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

55 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Clinical Neurology

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