Cerebral microdialysis: research technique or clinical tool

Cerebral microdialysis is a well-established laboratory tool that is increasingly used as a bedside monitor to provide on-line analysis of brain tissue biochemistry during neuro-intensive care. This review describes the principles of cerebral microdialysis and the rationale for its use in the clinical setting, including discussion of the most commonly used microdialysis biomarkers of acute brain injury. Potential clinical applications are reviewed and future research applications identified. Microdialysis has the potential to become an established part of mainstream multimodality monitoring during the management of acute brain injury but at present should be considered a research tool for use in specialist centres

On the integration of a microdialysis-based microTAS with calibration facility on a silicon-glass sandwich

The integration is discussed of all parts of a microdialysis-based micro Total Analysis System or ¿TAS. In particular a microdialysis probe, a potentiometric and amperometric ion- and enzyme sensor and a calibration dosing pump have been developed separately using different precision machining techniques. By modifying and adapting these parts they can be realized in one generic technology consisting of a stack of a silicon and a glass wafer. The silicon wafer contains the double lumen microdialysis probe connections, a dosing pump chamber with meander formed cavities containing the calibration solutions and small cavities for both the potentiometric and amperometric sensor. The glass wafer contains all the electrical contacts and wires for the sensors, the pump and Interconnections. Both wafers are anodically bonded to each other, yielding a hermetically sealed liquid handling syste

Method of calibration for glucose sensor implemented in an integrated microdialysis based system

In this paper the novel method of calibration of glucose amperometric type sensor implemented in an integrated microdialysis based micro system is presented. This method consists in evaluation of the charge, resulting from the glucose consumption in the enzymatic reaction, transferred to the electrode under stop-flow conditions

Chronic cocaine enhances release of neuroprotective amino acid taurine: a microdialysis study

Cocaine inhibits high-affinity neurotransmitter uptake at the presynaptic nerve terminals to increase synaptic levels of dopamine, norepinephrine and serotonin^1^. This increase of synaptic dopamine may cause neurotoxicity^2,3^. At least two different mechanisms have been proposed for the development of dopamine-related neurotoxicity: 1) dopamine produces a free radical that may induce cell toxicity^2,3^ and 2) dopamine reduces glutamate transport at its presynaptic sites to increase synaptic levels of this amino acid^4^ and augments glutamate transmission by activating dopamine D1 receptors in different areas of the brain^5-7^. Increase in glutamatergic transmission mediated by the activation on N-methyl dextro-aspartate (NMDA) receptors has been shown to cause excitotoxicity and neuro-degeneration^8^. Others and we have reported protection against different psychotropic drug-induced neurotoxicity that may be achieved by prior or simultaneous administration of various pharmacological agents. For example, repeated treatment of rats with haloperidol induced neuronal damage that is ameliorated by prior administration of either GM1 ganglioside^9^ or the endogenous amino acid, taurine^10^. Similarly, chronic gestational cocaine exposure causes neurotoxicity that could be prevented by co-administration of clozapine^11^. To our knowledge, there is no information if chronic cocaine would enhance release of endogenous protective agents that may oppose the over activation of glutamatergic system. Here we show that repeated cocaine treatment increased synaptic levels of the neuroprotective amino acid taurine that opposes the excessive excitatory actions of the glutamatergic system in the rat brain. Thus, mammalian brain has an auto-protective mechanism to counter excitotoxicity and taurine or its synthetic derivative may be useful in the management and treatment of cocaine addiction and its neurotoxic effect

