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

Activation of platelet-derived growth factor receptor beta (PDGFR) within t he caudal brainstem modulates the hypoxic ventilatory response. Since hypox ia does not induce apoptosis in the caudal brainstem, PDGFR could underlie such protective mechanism via a PI3 kinase-dependent phosphorylation of bot h Akt and BAD pathways. To further study this issue, caudal brainstem lysat es were harvested from Sprague-Dawley rats during hypoxia (10% O-2) after t reatment with either vehicle or CGP 57148B (100 mg/kg), a selective blood-b rain barrier-permeable PDGFR antagonist. Time-dependent increases in phosph orylated Akt occurred during hypoxia, peaking at 45' and lasting for up to 6 h, without parallel changes in total Akt protein. CGP 57148B attenuated A kt activation at all time points. Similarly, phosphorylation of BAD at seri ne136 but not at serine 112 occurred in the caudal brainstem as early as 15 ' of hypoxia, and was completely blocked by COP 57148B. Furthermore, CGP 57 148B treatment elicited significant increases in single-stranded DNA, caspa se-like activity, and cleaved caspase 3 after 14 h of hypoxia that were abs ent 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 hypox ic tolerance of brainstem neurons. (C) 2001 Elsevier Science B.V. All right s reserved.