Hypoxic Preconditioning Confers Long-Term Reduction of Brain Injury and Improvement of Neurological Ability in Immature Rats

Abstract

Exposure to preconditioning (PC) hypoxia 24 h before a severe hypoxic-ischemic (HI) insult reduces development of injury in the immature brain. Several protective regimens have proved effective in the short-term but not in the long-term perspective. The aim of the present study, therefore, was to evaluate the PC effect on long-term morphologic and neurologic outcome in the developing brain. Six-day-old rats were subjected to hypoxia (36°C, 8.0% O 2 ; PC/HI group) and sham controls to normoxia (36°C; HI group) for 3 h. Twenty-four hours later, all rats were exposed to cerebral HI produced by unilateral carotid artery occlusion combined with 1 h, 15 min of hypoxia (36°C, 7.7% O 2 ). A cylinder test was used to evaluate forelimb asymmetry to determine sensorimotor function at 4, 6, and 8 wk of age. Spatial/cognitive ability was assessed by Morris water maze trials at 7 wk of recovery. Neuropathologic analysis was performed 8 wk after insult. Brain damage was reduced (p Ͻ Hypoxic-ischemic (HI) brain injury during the perinatal period is a major cause of lifelong disability (1,2). The development of effective therapeutic and/or preventive strategies to treat these pathologic events relies on a better understanding of the critical pathophysiologic events that lead to HI brain injury.In 1986, Murry et al. (3) reported that the extent of myocardial infarction resulting from a sustained coronary occlusion was diminished when the heart had been subjected to brief periods of sublethal ischemia. The protection elicited by a previous sublethal intervention that renders the tissue less sensitive to a subsequent insult has been termed preconditioning (PC). PC can be induced in the CNS through a variety of exposures, for example, seizures (4), hypoxia (5), lipopolysaccharide (6), and mitochondrial toxins (7).A PC model has been developed for the immature brain, whereby exposure to 8% hypoxia 24 h before severe HI reduces injury by 70 -100% (5,8,9). Findings of protection have been demonstrated from 1 to 3 wk after insult. Recent studies indicate, however, that development of injury in the immature brain after HI may be delayed for up to 8 wk (10), and in some cases, the salutary effects of PC in the adult (11) are partly lost after long recovery periods after the severe insult. A number of treatments after HI in immature animals have also been shown to delay injury rather than provide a permanent protection (12). Furthermore, deficits in spatial/ cognitive and sensorimotor functions sometimes occur despite no or subtle brain injury, implicating the need for sophisticated functional assessments as a complement to evaluation of lesion size (13). Our aim, therefore, was to further characterize PC in the immature brain and to determine to what extent hypoxic PC provides long-lasting behavioral and histologic protection.

Lipopolysaccharide Preconditioning Reduces Neuroinflammation Against Hypoxic Ischemia and Provides Long-Term Outcome of Neuroprotection in Neonatal Rat

“…Long-term outcome evaluation of preconditioning in neonatal HI at both pathologic and behavioral levels have been reported for hypoxic (11), ligation (12), and ischemic (13) preconditioning models. Sparing neurons from pathologic damage may not necessarily translate into sparing them from dysfunction.…”

Long-Term Functional and Protective Actions of Preconditioning With Hypoxia, Cobalt Chloride, and Desferrioxamine Against Hypoxic-Ischemic Injury in Neonatal Rats

“…Those genes affected include HIF-1 (9) and HIF-1 target genes: glucose transporters, glycolytic enzymes (10), erythropoietin and vascular endothelial growth factor (VEGF) (11). Numerous experimental studies have highlighted the need to examine long-term functional improvements in addition to histologic outcomes after HI injury in the neonate (3,15,16). Therefore, we have investigated whether preconditioning with hypoxia (HP), DFX and CoCl 2 has long lasting cytoprotective actions and thus improves both morphologic and behavioral endpoints 5 wk after an HI insult performed in postnatal day 7 rat pups.…”

Global Gene Expression in the Developing Rat Brain After Hypoxic Preconditioning: Involvement of Apoptotic Mechanisms?

“…Exposure to sublethal hypoxic conditions (hypoxic PC) 24 h before HI confers substantial protection of the developing brain (2). We have recently observed that reduction in brain injury is long-lasting (8 wk) with respect to both histopathology and long-term sensorimotor behavioral tasks (3). There are reasons to believe that altered gene expression underlies this protective effect, e.g.…”