Matrine treatment induced an A2 astrocyte phenotype and protected the blood-brain barrier in CNS autoimmunity

Abstract

Type 1 astrocytes (A1), which are highly proinflammatory and neurotoxic, are prevalent in multiple sclerosis (MS). In addition, in MS and its animal model, experimental autoimmune encephalomyelitis (EAE), immune cells must cross the blood-brain barrier (BBB) and infiltrate into the parenchyma of the central nervous system (CNS) in order to induce neurological deficits. We have previously reported that treatment of EAE with matrine (MAT), a quinazine alkaloid derived from Sophorae Flavescens, effectively inhibited CNS inflammation and promoted neuroregeneration. However, the impact of MAT treatment on astrocyte phenotype is not known. In the present study, we showed that MAT treatment inhibited the generation of neurotoxic A1 astrocytes and promoted neuroprotective A2 astrocytes in the CNS of EAE, most likely by inhibiting production of the A1-inducing cytokine cocktail. MAT also downregulated the expression of vascular endothelial growth factor-A (VEGF-A) and upregulated tight junction proteins Claudin 5 and Occludin, thus protecting the BBB from CNS inflammation-induced damage. Moreover, MAT treatment promotes the formation of astrocyte tight junctions at glia limitans, thereby limiting parenchymal invasion of the CNS by immune cells. Taken together, the inhibition of A1 astrogliogenesis, and the dual effects on the BBB and astrocytic glia limitans, may be the mechanisms whereby MAT significantly improves EAE clinical scores and neuroprotection.