Traumatic injury activates MAP kinases in astrocytes: Mechanisms of hypothermia and hyperthermia

Tingting Huang, Juan Solano, Dansha He, Maher Loutfi, W. Dalton Dietrich, John W. Kuluz

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Hyperthermia is common following traumatic brain injury (TBI) and has been associated with poor neurologic outcome, and hypothermia has emerged as a potentially effective therapy for TBI, although its mechanism is still unclear. In this study we investigated the effects of temperature modulations on astrocyte survival following traumatic injury and the involved MAPK pathways. Trauma was produced by scratch injury of a monolayer of confluent astrocytes in culture, followed by incubation at hypothermia (30°C), normothermia (37°C), or hyperthermia (39°C). The activation of MAPK pathways including extracellular signal-regulated protein kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPK were measured at 0, 15, 30, 60, and 120min after traumatic injury followed by temperature modulation. Apoptosis of astrocytes was assessed by quantitation of cleaved caspase-3 expression 24h after injury. Our findings showed that only JNK activation at 15min after trauma was reduced by hypothermia, and this was associated with a marked reduction in apoptosis. Hyperthermia activated both ERK and JNK and increased apoptosis. The specific JNK inhibitor, SP60025, markedly reduced JNK-induced apoptosis at normothermia and hyperthermia, and showed a dose-dependent effect. In conclusion, the JNK pathway appears to mediate traumatic injury-induced apoptosis in astrocytes. Prolonged hyperthermia as a secondary insult worsens apoptosis by increasing JNK activation. Hypothermia protects against traumatic injury via early suppression on JNK activation and subsequent prevention of apoptosis. Manipulation of the JNK pathway in astrocytes may represent a therapeutic target for ameliorating the devastating progression of tissue injury and cell death after TBI.

Original languageEnglish
Pages (from-to)1535-1545
Number of pages11
JournalJournal of Neurotrauma
Volume26
Issue number9
DOIs
StatePublished - Sep 1 2009

Fingerprint

Hypothermia
Astrocytes
Fever
Phosphotransferases
Wounds and Injuries
Apoptosis
MAP Kinase Signaling System
MAP Kinase Kinase 4
Temperature
Extracellular Signal-Regulated MAP Kinases
p38 Mitogen-Activated Protein Kinases
Caspase 3
Protein Kinases
Nervous System
Cell Death
Therapeutics

Keywords

  • Apoptosis
  • Astrocyte
  • Hyperthermia
  • Hypothermia
  • MAPKs
  • SP60025
  • Traumatic brain injury

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Traumatic injury activates MAP kinases in astrocytes : Mechanisms of hypothermia and hyperthermia. / Huang, Tingting; Solano, Juan; He, Dansha; Loutfi, Maher; Dalton Dietrich, W.; Kuluz, John W.

In: Journal of Neurotrauma, Vol. 26, No. 9, 01.09.2009, p. 1535-1545.

Research output: Contribution to journalArticle

Huang, Tingting ; Solano, Juan ; He, Dansha ; Loutfi, Maher ; Dalton Dietrich, W. ; Kuluz, John W. / Traumatic injury activates MAP kinases in astrocytes : Mechanisms of hypothermia and hyperthermia. In: Journal of Neurotrauma. 2009 ; Vol. 26, No. 9. pp. 1535-1545.
@article{1f42b740cacf43c39399faf2729dad26,
title = "Traumatic injury activates MAP kinases in astrocytes: Mechanisms of hypothermia and hyperthermia",
abstract = "Hyperthermia is common following traumatic brain injury (TBI) and has been associated with poor neurologic outcome, and hypothermia has emerged as a potentially effective therapy for TBI, although its mechanism is still unclear. In this study we investigated the effects of temperature modulations on astrocyte survival following traumatic injury and the involved MAPK pathways. Trauma was produced by scratch injury of a monolayer of confluent astrocytes in culture, followed by incubation at hypothermia (30°C), normothermia (37°C), or hyperthermia (39°C). The activation of MAPK pathways including extracellular signal-regulated protein kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPK were measured at 0, 15, 30, 60, and 120min after traumatic injury followed by temperature modulation. Apoptosis of astrocytes was assessed by quantitation of cleaved caspase-3 expression 24h after injury. Our findings showed that only JNK activation at 15min after trauma was reduced by hypothermia, and this was associated with a marked reduction in apoptosis. Hyperthermia activated both ERK and JNK and increased apoptosis. The specific JNK inhibitor, SP60025, markedly reduced JNK-induced apoptosis at normothermia and hyperthermia, and showed a dose-dependent effect. In conclusion, the JNK pathway appears to mediate traumatic injury-induced apoptosis in astrocytes. Prolonged hyperthermia as a secondary insult worsens apoptosis by increasing JNK activation. Hypothermia protects against traumatic injury via early suppression on JNK activation and subsequent prevention of apoptosis. Manipulation of the JNK pathway in astrocytes may represent a therapeutic target for ameliorating the devastating progression of tissue injury and cell death after TBI.",
keywords = "Apoptosis, Astrocyte, Hyperthermia, Hypothermia, MAPKs, SP60025, Traumatic brain injury",
author = "Tingting Huang and Juan Solano and Dansha He and Maher Loutfi and {Dalton Dietrich}, W. and Kuluz, {John W.}",
year = "2009",
month = "9",
day = "1",
doi = "10.1089/neu.2008.0743",
language = "English",
volume = "26",
pages = "1535--1545",
journal = "Journal of Neurotrauma",
issn = "0897-7151",
publisher = "Mary Ann Liebert Inc.",
number = "9",

