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

S. H.H. Chan, J. Y.H. Chan, K. S. Hsu, F. C.H. Li, E. Y.H. Sun, W. L. Chen, A. Y.W. Chang

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE Little information exists on the mechanisms that precipitate brain stem death, the legal definition of death in many developed countries. We investigated the role of tropomyocin receptor kinase B (TrkB) and its downstream signalling pathways in the rostral ventrolateral medulla (RVLM) during experimental brain stem death. EXPERIMENTAL APPROACH An experimental model of brain stem death that employed microinjection of the organophosphate insecticide mevinphos bilaterally into the RVLM of Sprague-Dawley rats was used, in conjunction with cardiovascular, pharmacological and biochemical evaluations. KEY RESULTS A significant increase in TrkB protein, phosphorylation of TrkB at Tyr 516 (pTrkB Y516), Shc at Tyr 317 (pShc Y317) or ERK at Thr 202/Tyr 204, or Ras activity in RVLM occurred preferentially during the pro-life phase of experimental brain stem death. Microinjection bilaterally into RVLM of a specific TrkB inhibitor, K252a, antagonized those increases. Pretreatment with anti-pShc Y317 antiserum, Src homology 3 binding peptide (Grb2/SOS inhibitor), farnesylthioacetic acid (Ras inhibitor), manumycin A (Ras inhibitor) or GW5074 (Raf-1 inhibitor) blunted the preferential augmentation of Ras activity or ERK phosphorylation in RVLM and blocked the up-regulated NOS I/protein kinase G (PKG) signalling, the pro-life cascade that sustains central cardiovascular regulation during experimental brain stem death. CONCLUSIONS AND IMPLICATIONS Activation of TrkB, followed by recruitment of Shc/Grb2/SOS adaptor proteins, leading to activation of Ras/Raf-1/ERK signalling pathway plays a crucial role in ameliorating central cardiovascular regulatory dysfunction via up-regulation of NOS I/PKG signalling cascade in the RVLM in brain stem death. These findings provide novel information for developing therapeutic strategies against this fatal eventuality.

Original languageEnglish
Pages (from-to)2015-2028
Number of pages14
JournalBritish Journal of Pharmacology
Volume164
Issue number8
DOIs
Publication statusPublished - 2011 Dec

All Science Journal Classification (ASJC) codes

  • Pharmacology

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