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Transient selective brain cooling confers neurovascular and functional protection from acute to chronic stages of ischemia/reperfusion brain injury.

ABSTRACT: Ischemic injury can be alleviated by the judicious use of hypothermia. However, the optimal regimens and the temporal kinetics of post-stroke neurovascular responses to hypothermic intervention have not been systematically studied. These gaps slow the clinical translation of hypothermia as an anti-stroke therapy. Here, we characterized the effects of transient selective brain hypothermia (TSBH) from the hyperacute to chronic stages of focal ischemia/reperfusion brain injury induced by transient middle cerebral artery occlusion in mice. A simple cooling device was used to induce TSBH during cerebral ischemia. This treatment reduced mortality from 31.8% to 0% and improved neurological outcomes for at least 35 days post-injury. TSBH mitigated blood-brain barrier leakage during the hyperacute and acute injury stages (1-23?h post-reperfusion). This early protection of the blood-brain barrier was associated with anti-inflammatory phenotypic polarization of microglia/macrophages, reduced production of pro-inflammatory cytokines, and less brain infiltration of neutrophils and macrophages during the subacute injury stage (three days post-reperfusion). TSBH elicited enduring protective effects on both grey and white matter for at least 35 days post-injury and preserved the long-term electrophysiological function of fiber tracts. In conclusion, TSBH ameliorates ischemia/reperfusion injury in the neurovascular unit from hyperacute to chronic injury stages after experimental stroke.

SUBMITTER: Zhao J

PROVIDER: S-EPMC6668511 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Transient selective brain cooling confers neurovascular and functional protection from acute to chronic stages of ischemia/reperfusion brain injury.

Zhao Jingyan J Mu Hongfeng H Liu Liqiang L Jiang Xiaoyan X Wu Di D Shi Yejie Y Leak Rehana K RK Ji Xunming X

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20181018 7

Ischemic injury can be alleviated by the judicious use of hypothermia. However, the optimal regimens and the temporal kinetics of post-stroke neurovascular responses to hypothermic intervention have not been systematically studied. These gaps slow the clinical translation of hypothermia as an anti-stroke therapy. Here, we characterized the effects of transient selective brain hypothermia (TSBH) from the hyperacute to chronic stages of focal ischemia/reperfusion brain injury induced by transient ...[more]

PMID: 30334662

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Project description:BackgroundInhibiting SDH (succinate dehydrogenase), with the competitive inhibitor malonate, has shown promise in ameliorating ischemia/reperfusion injury. However, key for translation to the clinic is understanding the mechanism of malonate entry into cells to enable inhibition of SDH, its mitochondrial target, as malonate itself poorly permeates cellular membranes. The possibility of malonate selectively entering the at-risk heart tissue on reperfusion, however, remains unexplored.MethodsC57BL/6J mice, C2C12 and H9c2 myoblasts, and HeLa cells were used to elucidate the mechanism of selective malonate uptake into the ischemic heart upon reperfusion. Cells were treated with malonate while varying pH or together with transport inhibitors. Mouse hearts were either perfused ex vivo (Langendorff) or subjected to in vivo left anterior descending coronary artery ligation as models of ischemia/reperfusion injury. Succinate and malonate levels were assessed by liquid chromatography-tandem mass spectrometry LC-MS/MS, in vivo by mass spectrometry imaging, and infarct size by TTC (2,3,5-triphenyl-2H-tetrazolium chloride) staining.ResultsMalonate was robustly protective against cardiac ischemia/reperfusion injury, but only if administered at reperfusion and not when infused before ischemia. The extent of malonate uptake into the heart was proportional to the duration of ischemia. Malonate entry into cardiomyocytes in vivo and in vitro was dramatically increased at the low pH (≈6.5) associated with ischemia. This increased uptake of malonate was blocked by selective inhibition of MCT1 (monocarboxylate transporter 1). Reperfusion of the ischemic heart region with malonate led to selective SDH inhibition in the at-risk region. Acid-formulation greatly enhances the cardioprotective potency of malonate.ConclusionsCardioprotection by malonate is dependent on its entry into cardiomyocytes. This is facilitated by the local decrease in pH that occurs during ischemia, leading to its selective uptake upon reperfusion into the at-risk tissue, via MCT1. Thus, malonate's preferential uptake in reperfused tissue means it is an at-risk tissue-selective drug that protects against cardiac ischemia/reperfusion injury.

Project description:Activation of the protease-activated receptor 2 (PAR2) or the transient receptor potential vanilloid type 1 (TRPV1) channels expressed in cardiac sensory afferents containing calcitonin gene-related peptide (CGRP) and/or substance P (SP) has been proposed to play a protective role in myocardial ischemia-reperfusion (I/R) injury. However, the interaction between PAR2 and TRPV1 is largely unknown. Using gene-targeted TRPV1-null mutant (TRPV1(-/-)) or wild-type (WT) mice, we test the hypothesis that TRPV1 contributes to PAR2-mediated cardiac protection via increasing the release of CGRP and SP. Immunofluorescence labeling showed that TRPV1 coexpressed with PAR2, PKC-epsilon, or PKAc in cardiomyocytes, cardiac blood vessels, and perivascular nerves in WT but not TRPV1(-/-) hearts. WT or TRPV1(-/-) hearts were Langendorff perfused with the selective PAR2 agonist, SLIGRL, in the presence or absence of various antagonists, followed by 35 min of global ischemia and 40 min of reperfusion (I/R). The recovery rate of coronary flow, the maximum rate of left ventricular pressure development, left ventricular end-diastolic pressure, and left ventricular developed pressure were evaluated after I/R. SLIGRL improved the recovery of hemodynamic parameters, decreased lactate dehydrogenase release, and reduced the infarct size in both WT and TRPV1(-/-) hearts (P < 0.05). The protection of SLIGRL was significantly surpassed for WT compared with TRPV1(-/-) hearts (P < 0.05). CGRP(8-37), a selective CGRP receptor antagonist, RP67580, a selective neurokinin-1 receptor antagonist, PKC-epsilon V1-2, a selective PKC-epsilon inhibitor, or H-89, a selective PKA inhibitor, abolished SLIGRL protection by inhibiting the recovery of the rate of coronary flow, maximum rate of left ventricular pressure development, and left ventricular developed pressure, and increasing left ventricular end-diastolic pressure in WT but not TRPV1(-/-) hearts. Radioimmunoassay showed that SLIGRL increased the release of CGRP and SP in WT but not TRPV1(-/-) hearts (P < 0.05), which were prevented by PKC-epsilon V1-2 and H-89. Thus our data show that PAR2 activation improves cardiac recovery after I/R injury in WT and TRPV1(-/-) hearts, with a greater effect in the former, suggesting that PAR2-mediated protection is TRPV1 dependent and independent, and that dysfunctional TRPV1 impairs PAR2 action. PAR2 activation of the PKC-epsilon or PKA pathway stimulates or sensitizes TRPV1 in WT hearts, leading to the release of CGRP and SP that contribute, at least in part, to PAR2-induced cardiac protection against I/R injury.

Dataset Information

Transient selective brain cooling confers neurovascular and functional protection from acute to chronic stages of ischemia/reperfusion brain injury.

Publications

Transient selective brain cooling confers neurovascular and functional protection from acute to chronic stages of ischemia/reperfusion brain injury.

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