Ischemia-Induced Neuroinflammation Is Associated with Disrupted Development of Oligodendrocyte Progenitors in a Model of Periventricular Leukomalacia

Abstract

Microglial activation in crossing white matter tracts is a hallmark of noncystic periventricular leukomalacia (PVL), the leading pathology underlying cerebral palsy in prematurely born infants. Recent studies indicate that neuroinflammation within an early time window can produce long-lasting defects in oligodendroglial maturation, myelination deficit, as well as disruption of transcription factors important in oligodendroglial maturation. We recently reported an ischemic mouse model of PVL, induced by unilateral neonatal carotid artery ligation, leading to selective long-lasting bilateral myelination deficits, ipsilateral thinning of the corpus callosum, ventriculomegaly, as well as evidence of axonopathy. Here, we report that permanent unilateral carotid ligation on postnatal day 5 in CD-1 mice induces an inflammatory response, as defined by microglial activation and recruitment, as well as significant changes in cytokine expression (increased IL-1β, IL-6, TGF-β₁, and TNF-α) following ischemia. Transient reduction in counts of oligodendrocyte progenitor cells (OPCs) at 24 and 48 h after ischemia, a shift in OPC cell size and morphology towards the more immature form, as well as likely migration of OPCs were found. These OPC changes were topographically associated with areas showing microglial activation, and OPC counts negatively correlated with increased microglial staining. The presented data show a striking neuroinflammatory response in an ischemia-induced model of PVL, associated with oligodendroglial injury. Future studies modulating the neuroinflammatory response in this model may contribute to a better understanding of the interaction between microglia and OPCs in PVL and open opportunities for future therapies.

Development of Cerebral Gray and White Matter Injury and Cerebral Inflammation over Time after Inflammatory Perinatal Asphyxia

“…A proinflammatory state during the perinatal period can already affect oligodendrocyte precursors and elicit cerebral white matter damage and behavioral deficits, as shown in animal models [58,59,60,61,62,63,64]. However, in a control group we injected LPS (0.5 mg/kg) intraperitoneally without induction of HI, but we did not observe any aberrations in cerebral gray or white matter structures or tissue loss in our neonatal mouse model.…”

Nanomedicine in cerebral palsy

“…21 In response to an immune activation, microglial cells and astrocytes in the fetal and newborn brain can secrete cytokines such as IL1β and TNFα, causing injury to developing oligodendrocytes and neuronal progenitors. [31][32][33][34] Similarly, studies have demonstrated the presence of hypertrophic astrocytes in kittens and fetal sheep following LPS injection. 35,36 Diffuse astrogliosis is a major pathological feature in white matter injury and is associated with arrest of oligodendrocyte maturation.…”

Diffusion Tensor Imaging Abnormalities in the Cerebral White Matter Correlate with Sex-Dependent Neurobehavioral Deficits in Adult Mice with Neonatal Ischemia

“…For quantification of CC1+ oligodendrocytes, ROIs were manually selected in the corpus callosum, external capsule, internal capsule, and hippocampal fimbriae in a posterior section in both the ipsilateral (right) and the contralateral (left) hemisphere. Cell counts per area were measured using MCID Core as previously published [5]. …”

“…Apoptosis measured by caspase 3 staining was almost exclusively limited to OPCs within the white matter tracts [15]. Furthermore, we have also shown immediate up-regulation of proinflammatory cytokines [5]. The results of our previous studies suggest that unilateral ischemia leads to a bilateral dysfunction of axons presumably caused by impaired oligodendroglial support.…”

“…It is well established that selective vulnerability of oligodendrocyte progenitor cells (OPCs) plays an important role in the pathophysiology of NWMI in both humans and rodents. These cells show maturational arrest, which results in decreased numbers of mature oligodendrocytes and decreased myelination [4,5]. …”