Reduced neuronal degeneration after NFkB blockage in a model of sleep apnea by intermittent hypoxia

M. ANGELO; R. X. AVILES REYES; A. VILLARREAL; N. UNSAIN; P. A. BARKER; A. RAMOS

San Diego

Congreso; 2010 Neuroscience Meeting; 2010

Society for Neuroscience

Sleep apnea (SA) is a human pathology that produces important alterations in the cognitive performance. Using an experimental model of SA by intermittent hypoxia (IH), we previously demonstrated early severe alterations and neuronal death in hippocampus and brain cortex, two anatomical areas related to the cognitive impairments observed in human patients. Surprisingly, a significant neuronal survival was observed after longer exposure to IH (Aviles-Reyes et al., 2010, J. Neurochem 112:854). In order to analyze NFκB transcription factor involvement in the neuronal survival after IH, we exposed NFκB reporter mice or Wistar rats to IH cycles (alternating 10% - 21% O2) every 6 min during 8h per day during 3 consecutive days. A separated set of animals was cannulated 3 days before the IH exposure, allowed to recover from surgery and received an intrahippocampal infusion of NFκB blocker sulfasalazine (SFZ) (1uL; 1.25mM) or vehicle at the beginning of each day of IH exposure. On the 4th day, animals were deeply anesthetized and fixed by perfusion for immunocytochemistry or brains dissected for RT-PCR studies. IH exposure increased NFκB transcriptional activity as judged from NFκB reporter transgenic mice that presented increased NFκB dependent X-gal activity. XIAP, cIAP-2 and IκB mRNAs were significantly increased after 3 days of IH exposure. In vivo blockage of NFκB activation with intrahippocampal SFZ infusion resulted in a persistence of cytoplasmic p65 subunit immunostaining in the hippocampal pyramidal cell layer, indicative of the blockage of NFκB nuclear traslocation, and decreased the number of degenerating neurons as shown by a reduction of neurons with atypical nuclear morphology by NeuN immunostaining. Our results showed that NFκB dependent transcriptional activity is increased after IH exposure. However, NFκB blockage in vivo improved neuronal survival thus showing that NFκB may have a main role in the initial neuronal degeneration induced by IH, while NFκB prosurvival effects are probably evidenced at later time points.