In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice

Although tau is a cytoplasmic protein, it is also found in brain extracellular fluids, e.g., CSF. Recent findings suggest that aggregated tau can be transferred between cells and extracellular tau aggregates might mediate spread of tau pathology. Despite these data, details of whether tau is normally released into the brain interstitial fluid (ISF), its concentration in ISF in relation to CSF, and whether ISF tau is influenced by its aggregation are unknown. To address these issues, we developed a microdialysis technique to analyze monomeric ISF tau levels within the hippocampus of awake, freely moving mice. We detected tau in ISF of wild-type mice, suggesting that tau is released in the absence of neurodegeneration. ISF tau was significantly higher than CSF tau and their concentrations were not significantly correlated. Using P301S human tau transgenic mice (P301S tg mice), we found that ISF tau is fivefold higher than endogenous murine tau, consistent with its elevated levels of expression. However, following the onset of tau aggregation, monomeric ISF tau decreased markedly. Biochemical analysis demonstrated that soluble tau in brain homogenates decreased along with the deposition of insoluble tau. Tau fibrils injected into the hippocampus decreased ISF tau, suggesting that extracellular tau is in equilibrium with extracellular or intracellular tau aggregates. This technique should facilitate further studies of tau secretion, spread of tau pathology, the effects of different disease states on ISF tau, and the efficacy of experimental treatments

Mesocorticolimbic monoamine correlates of methamphetamine sensitization and motivation.

Methamphetamine (MA) is a highly addictive psychomotor stimulant, with life-time prevalence rates of abuse ranging from 5-10% world-wide. Yet, a paucity of research exists regarding MA addiction vulnerability/resiliency and neurobiological mediators of the transition to addiction that might occur upon repeated low-dose MA exposure, more characteristic of early drug use. As stimulant-elicited neuroplasticity within dopamine neurons innervating the nucleus accumbens (NAC) and prefrontal cortex (PFC) is theorized as central for addiction-related behavioral anomalies, we used a multi-disciplinary research approach in mice to examine the interactions between sub-toxic MA dosing, motivation for MA and mesocorticolimbic monoamines. Biochemical studies of C57BL/6J (B6) mice revealed short- (1 day), as well as longer-term (21 days), changes in extracellular dopamine, DAT and/or D2 receptors during withdrawal from 10, once daily, 2 mg/kg MA injections. Follow-up biochemical studies conducted in mice selectively bred for high vs. low MA drinking (respectively, MAHDR vs. MALDR mice), provided novel support for anomalies in mesocorticolimbic dopamine as a correlate of genetic vulnerability to high MA intake. Finally, neuropharmacological targeting of NAC dopamine in MA-treated B6 mice demonstrated a bi-directional regulation of MA-induced place-conditioning. These results extend extant literature for MA neurotoxicity by demonstrating that even subchronic exposure to relatively low MA doses are sufficient to elicit relatively long-lasting changes in mesocorticolimbic dopamine and that drug-induced or idiopathic anomalies in mesocorticolimbic dopamine may underpin vulnerability/resiliency to MA addiction

Use of long-term microdialysis subcutaneous glucose monitoring in the management of neonatal diabetes - A first case report

In neonatal diabetes mellitus (NDM), a rare genetic disorder, insulin therapy is required but the management is difficult. Frequent blood glucose determinations are necessary in most cases. Microdialysis subcutaneous glucose monitoring (MSGM) is feasible in neonates and has been proposed to reduce painful blood sampling and blood loss. We have applied long-term MSGM to a small-fordate female newborn with transient NDM. We found a good correlation of subcutaneous and blood glucose concentration over a wide range of values. MSGM enabled a reduction in blood glucose determinations during optimization of intravenous insulin treatment and initiation of continuous subcutaneous insulin infusion. We conclude that long-term MSGM is feasible and may reduce painful blood sampling and blood loss in NDM. Furthermore, long-term MSGM may hold a potential for avoiding hypoglycemic episodes and earlier discharge. Copyright (C) 2006 S. Karger AG, Basel

Circadian and Ultradian Rhythms of Free Glucocorticoid Hormone Are Highly Synchronized between the Blood, the Subcutaneous Tissue, and the Brain

