Brain to blood efflux as a mechanism underlying the neuroprotection mediated by rapid remote preconditioning in brain ischemia

Jachova, Jana; Gottlieb, Miroslav; Némethová, Miroslava; Bona, Martin; Bonova, Petra

doi:10.1007/s11033-020-05626-w

Cited by 8 publications

(6 citation statements)

References 40 publications

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“…Several studies have shown an increased efflux of extracellular glutamate from the ischemic brain to the peripheral blood circulation following the induction of ischemic tolerance. 28 , 33 , 34 Our results demonstrated comparable levels of glutamate in obese and lean rats in the control conditions, but only moderate postischemic glutamate increase in obese rats. RIPostC did not influence glutamate levels in the ischemic core or penumbra in ZDF rats.…”

Section: Discussionsupporting

confidence: 58%

Obesity as a Limiting Factor for Remote Ischemic Postconditioning-Mediated Neuroprotection after Stroke

Kotorová,

Končeková,

Gottlieb

et al. 2023

Journal of Obesity & Metabolic Syndrome

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Background Remote ischemic postconditioning (RIPostC) may protect the brain from ischemia/reperfusion (I/R) injury. The association between RIPostC and obesity has not yet been extensively studied. Methods Twelve-week-old male Zucker diabetic fatty (ZDF; n=68) and Zucker diabetic lean (ZDL; n=51) rats were subjected to focal cerebral ischemia for 90 minutes, followed by 24 hours of reperfusion. RIPostC was performed with 5-minute I/R cycles using a tourniquet on the right hind limb. Results The results showed a negative association between obesity and neurological impairment in ischemic animals. We observed a 70% greater infarct size in ZDF rats compared with their lean counterparts, as evaluated by 2,3,5-triphenyltetrazolium chloride staining. To measure the total fragmented DNA in peripheral lymphocytes, comet assay was performed. Obese rats exhibited higher levels of DNA damage (by approximately 135%) in peripheral blood lymphocytes even before the induction of stroke. RIPostC did not attenuate oxidative stress in the blood in obese rats subjected to ischemia. Focal cerebral ischemia increased core and penumbra tissue glutamate release in the brain and decreased it in the blood of ischemic ZDL rats, and these changes improved following RIPostC treatment. However, changes in blood and tissue glutamate content were not detected in ischemic ZDF rats or after RIPostC intervention. Conclusion Our findings suggest that obese animals respond more severely to ischemia-reperfusion brain injury. However, obese animals did not achieve neuroprotective benefits of RIPostC treatment.

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Section: Discussionsupporting

confidence: 58%

Obesity as a Limiting Factor for Remote Ischemic Postconditioning-Mediated Neuroprotection after Stroke

Kotorová,

Končeková,

Gottlieb

et al. 2023

Journal of Obesity & Metabolic Syndrome

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“…BBB disruption appears shortly after the onset of cerebral artery occlusion and lasts for days, changing the extent of BBB permeability alterations over time [ 56 ]. The increased BBB permeability due to BBB disruption after cerebral ischemia was confirmed in many experiments, e.g., by injecting tracers [ 57 ] or dye [ 31 ] intravenously into stroke animals.…”

Section: Discussionmentioning

confidence: 93%

“…In time of 24 h after global cerebral ischemia, we observed significantly decreased glutamate content in cortical as well as in hippocampal tissue related in tissue weight, similarly as it was described by Hu et al in tissue extract from ischemic cerebral hemisphere after MCAO [ 21 ], as well as by Zhang et al in mice after global cerebral ischemia in both cortex and hippocampus [ 20 ]. In contrast, strong regional specific analysis showed increased glutamate level, however calculated relatively to protein content, in 24 h of postischemic reperfusion in the ischemic core (striatum and overlying cortex) and penumbra (adjacent cortex) in MCAO model [ 31 ]. In the same study, rapid remote ischemic preconditioning normalized the glutamate level.…”

