xjb-5-131 and Brain-Injuries

The power of microdialysis for in vivo neurochemical monitoring is a result of intense efforts to enhance microdialysis procedures, the probes themselves, and the analytical systems used for the analysis of dialysate samples. Our goal is to refine microdialysis further by focusing attention on what happens when the probes are implanted into brain tissue. It is broadly acknowledged that some tissue damage occurs, such that the tissue nearest the probes is disrupted from its normal state. We hypothesize that mitigating such disruption would refine microdialysis. Herein, we show that the addition of dexamethasone, an anti-inflammatory drug, to the perfusion fluid protects evoked dopamine responses as measured by fast-scan cyclic voltammetry next to the probes after 24 h. We also show that dexamethasone stabilizes evoked dopamine responses measured at the probe outlet over a 4-24 h postimplantation interval. The effects of dexamethasone are attributable to its anti-inflammatory actions, as dexamethasone had no significant effect on two histochemical markers for dopamine terminals, tyrosine hydroxylase and the dopamine transporter. Using histochemical assays, we confirmed that the actions of dexamethasone are tightly confined to the immediate, local vicinity of the probe.

Topics: Analysis of Variance; Animals; Anti-Inflammatory Agents; Brain Injuries; Corpus Striatum; Cyclic N-Oxides; Dexamethasone; Disease Models, Animal; Dopamine; Dopamine Uptake Inhibitors; Electrochemical Techniques; Functional Laterality; Microdialysis; Nomifensine; Rats; Time Factors; Tyrosine 3-Monooxygenase

The brain contains a highly diversified complement of molecular species of a mitochondria-specific phospholipid, cardiolipin, which, because of its polyunsaturation, can readily undergo oxygenation. Using global lipidomics analysis in experimental traumatic brain injury (TBI), we found that TBI was accompanied by oxidative consumption of polyunsaturated cardiolipin and the accumulation of more than 150 new oxygenated molecular species of cardiolipin. RNAi-based manipulations of cardiolipin synthase and cardiolipin levels conferred resistance to mechanical stretch, an in vitro model of traumatic neuronal injury, in primary rat cortical neurons. By applying a brain-permeable mitochondria-targeted electron scavenger, we prevented cardiolipin oxidation in the brain, achieved a substantial reduction in neuronal death both in vitro and in vivo, and markedly reduced behavioral deficits and cortical lesion volume. We conclude that cardiolipin oxygenation generates neuronal death signals and that prevention of it by mitochondria-targeted small molecule inhibitors represents a new target for neuro-drug discovery.

Topics: Animals; Behavior, Animal; Brain Injuries; Cardiolipins; Cell Death; Cerebral Cortex; Cyclic N-Oxides; Free Radical Scavengers; Lipid Peroxidation; Membrane Proteins; Mitochondria; Neurons; Oxidation-Reduction; Primary Cell Culture; Rats; Transferases (Other Substituted Phosphate Groups)

Topics: Animals; Brain Injuries; Cardiolipins; Cell Death; Cyclic N-Oxides; Lipid Peroxidation