In vivo dynamics of acidosis and oxidative stress in the acute phase of an ischemic stroke in a rodent model

Kelmanson, Ilya V.; Shokhina, Arina G.; Kotova, Daria A.; Pochechuev, Matvey S.; Ivanova, Angelina; Kostyuk, Alexander I.; Panova, Anastasiya S.; Borodinova, Anastasia A.; Solotenkov, Maxim A.; Stepanov, Evgeny A.; Raevskii, Roman I.; Moshchenko, Aleksandr A.; Pak, Valeriy V.; Ermakova, Yulia G.; Belle, Gijsbert J. van; Tarabykin, V. S.; Balaban, Pavel M.; Федотов, И. В.; Федотов, А. Б.; Conrad, Marcus; Bogeski, Ivan; Katschinski, Dörthe M.; Doeppner, Thorsten R.; Bähr, Mathias; Желтиков, А. М.; Belousov, Vsevolod V.; Bilan, Dmitry S.

doi:10.1016/j.redox.2021.102178

Cited by 30 publications

(15 citation statements)

References 73 publications

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“…The ratiometric I A / I B readout from HyPer7 (Figure 4B) is equally informative, indicating that the level of H 2 O 2 concentration, 𝒞, tends to rapidly increase at early stages of artery occlusion ( t ≈ 20 to 26 minutes in Figure 4B), remaining virtually unchanged within most of the MCAO period and growing again right after the reperfusion ( t ≈ 80 minutes). This behavior of 𝒞 is largely consistent with a commonly adopted scenario of ischemic stroke [79–85, 101], which relates the initial toxic product release at the stage of a rapidly growing ischemia to a drastically reduced delivery of basic nutrients to the affected area and in which the renewed blood supply at the reperfusion stage tends to trigger a cascade of adverse reactions, leading to a further buildup of ROS.…”

Section: Resultssupporting

confidence: 81%

“…Extending optical methods to in vivo studies of acute brain conditions, such as the acute phase of ischemic stroke, poses further major challenges, as it requires transient signatures of a growing disorder to be discriminated and continuously monitored against a high-floor noise background, which is inherently individual, vastly changing from 1 animal model to another [79]. As these requirements have to be fulfilled in a highly intricate and unforgiving setting of in vivo work with carefully prepared populations of animal stroke models, the overall complexity of the task appears nothing short of overwhelming.…”

Section: Introductionmentioning

confidence: 99%

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Real‐time fiber‐optic recording of acute‐ischemic‐stroke signatures

Pochechuev

Bilan

Федотов

et al. 2022

Journal of Biophotonics

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We present an experimental framework and methodology for in vivo studies on rat stroke models that enable a real‐time fiber‐optic recording of stroke‐induced hydrogen peroxide and pH transients in ischemia‐affected brain areas. Arrays of reconnectable implantable fiber probes combined with advanced optogenetic fluorescent protein sensors are shown to enable a quantitative multisite time‐resolved study of oxidative‐stress and acidosis buildup dynamics as the key markers, correlates and possible drivers of ischemic stroke. The fiber probes designed for this work provide a wavelength‐multiplex forward‐propagation channel for a spatially localized, dual‐pathway excitation of genetically encoded fluorescence‐protein sensors along with a back‐propagation channel for the fluorescence return from optically driven fluorescence sensors. We show that the spectral analysis of the fiber‐probe‐collected fluorescence return provides means for a high‐fidelity autofluorescence background subtraction, thus enhancing the sensitivity of real‐time detection of stroke‐induced transients and significantly reducing measurement uncertainties in in vivo acute‐stroke studies as inherently statistical experiments operating with outcomes of multiply repeated measurements on large populations of individually variable animal stroke models.

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Section: Resultssupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Real‐time fiber‐optic recording of acute‐ischemic‐stroke signatures

Pochechuev

Bilan

Федотов

et al. 2022

Journal of Biophotonics

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“…The rapid acidosis within minutes is believed to be the very early damage to the brain after the onset of ischemic stroke, which is evidenced recently by a powerful acidosis image of the brain tissue that overlaps with the ischemic core from the first seconds of stroke strike . Previous studies have demonstrated that mild to moderate acidosis may be neuroprotective, while severe acidosis often leads to cerebral edema and worse functional outcomes. ,− However, the shortage supplement of oxygen and massive release of glutamate in the brain tissue may result in severe acidosis, and the mutual interaction of glutamate excitotoxicity and acidosis aggravates the brain damage during the ischemic stroke.…”

Section: Resultsmentioning

confidence: 99%

TRIOL Inhibits Rapid Intracellular Acidification and Cerebral Ischemic Injury: The Role of Glutamate in Neuronal Metabolic Reprogramming

Xue

Wei

Zhou

et al. 2022

ACS Chem. Neurosci.

