Abstract
Cerebral microdialysis can be used to detect mitochondrial dysfunction, a potential target of neuroprotective treatment. Cyclosporin A (CsA) is a mitochondrial stabiliser that in a recent clinical stroke trial showed protective potential in patients with successful recanalisation. To investigate specific metabolic effects of CsA during reperfusion, and hypothesising that microdialysis values can be used as a proxy outcome measure, we assessed the temporal patterns of cerebral energy substrates related to oxidative metabolism in a model of transient focal ischaemia. Transient ischaemia was induced by intracerebral microinjection of endothelin-1 (150 pmol/15 µL) through stereotaxically implanted guide cannulas in awake, freely moving rats. This was immediately followed by an intravenous injection of CsA (NeuroSTAT; 15 mg/kg) or placebo solution during continuous microdialysis monitoring. After reperfusion, the lactate/pyruvate ratio (LPR) was significantly lower in the CsA group vs placebo (n = 17, 60.6 ± 24.3%, p = 0.013). Total and striatal infarct volumes (mm3) were reduced in the treatment group (n = 31, 61.8 ± 6.0 vs 80.6 ± 6.7, p = 0.047 and 29.9 ± 3.5 vs 41.5 ± 3.9, p = 0.033). CsA treatment thus ameliorated cerebral reperfusion metabolism and infarct size. Cerebral microdialysis may be useful in evaluating putative neuroprotectants in ischaemic stroke.
Highlights
For several decades it has been recognised that mitochondrial dysfunction, characterised by impaired oxidative metabolism in spite of ample oxygen and substrate delivery, occurs after transient cerebral ischaemia[1,2]
The aim of the study was to (1) assess the temporal patterns of cerebral energy metabolites associated with mitochondrial dysfunction in the ET-1 rat model of transient focal ischaemia, (2) investigate whether intravenous cyclosporin A improved cerebral oxidative metabolism after reperfusion, and (3) investigate if such an effect correlated with 24-hour infarct volumes
The mean 60.6 ± 24.3% point difference in lactate/pyruvate ratio (LPR) between the two groups (CsA 126.2 ± 24.3% vs controls 186.8 ± 18.4%) in the 3–5 hours after induction of ischaemia was significant (p = 0.013)
Summary
For several decades it has been recognised that mitochondrial dysfunction, characterised by impaired oxidative metabolism in spite of ample oxygen and substrate delivery, occurs after transient cerebral ischaemia[1,2]. The infarct volume was significantly reduced in the subset of patients who had successful recanalisation after proximal cerebral artery occlusion These results imply that a positive treatment effect of CsA may be dependent on reperfusion and subsequent mitochondrial dysfunction rather than ischaemia per se. The aim of the study was to (1) assess the temporal patterns of cerebral energy metabolites associated with mitochondrial dysfunction in the ET-1 rat model of transient focal ischaemia, (2) investigate whether intravenous cyclosporin A improved cerebral oxidative metabolism after reperfusion, and (3) investigate if such an effect correlated with 24-hour infarct volumes
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