Markus Hillert

Publications (3)7.56 Total impact

• Article: Uptake of lithium into rat brain after acute and chronic administration.

  Markus Hillert, Martina Zimmermann, Jochen Klein
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  ABSTRACT: Lithium is licensed for the treatment of bipolar disorders and also discussed in relation to neuroprotective properties. Although the drug has a small therapeutic window, its uptake and passage into the brain are poorly understood. We administered lithium to rats, following an acute (3 mmol/kg, i.p.) or chronic (3 mmol/kg/day, p.o.) regime. Lithium levels were assessed in serum, brain homogenate, cerebrospinal fluid (CSF) and, by means of microdialysis, in the extracellular space (ECS) of the brain 2, 6 and 24h post injection or after 3 weeks of chronic administration. Lithium is detected in brain ECS within minutes of administration and reaches maximum levels in brain extracellular fluid after 30 min. In the early phase after lithium administration (2 and 6h), serum levels of lithium do not differ significantly from those assessed in CSF and brain homogenate. Afterwards, however, accumulation in brain tissue occurs. As a consequence, after 24h and 3 weeks, lithium levels in brain homogenate (i.e., intracellular levels) are significantly higher than in CSF or dialysates (i.e., extracellular levels). In conclusion, lithium rapidly reaches the brain, but after prolonged treatment, brain intracellular levels are high and poorly represented by plasma or CSF measurements.
  Neuroscience Letters 05/2012; 521(1):62-6. · 2.11 Impact Factor
• Article: Role of glycine receptors and glycine release for the neuroprotective activity of bilobalide.

  Cornelia Kiewert, Vikas Kumar, Oksana Hildmann, Joachim Hartmann, Markus Hillert, Jochen Klein
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  ABSTRACT: Bilobalide, a constituent of Ginkgo biloba, has neuroprotective properties. Its mechanism of action is unknown but it was recently found to interact with neuronal transmission mediated by glutamate, gamma-aminobutyric acid (GABA) and glycine. The goal of this study was to test the interaction of bilobalide with glycine in assays of neuroprotection. In rat hippocampal slices exposed to N-methyl-D-aspartate (NMDA), release of choline indicates breakdown of membrane phospholipids. NMDA-induced choline release was almost completely blocked in the presence of bilobalide (10 microM). Glycine (10-100 microM) antagonized the inhibitory action of bilobalide in this assay. In a second assay of excitotoxicity, we measured tissue water content as an indicator of cytotoxic edema formation in hippocampal slices which were exposed to NMDA. In this assay, edema formation was suppressed by bilobalide but bilobalide's action was attenuated in the presence of glycine and of D-serine (100 microM each). To investigate bilobalide's interaction with glycine receptors directly, we determined 36chloride flux in rat cortico-hippocampal synaptoneurosomes. Glycine (100 microM) was inactive in this assay indicating an absence of functional glycine-A receptors in this preparation. [3H]Glycine was used to assess binding at the glycine binding site of the NMDA receptor but bilobalide was found to be inactive in this assay. Finally, [3H]glycine release was monitored in hippocampal slices exposed to oxygen-glucose deprivation. In this model, glycine release was induced by ischemia, an effect that was strongly reduced by bilobalide. We conclude that bilobalide does not interact with glycine receptors in neurochemical assays but it significantly reduces the release of glycine under ischemic conditions. This effect likely contributes to bilobalide's neuroprotective effects in assays of excitotoxicity and ischemia.
  Brain Research 04/2008; 1201:143-50. · 2.73 Impact Factor
• Article: Effects of chloride flux modulators in an in vitro model of brain edema formation.

  Vikas Kumar, Runa S Naik, Markus Hillert, Jochen Klein
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  ABSTRACT: Brain edema is a serious consequence of hemispheric stroke and traumatic brain injury and contributes significantly to patient mortality. In the present study, we measured water contents in hippocampal slices as an in vitro model of edema formation. Excitotoxic conditions induced by N-methyl-D-aspartate (NMDA, 300 microM), as well as ischemia induced by oxygen-glucose deprivation (OGD), caused cellular edema formation as indicated by an increase of slice water contents. In the presence of furosemide, an inhibitor of the Na,K,Cl-cotransporter, NMDA-induced edema were reduced by 64% while OGD-induced edema were unaffected. The same observation, i.e., reduction of excitotoxic edema formation but no effect on ischemia-induced edema, was made with chloride transport inhibitors such as DIDS and niflumic acid. Under ischemic conditions, modulation of GABAA receptors by bicuculline, a GABA antagonist, or by diazepam, a GABAergic agonist, did not significantly affect edema formation. Further experiments demonstrated that low chloride conditions prevented NMDA-induced, but not OGD-induced, water influx. Omission of calcium ions had no effect. Our results show that NMDA-induced edema formation is highly dependent on chloride influx as it was prevented by low-chloride conditions and by various compounds that interfere with chloride influx. In contrast, OGD-induced edema observed in brain slices was not affected by modulators of chloride fluxes. The results are discussed with reference to ionic changes occurring during tissue ischemia.
  Brain Research 12/2006; 1122(1):222-9. · 2.73 Impact Factor