}

TY - JOUR

T1 - Traumatic injury activates MAP kinases in astrocytes

T2 - Mechanisms of hypothermia and hyperthermia

AU - Huang, Tingting

AU - Solano, Juan

AU - He, Dansha

AU - Loutfi, Maher

AU - Dalton Dietrich, W.

AU - Kuluz, John W.

PY - 2009/9/1

Y1 - 2009/9/1

N2 - Hyperthermia is common following traumatic brain injury (TBI) and has been associated with poor neurologic outcome, and hypothermia has emerged as a potentially effective therapy for TBI, although its mechanism is still unclear. In this study we investigated the effects of temperature modulations on astrocyte survival following traumatic injury and the involved MAPK pathways. Trauma was produced by scratch injury of a monolayer of confluent astrocytes in culture, followed by incubation at hypothermia (30°C), normothermia (37°C), or hyperthermia (39°C). The activation of MAPK pathways including extracellular signal-regulated protein kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPK were measured at 0, 15, 30, 60, and 120min after traumatic injury followed by temperature modulation. Apoptosis of astrocytes was assessed by quantitation of cleaved caspase-3 expression 24h after injury. Our findings showed that only JNK activation at 15min after trauma was reduced by hypothermia, and this was associated with a marked reduction in apoptosis. Hyperthermia activated both ERK and JNK and increased apoptosis. The specific JNK inhibitor, SP60025, markedly reduced JNK-induced apoptosis at normothermia and hyperthermia, and showed a dose-dependent effect. In conclusion, the JNK pathway appears to mediate traumatic injury-induced apoptosis in astrocytes. Prolonged hyperthermia as a secondary insult worsens apoptosis by increasing JNK activation. Hypothermia protects against traumatic injury via early suppression on JNK activation and subsequent prevention of apoptosis. Manipulation of the JNK pathway in astrocytes may represent a therapeutic target for ameliorating the devastating progression of tissue injury and cell death after TBI.

AB - Hyperthermia is common following traumatic brain injury (TBI) and has been associated with poor neurologic outcome, and hypothermia has emerged as a potentially effective therapy for TBI, although its mechanism is still unclear. In this study we investigated the effects of temperature modulations on astrocyte survival following traumatic injury and the involved MAPK pathways. Trauma was produced by scratch injury of a monolayer of confluent astrocytes in culture, followed by incubation at hypothermia (30°C), normothermia (37°C), or hyperthermia (39°C). The activation of MAPK pathways including extracellular signal-regulated protein kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPK were measured at 0, 15, 30, 60, and 120min after traumatic injury followed by temperature modulation. Apoptosis of astrocytes was assessed by quantitation of cleaved caspase-3 expression 24h after injury. Our findings showed that only JNK activation at 15min after trauma was reduced by hypothermia, and this was associated with a marked reduction in apoptosis. Hyperthermia activated both ERK and JNK and increased apoptosis. The specific JNK inhibitor, SP60025, markedly reduced JNK-induced apoptosis at normothermia and hyperthermia, and showed a dose-dependent effect. In conclusion, the JNK pathway appears to mediate traumatic injury-induced apoptosis in astrocytes. Prolonged hyperthermia as a secondary insult worsens apoptosis by increasing JNK activation. Hypothermia protects against traumatic injury via early suppression on JNK activation and subsequent prevention of apoptosis. Manipulation of the JNK pathway in astrocytes may represent a therapeutic target for ameliorating the devastating progression of tissue injury and cell death after TBI.

KW - Apoptosis

KW - Astrocyte

KW - Hyperthermia

KW - Hypothermia

KW - MAPKs

KW - SP60025

KW - Traumatic brain injury

UR - http://www.scopus.com/inward/record.url?scp=70450206734&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70450206734&partnerID=8YFLogxK

U2 - 10.1089/neu.2008.0743

DO - 10.1089/neu.2008.0743

M3 - Article

C2 - 19331517

AN - SCOPUS:70450206734

VL - 26

SP - 1535

EP - 1545

JO - Journal of Neurotrauma

JF - Journal of Neurotrauma

SN - 0897-7151

IS - 9

ER -