RAGE and NF-KB are involved in neuronal death induced by sleep apnea

AVILES REYES ROLANDO XAVIER; ANGELO MARIA FLORENCIA; UNSAIN NICOLAS; VILLARREAL ALEJANDRO; BARKER PHIL; ALBERTO JAVIER RAMOS

Congreso; Meeting of International Brain Research Oganization; 2011

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. It has been hypothesized that improved survival may be related to an ischemic tolerance phenomenon in which the brain protects itself against future injury by adapting to low doses of noxious insults. The neuroprotection induced by hypoxic preconditioning (HP); support the fact that the mammalian brain can adapt to injurious insults such as cerebral 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 an experimental model of SA by intermittent hypoxia (IH) by cycling oxygen level (6 min 21% + 6 min 10%; 3 and 5 days; 8 h/day), during the sleep phase (Hx group). Control animals were exposed to room air (Nx). A subgroup of animals were exposed to HI for 3 or 5 days; one day after HI, the animals were subjected a focal brain ischemia by cortical devascularization method, and sacrificed 3 or 7 days post lesion (dpl) (groups Nx+I or Hx+I). Our results showed that reactive gliosis (analyzed by GFAP+ and Vimentin+ immunostaining) was significantly diminished in animals previously exposed to Hx+I compared with Nx+I animals. Reduced number of altered neurons with atypical NeuN staining were observed in Hx+I compared with Nx+I group. Fluoro Jade B staining also showed a reduced number of degenerating neurons in the Hx+I animals. XIAP -/- mice lost the protection to a subsequent ischemia induced by the Hx exposure. RT-PCR studies showed the Heat Shock Proteins (HSP) mRNAs induction was significantly increased in hippocampus of wt Hx animals. The activity of NF-êB was increased in Hx animals as shown by the NF-êB reporter transgenic mice and increased levels of IêB in wt mice. The inhibitor of apoptosis proteins (IAPs) specifically c-IAP, XIAP and Bcl-XL showed an increase in Hx animals. XIAP -/- knockout animals showed that expression of molecular chaperons and IAPs was limited in parietal cortex and hippocampus. 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.