IMR-1 ameliorates perinatal LPS-induced brain injury by promoting the conversion of glial cells into neurons

This study aimed to examine the impact of blocking Notch1 signaling on brain injury induced by lipopolysaccharide (LPS) in rats. A “multiple strikes” brain injury model was established by administering LPS injections twice, followed by treatment with the Notch1 signaling inhibitor IMR-1. Pregnant rats received an intraperitoneal injection of LPS on gestational day 18, and postnatal day 21 (P21) rats were subjected to a second LPS injection to induce brain injury. Furthermore, rats in the Recurrent-LPS group received an intraventricular injection of IMR-1 on postnatal day 22 (P22). Cognitive and motor functions were evaluated across all rat groups. The expression levels of GFAP, IBA1, NG2, MBP and NeuN in brain tissue were analyzed using Western blotting, immunofluorescence techniques. Additionally, primary glial cells were isolated to assess their potential for neuronal differentiation under conditions of LPS stimulation and IMR-1 treatment. The Morris water maze behavioral experiments demonstrated that LPS significantly impaired the motor and cognitive functions of infant rats, whereas IMR-1 treatment markedly ameliorated the LPS-induced behavioral deficits. Hematoxylin-eosin staining and transmission electron microscopy analyses demonstrated that IMR-1 treatment significantly mitigated brain tissue damage induced by LPS. Immunofluorescence assays revealed alterations in neuronal and glial cell in populations within the brain tissue. In the LPS model group, there was a notable reduction in neuronal cells and oligodendrocytes, accompanied by an increase in glial cells, including astrocytes, microglia, and oligodendrocyte precursor cells. Treatment with IMR-1 resulted in an increase in neuronal cells and oligodendrocytes while reducing the numbers of astrocytes, microglia, and oligodendrocyte precursor cells in the LPS model group. Primary isolation and characterization of glial cells from brain tissue were conducted to develop an in vitro brain injury model using LPS, followed by IMR-1 treatment and culture under conditions conducive to neuronal induction and maturation. Immunofluorescence experiments indicated that IMR-1 treatment facilitated the transdifferentiation of astrocytes and oligodendrocyte precursor cells into neurons. In conclusion, inhibition of Notch1 signaling significantly alleviates LPS-induced diffuse brain injury in rats, potentially by promoting the conversion of glial cells into neurons.