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As one of the key injury incidents, tissue acidosis in the brain occurs very quickly within several minutes upon the onset of ischemic stroke. Glutamate, an excitatory amino acid inducing neuronal excitotoxicity, has been reported to trigger the decrease in neuronal intracellular pH (pHi) via modulating proton-related membrane transporters. However, there remains a lack of clarity on the possible role of glutamate in neuronal acidosis via regulating metabolism. Here, we show that 200 μM glutamate treatment quickly promotes glycolysis and inhibits mitochondrial oxidative phosphorylation of primary cultured neurons within 15 min, leading to significant cytosolic lactate accumulation, which contributes to the rapid intracellular acidification and neuronal injury. The reprogramming of neuronal metabolism by glutamate is dependent on adenosine monophosphate-activated protein kinase (AMPK) signaling since the inhibition of AMPK activation by its selective inhibitor compound C significantly reverses these deleterious events in vitro. Moreover, 5α-androst-3β,5α,6β-TRIOL (TRIOL), a neuroprotectant we previously reported, can also remarkably reverse intracellular acidification and alleviate neuronal injury through the inhibition of AMPK signaling. Furthermore, TRIOL remarkably reduced the infarct volume and attenuated neurologic impairment in acute ischemic stroke models of middle cerebral artery occlusion in vivo. In summary, we reveal a novel role of glutamate in rapid intracellular acidification injury resulting from glutamate-induced lactate accumulation through AMPK-mediated neuronal reprogramming. Moreover, inhibition of the quick drop in neuronal pHi by TRIOL significantly reduces the cerebral damages, suggesting that it is a promising drug candidate for ischemic stroke.

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“…Ischemic stroke (IS) acts as a leading cause of death and disability ( Benjamin et al, 2019 ; Kelmanson et al, 2021 ). Due to the limitation of the treatment time window and medical conditions, about 70–80% of the surviving patients with cerebral infarction still have varying degrees of dysfunction ( Girotra et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Repetitive Transcranial Magnetic Stimulation Improves Neurological Function and Promotes the Anti-inflammatory Polarization of Microglia in Ischemic Rats

Luo

Feng

et al. 2022

Front. Cell. Neurosci.

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Ischemic stroke (IS) is a severe neurological disease that is difficult to recovery. Previous studies have shown that repetitive transcranial magnetic stimulation (rTMS) is a promising therapeutic approach, while the exact therapy mechanisms of rTMS in improving neural functional recovery remain unclear. Furthermore, the inflammatory environment may influence the rehabilitation efficacy. Our study shows that long-term rTMS stimulation will significantly promote neurogenesis, inhibit apoptosis, and control inflammation. rTMS inhibits the activation of transcription factors nuclear factor kappa b (NF-κB) and signal transducer and activator of transcription 6 (STAT6) and promotes the anti-inflammatory polarization of microglia. Obvious promotion of anti-inflammatory cytokines production is observed both in vitro and in vivo through rTMS stimulation on microglia. In addition, neural stem cells (NSCs) cultured in conditioned medium (CM) from microglia treated with rTMS showed downregulation of apoptosis and upregulation of neuronal differentiation. Overall, our results illustrate that rTMS can modulate microglia with anti-inflammatory polarization variation, promote neurogenesis, and improve neural function recovery.

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In vivo dynamics of acidosis and oxidative stress in the acute phase of an ischemic stroke in a rodent model

Cited by 30 publications

References 73 publications

Real‐time fiber‐optic recording of acute‐ischemic‐stroke signatures

Real‐time fiber‐optic recording of acute‐ischemic‐stroke signatures

TRIOL Inhibits Rapid Intracellular Acidification and Cerebral Ischemic Injury: The Role of Glutamate in Neuronal Metabolic Reprogramming

Repetitive Transcranial Magnetic Stimulation Improves Neurological Function and Promotes the Anti-inflammatory Polarization of Microglia in Ischemic Rats

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