predictions of an irreversible change to damagingly high levels of endogenous ROS when PD risks are sufficiently large. Conclusions: Our current results only consider one form of PD risk, however, we are sufficiently confident in them to conclude that: (i) continuous long-term measurement of neurochemical dynamics provide a novel way to measure the temporal change and system dynamics which determine Parkinsonian damage, and (ii) the bistable feedback switching predicted by mathematical modelling seems to exist and that a deeper analysis of its characteristics would provide a way of understanding the pathogenic mechanisms that initiate Parkinsonian cell damage.
