Amelioration of central cardiovascular regulatory dysfunction by tropomyocin receptor kinase B in a mevinphos intoxication model of brain stem death

Chan, Samuel H.H.; Chan, Julie Y.H.; Li, F C H; Sun, Enya Y.H.; Chen, W L; Chang, Alice Y.W.

doi:10.1111/j.1476-5381.2011.01508.x

Cited by 11 publications

(10 citation statements)

References 54 publications

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“…It was administered intravenously, with saline serving as the vehicle control. Temporal changes in pulsatile AP, mean AP (MAP), HR and power density of the LF component were routinely followed for 20 min in an on-line and real-time manner [14] , [16] , [52] , or until the animal succumbed to METH. The survival rate within 240 min was also recorded.…”

Section: Methodsmentioning

confidence: 99%

“…Simultaneous and continuous measurement of tissue oxygen tension, blood flow and temperature (Oxford Optronix, Oxford, England) was carried out by a combined oxygen/temperature/blood flow probe stereotaxically positioned into the RVLM [14] , [52] . The coordinates used were: 4.5 to 5 mm posterior to lambda, 1.8 to 2.1 mm lateral to midline and 8.1 to 8.4 mm below dorsal surface of cerebellum.…”

Section: Methodsmentioning

confidence: 99%

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Bioenergetics Failure and Oxidative Stress in Brain Stem Mediates Cardiovascular Collapse Associated with Fatal Methamphetamine Intoxication

Yen²,

Chan

et al. 2012

PLoS ONE

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BackgroundWhereas sudden death, most often associated with cardiovascular collapse, occurs in abusers of the psychostimulant methamphetamine (METH), the underlying mechanism is much less understood. The demonstration that successful resuscitation of an arrested heart depends on maintained functionality of the rostral ventrolateral medulla (RVLM), which is responsible for the maintenance of stable blood pressure, suggests that failure of brain stem cardiovascular regulation, rather than the heart, holds the key to cardiovascular collapse. We tested the hypothesis that cessation of brain stem cardiovascular regulation because of a loss of functionality in RVLM mediated by bioenergetics failure and oxidative stress underlies the cardiovascular collapse elicited by lethal doses of METH.Methodology/Principal FindingsSurvival rate, cardiovascular responses and biochemical or morphological changes in RVLM induced by intravenous administration of METH in Sprague-Dawley rats were investigated. High doses of METH induced significant mortality within 20 min that paralleled concomitant the collapse of arterial pressure or heart rate and loss of functionality in RVLM. There were concurrent increases in the concentration of METH in serum and ventrolateral medulla, along with tissue anoxia, cessation of microvascular perfusion and necrotic cell death in RVLM. Furthermore, mitochondrial respiratory chain enzyme activity or electron transport capacity and ATP production in RVLM were reduced, and mitochondria-derived superoxide anion level was augmented. All those detrimental physiological and biochemical events were reversed on microinjection into RVLM of a mobile electron carrier in the mitochondrial respiratory chain, coenzyme Q10; a mitochondria-targeted antioxidant and superoxide anion scavenger, Mito-TEMPO; or an oxidative stress-induced necrotic cell death inhibitor, IM-54.ConclusionWe conclude that sustained anoxia and cessation of local blood flow that leads to bioenergetics failure and oxidative stress because of mitochondrial dysfunction, leading to acute necrotic cell death in RVLM underpins cardiovascular collapse elicited by lethal doses of METH.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Bioenergetics Failure and Oxidative Stress in Brain Stem Mediates Cardiovascular Collapse Associated with Fatal Methamphetamine Intoxication

Yen²,

Chan

et al. 2012

PLoS ONE

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“…In addition, the phosphorylation of ATF-2 in Thr71 and of c-Jun in Ser73 in RVLM was also increased during this phase Chan et al [48]. Furthermore, Chan et al [49] have shown that Mev induced pro-life brainstem death via NO produced by NOS I in the Rostral Ventrolateral Medulla (RVLM), followed by stimulation of the soluble guanylyl cyclase/cGMP/PKG cascade. Further, it was shown that Bis (pinacolylmethyl) phosphonate (BPMP) induced the ERK signaling pathway to cause vacuolation in mitochondria in cultured rat astrocytes, and the authors suspected that the activated Ras/Raf-1/ERK signaling pathway was involved in modulating central cardiovascular function through NOS I/PKG upregulation [50].…”

Section: Organophosphorus Compound-induced Neurodegenerative Diseasesmentioning

confidence: 96%

Organophosphorus Compounds and MAPK Signaling Pathways

Farkhondeh

Buhrmann

Pourbagher‐Shahri

et al. 2020

IJMS

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The molecular signaling pathways that lead to cell survival/death after exposure to organophosphate compounds (OPCs) are not yet fully understood. Mitogen-activated protein kinases (MAPKs) including the extracellular signal-regulated protein kinase (ERK), the c-Jun NH2-terminal kinase (JNK), and the p38-MAPK play the leading roles in the transmission of extracellular signals into the cell nucleus, leading to cell differentiation, cell growth, and apoptosis. Moreover, exposure to OPCs induces ERK, JNK, and p38-MAPK activation, which leads to oxidative stress and apoptosis in various tissues. However, the activation of MAPK signaling pathways may differ depending on the type of OPCs and the type of cell exposed. Finally, different cell responses can be induced by different types of MAPK signaling pathways after exposure to OPCs.

