Cyclosporin A ameliorates cerebral oxidative metabolism and infarct size in the endothelin-1 rat model of transient cerebral ischaemia

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 (mm 3 ) 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.

Ethyl Pyruvate Increases Post-Ischemic Levels of Mitochondrial Energy Metabolites: A 13C-Labeled Cerebral Microdialysis Study

“…All aspects related to the ET-1 rat model of transient focal cerebral ischemia, except labeled microdialysis and LC-MS, are described in detail in a previous publication from our group [ 16 ]. Briefly, the sedated animals underwent surgery and stereotaxic implantation of cerebral ET-1 and microdialysis probes and femoral vein catheter on Day 1 ( Figure 1 B).…”

“…It could also be due to lack of power, because of the small sample size (n = 5 or 6). In the current study, the timing of administration was chosen for translational purposes (pre-reperfusion) and may be suboptimal regarding maximal treatment effect [16]. Previous studies have indicated that a different outcome in infarct size may be obtained with a longer recuperation period [29].…”

“…This enabled digital measurement of the infarcted area using NDP-view 2 as seen in Figure 5 for each slide at a time. The cumulated infarct volume was then calculated using the cavalieri principle as mentioned in [16]. Histological comparison of infarction volumes was performed on the 11 randomized rats.…”

“…Like pyruvate, EP is an effective scavenger of reactive oxygen species (ROS) and has been shown to exert anti-inflammatory properties [12,14]. Some studies suggest that EP might also serve as a substrate for the TCA cycle and may, thus, help to optimize ATP levels in the event of mitochondrial dysfunction [13,15,16].…”

Cyclosporine therapy in cytokine storm due to coronavirus disease 2019 (COVID-19)

“…To break this vicious circle, it is necessary to decrease lactate production and to improve the anaerobic environment. Cyclosporine has been shown to lower the lactate/pyruvate ratio in ischemia-reperfusion injury [9]. The most common NHE isoform in the body is NHE-1.…”