Inosine pretreatment of pregnant rats ameliorates maternal inflammation-mediated hypomyelination in pups via microglia polarization switch.

ABSTRACT

Periventricular leukomalacia (PVL) is a neurological condition observed in premature infants, characterized by hypomyelination and activation of microglia. Maternal inflammation-induced brain injury in offspring significantly contributes to the development of PVL. Currently, there are no clinical pharmaceutical interventions available for pregnant women to prevent maternal inflammation-mediated brain injury in their offspring. Inosine has been shown to modulate the immune response in diverse stressful circumstances, such as injury, ischemia, and inflammation. The aim of this investigation was to examine the potential prophylactic impact of inosine on offspring PVL induced by maternal inflammation. This was accomplished by administering a 1 mg/ml inosine solution (40 ml daily) to pregnant Sprague-Dawley (SD) rats for 16 consecutive days prior to their intraperitoneal injection of lipopolysaccharide (350 µg/kg, once a day, for two days). The results showed that maternal inosine pretreatment significantly reversed the reduction in MBP and CNPase (myelin-related markers), CC-1 and Olig2 (oligodendrocyte-related markers) in their PVL pups (P7), suggesting that inosine administration during pregnancy could improve hypomyelination and enhance the differentiation of oligodendrocyte precursor cells (OPCs) in their PVL pups. Furthermore, the protective mechanism of inosine against PVL is closely associated with the activation and polarization of microglia. This is evidenced by a notable reduction in the quantity of IBA 1-positive microglia, a decrease in the level of CD86 (a marker for M1 microglia), an increase in the level of Arg 1 (a marker for M2 microglia), as well as a decrease in the level of pro-inflammatory factors TNF-α, IL-1ß, and IL-6, and an increase in the level of anti-inflammatory factors IL-4 and IL-10 in the brain of PVL pups following maternal inosine pretreatment. Taken together, inosine pretreatment of pregnant rats can improve hypomyelination in their PVL offspring by triggering the M1/M2 switch of microglia.