Section: Discussionmentioning

confidence: 99%

Metabolomic Recovery as a Result of Ischemic Preconditioning Was More Pronounced in Hippocampus than in Cortex That Appeared More Sensitive to Metabolomic Blood Components

et al. 2021

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The study of an organism’s response to ischemia at different levels is essential to understand the mechanism of the injury as well as protection. We used the occlusion of four vessels as an animal model of global cerebral ischemia to investigate metabolic alterations in cerebral cortex, hippocampus, blood plasma, as well as in a remote organ, the heart, in rats undergoing 24 h postischemic reperfusion. By inducing sublethal ischemic stimuli, we focused on endogenous phenomena known as ischemic tolerance that is currently the best known and most effective way of protecting against ischemic injury. NMR spectroscopy was used to analyze relative metabolite levels in homogenates from rats’ cerebral cortex, hippocampus, and heart together with deproteinized blood plasma. In individual animals subjected to global cerebral ischemia, relative concentrations of the essential amino acids isoleucine, valine, phenylalanine, and tyrosine in cerebral cortex correlated with those in blood plasma (p < 0.05, or boundary significant p < 0.09). This did not apply for the hippocampus, suggesting a closer relation between ischemic cortex and metabolomic blood components. Hippocampal non-participation on correlation with blood components may emphasize the observed partial or full normalization the post-ischemically altered levels of a number of metabolites in the preconditioned animals. Remarkably, that was observed for cortex to a lesser extent. As a response to the global cerebral ischemia in heart tissue, we observed decreased glutamate and increased 3-hydroxybutyrate. Ischemically induced semi-ketotic state and other changes found in blood plasma partially normalized when ischemic preconditioning was introduced. Some metabolomic changes were so strong that even individual metabolites were able to differentiate between ischemic, ischemically preconditioned, and control brain tissues.

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“…Unfortunately, direct NMDAR blockers have failed in the treatment of excitotoxic damage after ischaemia [ 20 , 21 ], probably due to the dual roles of NMDARs in neuronal survival and death (reviewed in [ 20 ]). Because the decrease in extracellular glutamate seems to be related to improved neuronal survival after ischaemia [ 9 , 10 , 22 ], our investigation has focused on the mechanisms of the brain to blood efflux for restoring glutamate homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…While brain concentrations of glutamate decrease after the RIPC treatment, the blood levels rise. This could indicate that RIPC can mediate accelerated brain-to-blood efflux of glutamate which, in fact, could positively influence neuronal survival in ischaemia-affected brain regions [ 9 , 10 ]. The efflux of glutamate from the brain to the blood is accelerated naturally based on the concentration gradient [ 8 ], but the involvement of other mechanisms intensifying this process should not be excluded.…”

Section: Introductionmentioning

confidence: 99%

Remote Ischaemic Preconditioning Accelerates Brain to Blood Glutamate Efflux via EAATs-mediated Transport

Končekova,

Kotorova,

Gottlieb

et al. 2023

Neurochem Res

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Remote ischaemic conditioning (RIC) becomes an attractive strategy for the endogenous stimulation of mechanisms protecting neurons against ischaemia. Although the processes underlying the RIC are not clearly understood, the homeostasis of glutamate seems to play an important role. The present study is focused on the investigation of the brain to blood efflux of glutamate in a condition mimicking ischaemia-mediated excitotoxicity and remote ischaemic preconditioning (RIPC). The animals were pre-treated with a hind-limb tourniquet one hour before the intraventricular administration of glutamate and its release was monitored as the concentration of glutamate/glutathione in blood and liquor for up to 1 h. The transport mediated by excitatory amino acid transporters (EAATs) was verified by their inhibition with Evans Blue intraventricular co-administration. RIPC mediated the efflux of glutamate exceeding from CSF to blood in the very early stage of intoxication. As a consequence, the blood level of glutamate rose in a moment. EAATs inhibition confirmed the active role of glutamate transporters in this process. In the blood, elevated levels of glutamate served as a relevant source of antioxidant glutathione for circulating cells in RIPC-treated individuals. All of those RIPC-mediated recoveries in processes of glutamate homeostasis reflect the improvement of oxidative stress, suggesting glutamate-accelerated detoxication to be one of the key mechanisms of RIPC-mediated neuroprotection.

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Brain to blood efflux as a mechanism underlying the neuroprotection mediated by rapid remote preconditioning in brain ischemia

Cited by 8 publications

References 40 publications

Obesity as a Limiting Factor for Remote Ischemic Postconditioning-Mediated Neuroprotection after Stroke

Obesity as a Limiting Factor for Remote Ischemic Postconditioning-Mediated Neuroprotection after Stroke

Metabolomic Recovery as a Result of Ischemic Preconditioning Was More Pronounced in Hippocampus than in Cortex That Appeared More Sensitive to Metabolomic Blood Components

Remote Ischaemic Preconditioning Accelerates Brain to Blood Glutamate Efflux via EAATs-mediated Transport

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