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.
Subject(s)
Apoptosis/drug effects , Carrier Proteins/drug effects , Hypoxia, Brain/metabolism , Nerve Degeneration/prevention & control , Protein Serine-Threonine Kinases , Proto-Oncogene Proteins/drug effects , Receptor, Platelet-Derived Growth Factor beta/drug effects , Solitary Nucleus/drug effects , Animals , Apoptosis/physiology , Benzamides , Carrier Proteins/metabolism , Caspases/drug effects , Caspases/metabolism , Cell Survival/drug effects , Cell Survival/physiology , DNA, Single-Stranded/metabolism , Enzyme Inhibitors/pharmacology , Hypoxia, Brain/pathology , Hypoxia, Brain/physiopathology , Imatinib Mesylate , Immunohistochemistry , Male , Nerve Degeneration/metabolism , Nerve Degeneration/physiopathology , Neurons/drug effects , Neurons/metabolism , Neuroprotective Agents/pharmacology , Phosphorylation/drug effects , Piperazines/pharmacology , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-akt , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Platelet-Derived Growth Factor beta/metabolism , Respiratory Physiological Phenomena/drug effects , Signal Transduction/drug effects , Signal Transduction/physiology , Solitary Nucleus/metabolism , Solitary Nucleus/physiopathology , bcl-Associated Death ProteinABSTRACT
BACKGROUND: Many anesthetic drugs have been shown to disrupt conscious recall (explicit memory) in volunteers. However, unconscious processing (implicit memory) of intraoperative auditory material may occur during general anesthesia and may provide an opportunity for intraoperative therapeutic intervention. In this study, we examined patients undergoing elective cardiac surgery for evidence of intraoperative implicit and explicit memory. METHODS AND RESULTS: Twenty-five subjects provided written informed consent and underwent general anesthesia and cardiopulmonary bypass for cardiac surgery. During the operation, patients were randomized to receive 1 of 2 different audiotapes of associated word pairs. Postoperatively, a blinded observer conducted a standardized interview to determine the extent of intraoperative implicit and explicit memory. With the use of free association, significant intraoperative implicit memory was found. In contrast, no patient had spontaneous or directed recall of intraoperative events, and we did not find evidence of intraoperative explicit memory with a recognition task. CONCLUSIONS: Patients undergoing general anesthesia for cardiac surgery were reliably able to reinforce associations between word pairs solely on the basis of their intraoperative presentation. This provides further evidence that patients are capable of processing intraoperative auditory information.
