Abstract
Hypoxic exposure in the perinatal period causes periventricular white matter damage (PWMD), a condition associated with myelination abnormalities. Under hypoxic conditions, glial cells were activated and released a large number of inflammatory mediators in the PWM in neonatal brain, which may result in oligodendrocyte (OL) loss and axonal injury. This study aims to determine if astrocytes are activated and generate proinflammatory cytokines that may be coupled with the oligodendroglial loss and hypomyelination observed in hypoxic PWMD. Twenty-four 1-day-old Wistar rats were exposed to hypoxia for 2 h. The rats were then allowed to recover under normoxic conditions for 7 or 28 days before being killed. Another group of 24 rats kept outside the chamber was used as age-matched controls. Upregulated expression of TNF-α and IL-1β was observed in astrocytes in the PWM of P7 hypoxic rats by double immunofluorescence, western blotting and real time RT-PCR. This was linked to apoptosis and enhanced expression of TNF-R1 and IL-1R1 in APC+ OLs. PLP expression was decreased significantly in the PWM of P28d hypoxic rats. The proportion of myelinated axons was markedly reduced by electron microscopy (EM) and the average g-ratios were higher in P28d hypoxic rats. Upregulated expression of TNF-α and IL-1β in primary cultured astrocytes as well as their corresponding receptors in primary culture APC+ oligodendrocytes were detected under hypoxic conditions. Our results suggest that following a hypoxic insult, astrocytes in the PWM of neonatal rats produce inflammatory cytokines such as TNF-α and IL-1β, which induce apoptosis of OLs via their corresponding receptors associated with them. This results in hypomyelination in the PWM of hypoxic rats.
Highlights
Periventricular white matter damage (PWMD) is the major neuropathological form of brain injury observed in preterm infants, and is the leading cause of cerebral palsy [1,2,3]
We previously reported that PWMD caused by hypoxia has been associated with microglial activation, diffuse reactive astrogliosis, axonal injury, oligodendrocyte (OL) progenitor apoptosis and myelination disturbances [7,8,9]
Our previous studies have shown that a strong and persistent inflammation occurred in the periventricular white matter (PWM) in hypoxic neonatal brain, which is closely associated with axonal disruption and pre-OLs injury [10,11]
Summary
Periventricular white matter damage (PWMD) is the major neuropathological form of brain injury observed in preterm infants, and is the leading cause of cerebral palsy [1,2,3]. We previously reported that PWMD caused by hypoxia has been associated with microglial activation, diffuse reactive astrogliosis, axonal injury, oligodendrocyte (OL) progenitor apoptosis and myelination disturbances [7,8,9]. Our previous studies have shown that a strong and persistent inflammation occurred in the periventricular white matter (PWM) in hypoxic neonatal brain, which is closely associated with axonal disruption and pre-OLs injury [10,11]. This study aims to explore if astrocytes are activated and contribute to the occurrence of hypomyelination under hypoxic conditions in the neonatal brain Expression of cytokines such as TNF-a and IL1b in astrocytes was first observed by double immunofluorescence. We report here that astrocytes are one of the main sources of proinflammatory cytokines that may contribute to inducing hypomyelination, a salient characteristic feature of PWMD
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