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Intracerebral microdialysis studies of blood-brain barrier permeability and neurochemical parameters in a murine stroke model

Year: 2010
Type: dissertation
Abstract: Damage to the blood-brain barrier (BBB) secondary to prolonged ischemia and \nsubsequent reperfusion is an important pathological hallmark of ischemia-reperfusion \ninjury resulting in vasogenic edema, hemorrhagic transformation and reduced benefits \noffered by reperfusion. Evaluation of the dynamics of BBB opening thus forms the basis \nfor the development of therapies that can counteract reperfusion induced hyperpermeability \nof the BBB. Intracerebral microdialysis is a commonly used in vivo \nsampling technique to study the brain tissue biochemistry and pharmacokinetics of drug \nuptake by brain, under normal and pathological conditions like cerebral ischemia. \nBesides its use for measuring neurochemical changes during and after cerebral ischemia, \nwe proposed to use this technique to make quantitative estimates of BBB permeability \nchanges resulting from cerebral ischemia and reperfusion. Hence, studying the BBB \nopening following ischemia reperfusion using intracerebral microdialysis constitutes the \ncentral goal of the present dissertation achieved by fulfilling the following objectives: a) \nto determine alterations in brain tissue biochemistry and BBB permeability associated \nwith microdialysis probe implantation, b) to establish a sensitive quantitative \nmicrodialysis model to study the dynamics of BBB opening and c) to investigate the time \nframe of BBB opening and neurochemical alterations following ischemia reperfusion, in \na middle cerebral artery occlusion murine stroke model, using intracerebral microdialysis. \nOur results demonstrate that a recovery time of 24h post probe implantation is suitable to \ninitiate microdialysis sampling since by this time tissue damage and BBB disruption caused due to acute probe implantation had declined. Further, using a novel finite \nelement model approach for simulating transient probe extraction fraction and a brain \npharmacokinetic model based on symmetrical exchange across the BBB by passive \ndiffusion (PS) and an additional term for clearance from brain extracellular space (Kout \ne.g. due to bulk flow), we found a 6 fold increase in the BBB permeability surface area \n(PS) product of [14C]sucrose following osmotic opening of the BBB and a 6 fold \ndifference in the PS of [14C]sucrose and [14C]mannitol across an intact BBB. Following \nischemia reperfusion, the PS product of [14C]sucrose was significantly higher than in \nsham-operated animals when measured during intervals 0.25-2h, 4h-6h, 24-26h and 72- \n74h, but not 8-10h and 18-20h post ischemia reperfusion, reinforcing the biphasic nature \nof BBB opening post ischemia reperfusion. Neurochemical profiling up to 24h post \nreperfusion showed that while energy-substrates (glucose and lactate) are normalized 4- \n6h post reperfusion, markers of tissue damage (glutamate, glycerol, hydroxyl radical and \nnuclear factor kappa B), continue to be elevated up to and beyond this time point, \nsuggesting their contribution in ischemia reperfusion injury. \nThe results of this dissertation demonstrate that intracerebral microdialysis is a powerful \ntool to study the temporal alterations in both BBB permeability and neurochemical \nenvironment associated with ischemia reperfusion. The data obtained can be used to \nenhance our understanding of temporal changes at the level of not only the brain \nparenchyma but also the BBB allowing identification of time-dependent therapeutic \ntargets for stroke treatment.
Language: English
Subfield: Neurology
Open Access status: green
OpenAlex ID: W3217415674
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