Hypoxic preconditioning induced by intermittent hypoxia in an experimental model of sleep apnea.

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

St. Louis, Missouri

Congreso; 42nd Annual American Society for Neurochemistry (ASN) Meeting; 2011

American Society for Neurochemistry (ASN)

HYPOXIC PRECONDITIONING INDUCED BY INTERMITTENT HYPOXIA IN AN EXPERIMENTAL MODEL OF SLEEP APNEA Avilés-Reyes, R.X.1, Angelo, M.F.1, Unsain, N.2, Villarreal, A.1, Barker, P.A.2, Ramos, A.J.1 1 Univesidad de Buenos Aires, Facultad de Medicina, Laboratorio de Neuropatología Molecular, IBCN, UBA-CONICET, Buenos Aires, Argentina 2 McGill University, Centre for Neuronal Survival, Montreal Neurological Institute, Montreal, Canada Sleep apnea (SA) and cerebral ischemia are serious public health pro­blems in adult population having high prevalence, morbility and mortality. Clinical studies have shown that SA patients have reduced mortality after an ischemic stroke. The neuro­pro­tection induced by hypo­xic preconditioning (HP); support the fact that the brain can adapt to insults such as ischemia, thus increasing the chances of survival from subsequent injury. To test this hypo­thesis, we exposed adult rats or mice (wild type wt, XIAP-/- or NF-kB reporter) to SA model of inter­mittent hypo­xia (IH) by cycling oxygen level (6 min 21% + 6 min 10%; 3 and 5 days; 8 h/day), in the sleep phase (Hx group). Control animals were exposed to room air (Nx). A subgroup of animals exposed to 3-5 days of HI or Nx were then subjected to ischemia by cortical devascularization (groups Hx+I or Nx+I). Our results showed that astrogliosis (analyzed by GFAP+ and Vimentin+) was diminished in animals previously exposed to Hx+I. Reduced number of altered neuro­ns were observed in Hx+I compared with Nx+I group. Fluoro Jade B staining showed a reduced number of degenerating neuro­ns in the Hx+I animals. XIAP-/- mice lost this pro­tection to subsequent ischemia induced by the Hx exposure. RT-PCR studies showed the Heat Shock Proteins (HSP) mRNAs induction was increased in Hx exposed animals. The NF-κB activity was increased in Hx animals as shown by the NF-κB reporter trans­genic mice and increased levels of IκB in wt mice. The inhibitor of apoptosis pro­teins (IAPs) specifically c-IAP, XIAP and Bcl-XL showed an increase in Hx animals. XIAP -/- mice showed limited expression of HSPs and IAPs. We conclude that IH develop a degree of cellular brain adaptation or tolerance that induces partial neuro­pro­tection to a subsequent ischemic injury, supporting clinical observations from SA patients, pro­bably are involving HSPs and NF-kB target genes specifically XIAP. Grants: CONICET PIP 1728, PICT 2008-1590; IBRO -Aguayo Fellowship 2009