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

ANGELO M; AVILES REYES RX; VILLARREAL A; UNSAIN N; BARKER PA; RAMOS AJ

Congreso; Society for Neuroscience 40th Annual 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 NFkB transcription factor involvement in the neuronal survival after IH, we exposed NFƒÛB 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 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 NFkB transcriptional activity as judged from NFkB reporter transgenic mice that presented increased NFkB dependent X-gal activity. XIAP, cIAP-2 and IkB mRNAs were significantly increased after 3 days of IH exposure. In vivo blockage of NFkB 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 NFkB 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 NFkB dependent transcriptional activity is increased after IH exposure. The expression of some NFkB target genes is also increased. However, NFkB blockage in vivo improved neuronal survival thus showing that NFkB may have a main role in the initial neuronal degeneration induced by IH, while prosurvival effects may occur at a later time points.