Total glucocorticoid hormone levels in plasma of various species, including humans, follow a circadian rhythm that is made up from an underlying series of hormone pulses. In blood most of the glucocorticoid is bound to corticosteroid-binding globulin and albumin, resulting in low levels of free hormone. Although only the free fraction is biologically active, surprisingly little is known about the rhythms of free glucocorticoid hormones. We used single-probe microdialysis to measure directly the free corticosterone levels in the blood of freely behaving rats. Free corticosterone in the blood shows a distinct circadian and ultradian rhythm with a pulse frequency of approximately one pulse per hour together with an increase in hormone levels and pulse height toward the active phase of the light/dark cycle. Similar rhythms were also evident in the subcutaneous tissue, demonstrating that free corticosterone rhythms are transferred from the blood into peripheral target tissues. Furthermore, in a dual-probe microdialysis study, we demonstrated that the circadian and ultradian rhythms of free corticosterone in the blood and the subcutaneous tissue were highly synchronized. Moreover, free corticosterone rhythms were also synchronous between the blood and the hippocampus. These data demonstrate for the first time an ultradian rhythm of free corticosterone in the blood that translates into synchronized rhythms of free glucocorticoid hormone in peripheral and central tissues. The maintenance of ultradian rhythms across tissue barriers in both the periphery and the brain has important implications for research into aberrant biological rhythms in disease and for the development of improved protocols for glucocorticoid therapy

High-Performance Bioinstrumentation for Real-Time Neuroelectrochemical Traumatic Brain Injury Monitoring

Traumatic brain injury (TBI) has been identified as an important cause of death and severe disability in all age groups and particularly in children and young adults. Central to TBIs devastation is a delayed secondary injury that occurs in 30–40% of TBI patients each year, while they are in the hospital Intensive Care Unit (ICU). Secondary injuries reduce survival rate after TBI and usually occur within 7 days post-injury. State-of-art monitoring of secondary brain injuries benefits from the acquisition of high-quality and time-aligned electrical data i.e., ElectroCorticoGraphy (ECoG) recorded by means of strip electrodes placed on the brains surface, and neurochemical data obtained via rapid sampling microdialysis and microfluidics-based biosensors measuring brain tissue levels of glucose, lactate and potassium. This article progresses the field of multi-modal monitoring of the injured human brain by presenting the design and realization of a new, compact, medical-grade amperometry, potentiometry and ECoG recording bioinstrumentation. Our combined TBI instrument enables the high-precision, real-time neuroelectrochemical monitoring of TBI patients, who have undergone craniotomy neurosurgery and are treated sedated in the ICU. Electrical and neurochemical test measurements are presented, confirming the high-performance of the reported TBI bioinstrumentation

Nitric oxide formation during cortical spreading depression is critical for rapid subsequent recovery of ionic homeostasis

NoCortical spreading depression (CSD) is a temporary disruption of local ionic homeostasis that propagates slowly across the cerebral cortex. Cortical spreading depression promotes lesion progression in experimental stroke, and may contribute to the initiation of migraine attacks. The purpose of this study was to investigate the roles of the marked increase of nitric oxide (NO) formation that occurs with CSD. Microdialysis electrodes were implanted in the cortex of anesthetized rats to perform the following operations within the same region: (1) elicitation of CSD by perfusion of high K+ medium; (2) recording of CSD elicitation; (3) application of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME); and (4) recording of dialysate pH changes. The primary effect of L-NAME (0.3 to 3.0 mmol/L in the perfusion medium) was a marked widening of individual CSD wave, resulting essentially from a delayed initiation of the repolarization phase. This change was due to NO synthase inhibition because it was not observed with the inactive isomer D-NAME, and was reversed by L-arginine. This effect did not appear to be linked to the suppression of a sustained, NO-mediated vascular change associated with the superposition of NO synthase inhibition on high levels of extracellular K+. The delayed initiation of repolarization with local NO synthase inhibition may reflect the suppression of NO-mediated negative feedback mechanisms acting on neuronal or glial processes involved in CSD genesis. However, the possible abrogation of a very brief, NO-mediated vascular change associated with the early phase of CSD cannot be ruled out