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“…More importantly, the distinct phases of augmentation followed by reduction of the LF power exhibited during Mev intoxication [14-17] can be designated the pro-life and pro-death phase of central cardiovascular regulation in this model of brain stem death [6]. Based on this model, our laboratory has previously demonstrated that activation of MAPK kinase 1/2 (MEK1/2) in RVLM, followed by ERK1/2 and MAPK signal-interacting kinase 1/2 (MNK1/2) activation, is responsible for the pro-life phase by sustaining the central cardiovascular regulatory machinery during brain stem death [18,19]. …”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, we previously demonstrated that ERK1/2 in RVLM plays a pro-life role in experimental brain stem death [18,19]. In our continual search for the cellular and molecular underpinning of brain stem death, the next logical direction is to evaluate the contribution of the other two family members of MAPKs, JNK or p38MAPK in RVLM to this fatal phenomenon.…”

Section: Introductionmentioning

confidence: 99%

Pro-life role for c-Jun N-terminal kinase and p38 mitogen-activated protein kinase at rostral ventrolateral medulla in experimental brain stem death

Chang

2012

J Biomed Sci

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BackgroundBased on an experimental brain stem death model, we demonstrated previously that activation of the mitogen-activated protein kinase kinase 1/2 (MEK1/2)/extracellular signal-regulated kinase 1/2 (ERK1/2)/ mitogen-activated protein kinase signal-interacting kinase 1/2 (MNK1/2) cascade plays a pro-life role in the rostral ventrolateral medulla (RVLM), the origin of a life-and-death signal detected from systemic arterial pressure, which sequentially increases (pro-life) and decreases (pro-death) to reflect progressive dysfunction of central cardiovascular regulation during the advancement towards brain stem death in critically ill patients. The present study assessed the hypothesis that, in addition to ERK1/2, c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK), the other two mammalian members of MAPKs that are originally identified as stress-activated protein kinases, are activated specifically by MAPK kinase 4 (MAP2K4) or MAP2K6 and play a pro-life role in RVLM during experimental brain stem death. We further delineated the participation of phosphorylating activating transcriptional factor-2 (ATF-2) and c-Jun, the classical transcription factor activated by JNK or p38MAPK, in this process.ResultsAn experimental model of brain stem death that employed microinjection of the organophosphate insecticide mevinphos (Mev; 10 nmol) bilaterally into RVLM of Sprague–Dawley rats was used, alongside cardiovascular, pharmacological and biochemical evaluations. Results from ELISA showed that whereas the total JNK, p38MAPK, MAP2K4 and MAP2K6 were not affected, augmented phosphorylation of JNK at Thr183 and Tyr185 and p38MAPK at Thr180 and Tyr182, accompanied by phosphorylation of their upstream activators MAP2K4 at Ser257 and Thr261 and MAP2K6 at Ser207 and Thr211 in RVLM occurred preferentially during the pro-life phase of experimental brain stem death. Moreover, the activity of transcription factors ATF-2 at Thr71 and c-Jun at Ser73, rather than Elk-1 at Ser383 in RVLM were also augmented during the pro-life phase. Furthermore, pretreatment by microinjection into the bilateral RVLM of specific JNK inhibitors, JNK inhibitor I (100 pmol) or SP600125 (5 pmol), or specific p38MAPK inhibitors, p38MAPK inhibitor III (500 pmol) or SB203580 (2 nmol), exacerbated the depressor effect and blunted the augmented life-and-death signal exhibited during the pro-life phase. On the other hand, pretreatment with the negative control for JNK or p38MAPK inhibitor, JNK inhibitor I negative control (100 pmol) or SB202474 (2 nmol), was ineffective in the vehicle-controls and Mev-treatment groups.ConclusionsOur results demonstrated that activation of JNK or p38MAPK in RVLM by their upstream activators MAP2K4 or MAP2K6 plays a preferential pro-life role by sustaining the central cardiovascular regulatory machinery during experimental brain stem death via phosphorylation and activation of nuclear transcription factor ATF-2 or c-Jun.

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Amelioration of central cardiovascular regulatory dysfunction by tropomyocin receptor kinase B in a mevinphos intoxication model of brain stem death

Cited by 11 publications

References 54 publications

Bioenergetics Failure and Oxidative Stress in Brain Stem Mediates Cardiovascular Collapse Associated with Fatal Methamphetamine Intoxication

Bioenergetics Failure and Oxidative Stress in Brain Stem Mediates Cardiovascular Collapse Associated with Fatal Methamphetamine Intoxication

Organophosphorus Compounds and MAPK Signaling Pathways

Pro-life role for c-Jun N-terminal kinase and p38 mitogen-activated protein kinase at rostral ventrolateral medulla in experimental brain stem death

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