Abstract
BackgroundPeriventricular leukomalacia (PVL), a devastating brain injury affecting premature infants, is the most common cause of cerebral palsy. PVL is caused by hypoxia ischemia (HI) and is characterized by white matter necrotic lesions, microglial activation, upregulation of NF-κB, and neuronal death. The microglia is the main cell involved in PVL pathogenesis. The goal of this study was to investigate the role of microglial NF-κB activity and its prophylactic inhibition in a neonate mouse model of HI.MethodsTransgenic mice with specific knockout NF-κB in microglia and colony stimulating factor 1 receptor Cre with floxed IKKβ (CSF-1R Cre + IKKβflox/wt ) were used. Postnatal day 5 (P5) mice underwent sham or bilateral temporary carotid artery ligation followed by hypoxia. After HI insult, inflammatory cytokines, volumetric MRI, histopathology, and immunohistochemistry for oligodendroglia and microglial activation markers were analyzed. Long-term neurobehavioral assessment, including grip strength, rotarod, and open field testing, was performed at P60.ResultsWe demonstrate that selective inhibition of NF-κB in microglia decreases HI-induced brain injury by decreasing microglial activation, proinflammatory cytokines, and nitrative stress. Rescue of oligodendroglia is evidenced by immunohistochemistry, decreased ventriculomegaly on MRI, and histopathology. This selective inhibition leads to attenuation of paresis, incoordination, and improved grip strength, gait, and locomotion.ConclusionWe conclude that NF-κb activation in microglia plays a major role in the pathogenesis of hypoxic ischemic injury of the immature brain, and its prophylactic inhibition offers significant neuroprotection. Using a specific inhibitor of microglial NF-κB may offer a new prophylactic or therapeutic alternative in preterm infants affected by HI and possibly other neurological diseases in which microglial activation plays a role.
Highlights
Periventricular leukomalacia (PVL), a devastating brain injury affecting premature infants, is the most common cause of cerebral palsy
We demonstrate that prophylactic selective inhibition of NF-κB in the microglia dramatically attenuates hypoxia ischemia (HI)-induced white matter injury in a mouse model of hypoxic ischemic injury of the immature brain
cerebrospinal fluid (CSF)-1R-cre is expressed mainly in microglia in our mouse model To determine the relevance of NF-κB inhibition in myeloid cells mainly microglia in PVL pathology, we crossed mice with conditional mutant of IKKb (IKKbf/f), which have exon 3 of the ikbkb (IKKb) gene flanked by loxP sites to a strain expressing cre recombinase driven by the promoter for the gene c-fms, which encodes colony stimulating factor receptor 1 (CSF-1R)
Summary
Periventricular leukomalacia (PVL), a devastating brain injury affecting premature infants, is the most common cause of cerebral palsy. PVL is caused by hypoxia ischemia (HI) and is characterized by white matter necrotic lesions, microglial activation, upregulation of NF-κB, and neuronal death. Periventricular leukomalacia (PVL) is a major neuropathologic white matter brain injury and the most common cause of cerebral palsy (CP) in premature infants. In the USA, about 65,000 very low birth weight infants (< 1500 g) are born annually. Ten percent of those infants show signs of CP and 25–50% display cognitive or behavioral deficits [1]. Affected infants show definitive signs of cerebral palsy such as spastic diplegia or seizures, mental retardation, visual and hearing impairment, scoliosis, or incontinence by 6–9 months of age
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