Notch pathway up-regulation via curcumin mitigates bisphenol-A (BPA) induced alterations in hippocampal oligodendrogenesis

Abstract

CNS myelination process involves proliferation and differentiation of oligodendrocyte progenitor cells (OPCs). Defective myelination causes onset of neurological disorders. Bisphenol-A (BPA), a component of plastic items, exerts adverse effects on human health. Our previous studies indicated that BPA impairs neurogenesis and myelination process stimulating cognitive dysfunctions. But, the underlying mechanism(s) of BPA induced de-myelination and probable neuroprotection by curcumin remains elusive. We found that curcumin protected BPA mediated adverse effects on oligosphere growth kinetics. Curcumin significantly improved proliferation and differentiation of OPCs upon BPA exposure both in-vitro and in-vivo. Curcumin enhanced the mRNA expression and protein levels of myelination markers in BPA treated rat hippocampus. Curcumin improved myelination potential via increasing β-III tubulin-/MBP⁺ cells (neuron-oligodendrocyte co-culture) and augmented fluoromyelin intensity and neurofilament/MBP⁺ neurons in vivo. In silico docking studies suggested Notch pathway genes (Notch-1, Hes-1 and Mib-1) as potential targets of BPA and curcumin. Curcumin reversed BPA mediated myelination inhibition via increasing the Notch pathway gene expression. Genetic and pharmacological Notch pathway inhibition by DAPT and Notch-1 siRNA exhibited decreased curcumin mediated neuroprotection. Curcumin improved BPA mediated myelin sheath degeneration and neurobehavioral impairments. Altogether, results suggest that curcumin protected BPA induced de-myelination and behavioural deficits through Notch pathway activation.