In vivo PDGF beta receptor activation in the dorsocaudal brainstem of the rat prevents hypoxia-induced apoptosis via activation of Akt and BAD

Brain Res. 2001 Mar 23;895(1-2):111-8. doi: 10.1016/s0006-8993(01)02054-6.

Abstract

Activation of platelet-derived growth factor receptor beta (PDGFR) within the caudal brainstem modulates the hypoxic ventilatory response. Since hypoxia does not induce apoptosis in the caudal brainstem, PDGFR could underlie such protective mechanism via a PI3 kinase-dependent phosphorylation of both Akt and BAD pathways. To further study this issue, caudal brainstem lysates were harvested from Sprague--Dawley rats during hypoxia (10% O(2)) after treatment with either vehicle or CGP 57148B (100 mg/kg), a selective blood-brain barrier-permeable PDGFR antagonist. Time-dependent increases in phosphorylated Akt occurred during hypoxia, peaking at 45' and lasting for up to 6 h, without parallel changes in total Akt protein. CGP 57148B attenuated Akt activation at all time points. Similarly, phosphorylation of BAD at serine136 but not at serine 112 occurred in the caudal brainstem as early as 15' of hypoxia, and was completely blocked by CGP 57148B. Furthermore, CGP 57148B treatment elicited significant increases in single-stranded DNA, caspase-like activity, and cleaved caspase 3 after 24 h of hypoxia that were absent in the caudal brainstem of hypoxic vehicle-treated animals. We conclude that PDGFR-dependent in vivo activation of both Akt and BAD during hypoxia prevents induction of apoptosis, and may contribute to the increased hypoxic tolerance of brainstem neurons.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Benzamides
  • Carrier Proteins / drug effects*
  • Carrier Proteins / metabolism
  • Caspases / drug effects
  • Caspases / metabolism
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • DNA, Single-Stranded / metabolism
  • Enzyme Inhibitors / pharmacology
  • Hypoxia, Brain / metabolism*
  • Hypoxia, Brain / pathology
  • Hypoxia, Brain / physiopathology
  • Imatinib Mesylate
  • Immunohistochemistry
  • Male
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / physiopathology
  • Nerve Degeneration / prevention & control*
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology
  • Phosphorylation / drug effects
  • Piperazines / pharmacology
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / drug effects*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Pyrimidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Platelet-Derived Growth Factor beta / drug effects*
  • Receptor, Platelet-Derived Growth Factor beta / metabolism
  • Respiratory Physiological Phenomena / drug effects
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Solitary Nucleus / drug effects*
  • Solitary Nucleus / metabolism
  • Solitary Nucleus / physiopathology
  • bcl-Associated Death Protein

Substances

  • Bad protein, rat
  • Benzamides
  • Carrier Proteins
  • DNA, Single-Stranded
  • Enzyme Inhibitors
  • Neuroprotective Agents
  • Piperazines
  • Proto-Oncogene Proteins
  • Pyrimidines
  • bcl-Associated Death Protein
  • Imatinib Mesylate
  • Receptor, Platelet-Derived Growth Factor beta
  • Akt1 protein, rat
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Caspases