Retrodialysis of Pharmacological Agents Mitigates Tissue Damage during Brain Microdialysis and Preserves Dopamine Activity in Surrounding Tissue

摘要

Microdialysis is a powerful technique used to recover analytes from the brain. Microdialysis is compatible with multiple detectors allowing simultaneous analysis of neurotransmitters, metabolites, neuropeptides, and amino acids. The use of microdialysis has made advances in understanding brain function and diseases and is currently used to monitor traumatic brain injured patients. However, microdialysis probe implantation causes a penetration injury eliciting a foreign body response in the surrounding brain tissue. Tissue around the probe becomes unhealthy which brings into question, how the state of the tissue around the probe effects analytes that are recovered by microdialysis.udDopamine, a neurotransmitter involved in a variety of physiological functionality and neurological disorders, is often recovered using microdialysis. Dopamine is electroactive, and can also be measured using carbon fiber microelectrodes coupled with voltammetry. The small size of these electrodes allows for high spatial resolution without damaging the tissue. Using microelectrodes our lab has previously found that probe implantation creates a gradient of reductions in evoked dopamine responses the closer the electrode is to the probe. This dissertation builds off of this finding, with the goal of mitigating the penetration injury to preserve dopamine neurotransmission. First, it was discovered that probe implantation completely abolished evoked dopamine responses near probes. Administration of a dopamine transporter inhibitor showed that terminals survive probe implantation justifying our efforts to mitigate probe induced tissue damage. Retrodialysis of an anti-inflammatory drug dexamethasone and a reactive oxygen species scavenger XJB-5-131 prevented dopamine terminal loss and preserved evoked dopamine responses for four hours. Further work proved that dexamethasone preserves evoked dopamine release for up to 24 hours. As dexamethasone is a steroid that could potentially affect neurotransmission, other pharmacological agents were investigated, all proving to improve evoked DA responses in tissue surrounding probes. Pharmacological mitigation of tissue damage provides new insight into acute extenuation of probe induced damage which has the potential to successfully mitigate chronic implantation for long-term in vivo monitoring of neurochemicals.udIn a separate study, microelectrodes were used to spatially map dopamine responses in the rat brain. Distinct dopamine kinetics exist in sub-regions of the striatum that correlate to patch-matrix compartments.ud