Abstract
BackgroundHypoxic-ischemic (HI) encephalopathy causes life-long morbidity and premature mortality in term neonates. Therapies in addition to whole-body cooling are under development to treat the neonate at risk for HI encephalopathy, but are not a quickly measured serum inflammatory or neuronal biomarkers to rapidly and accurately identify brain injury in order to follow the efficacy of therapies.MethodsIn order to identify potential biomarkers for early inflammatory and neurodegenerative events after neonatal hypoxia-ischemia, both male and female Wistar rat pups at postnatal day 7 (P7) were used and had their right carotid artery permanently doubly occluded and exposed to 8% oxygen for 90 min. Sensory and cognitive parameters were assessed by open field, rotarod, CatWalk, and Morris water maze (MWM) test. Plasma and CSF biomarkers were investigated on the acute (24 h and 72 h) and chronic phase (4 weeks). Brains were assessed for gene expression analysis by quantitative RT-PCR Array.ResultsWe found a delay of neurological reflex maturation in HI rats. We observed anxiolytic-like baseline behavior in males more than females following HI injury. HI rats held on the rotarod for a shorter time comparing to sham. HI injury impaired spatial learning ability on MWM test. The CatWalk assessment demonstrated a long-term deficit in gait parameters related to the hind paw. Proinflammatory biomarkers such as IL-6 in plasma and CCL2 and TNF-α in CSF showed an upregulation at 24 h after HI while other cytokines, such as IL-17A and CCL5, were upregulated after 72 h in CSF. At 24 h post-injury, we observed an increase of Edn1, Hif1-α, and Mmp9 mRNA levels in the ipsilateral vs the contralateral hemisphere of HI rats. An upregulation of genes involved with clotting and hematopoietic processes was observed 72 h post-injury.ConclusionsOur work showed that, in the immature brain, the HI injury induced an early increased production of several proinflammatory mediators detectable in plasma and CSF, followed by tissue damage in the hypoxic hemisphere and short-term as well as long-lasting neurobehavioral deficits.
Highlights
Hypoxic-ischemic (HI) encephalopathy causes life-long morbidity and premature mortality in term neonates
Delay of neurological reflexes maturation in HI rats As it is shown in Fig. 1c, the right eye opening day was delayed in hypoxic-ischemic animals (P < 0.0001)
Our results demonstrate that an early regulation of most inflammatory biomarkers was observed as soon as 24 and 72 h, after HI, while no significant change neither between HI and sham males nor between HI and sham females was observed at the chronic phase, in both plasma and Cerebral spinal fluid (CSF)
Summary
Hypoxic-ischemic (HI) encephalopathy causes life-long morbidity and premature mortality in term neonates. Hypoxia-ischemia (HI) is a contributing factor to neonatal morbidity and mortality, often leading to chronic neurological disorders and disabilities, such as mental retardation, motor and behavioral developmental problems, cerebral palsy, seizure, and epilepsy [1,2,3,4]. The clinical diagnosis of neonatal HI and the assessment of disease severity mainly relies on the Sarnat score, brain CT (computed tomography) scans [8], MRI (magnetic resonance imaging), ultrasound diagnosis, and EEG (electroencephalogram) detection methods [9, 10]. Because of the influence of the progressive disease process and other factors, the Sarnat score is subjective, and other tests have limitations and double effectiveness in premature/newborn infants. The early clinical detection of blood or CSF biomarkers might have a prognostic value, allowing a treatment monitoring, compared with MRI or CT results
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