Noradrenaline protects neurons against H 2 O 2 -induced death by increasing the supply of glutathione from astrocytes via β 3 -adrenoceptor stimulation

J Neurosci Res. 2021 Feb;99(2):621-637. doi: 10.1002/jnr.24733. Epub 2020 Sep 20.

Abstract

Oxidative stress has been implicated in a variety of neurodegenerative disorders, such as Alzheimer's and Parkinson's disease. Astrocytes play a significant role in maintaining survival of neurons by supplying antioxidants such as glutathione (GSH) to neurons. Recently, we found that noradrenaline increased the intracellular GSH concentration in astrocytes via β3 -adrenoceptor stimulation. These observations suggest that noradrenaline protects neurons from oxidative stress-induced death by increasing the supply of GSH from astrocytes to neurons via the stimulation of β3 -adrenoceptor in astrocytes. In the present study, we examined the protective effect of noradrenaline against H2 O2 -induced neurotoxicity using two different mixed cultures: the mixed culture of human astrocytoma U-251 MG cells and human neuroblastoma SH-SY5Y cells, and the mouse primary cerebrum mixed culture of neurons and astrocytes. H2 O2 -induced neuronal cell death was significantly attenuated by pretreatment with noradrenaline in both mixed cultures but not in single culture of SH-SY5Y cells or in mouse cerebrum neuron-rich culture. The neuroprotective effect of noradrenaline was inhibited by SR59230A, a selective β3 -adrenoceptor antagonist, and CL316243, a selective β3 -adrenoceptor agonist, mimicked the neuroprotective effect of noradrenaline. DL-buthionine-[S,R]-sulfoximine, a GSH synthesis inhibitor, negated the neuroprotective effect of noradrenaline in both mixed cultures. MK571, which inhibits the export of GSH from astrocytes mediated by multidrug resistance-associated protein 1, also prevented the neuroprotective effect of noradrenaline. These results suggest that noradrenaline protects neurons against H2 O2 -induced death by increasing the supply of GSH from astrocytes via β3 -adrenoceptor stimulation.

Keywords: RRID:AB_2298772; RRID:AB_561049; RRID:CVCL_0019; RRID:CVCL_0021; RRID:SCR_014242; astrocytes; glutathione; neuroprotection; noradrenaline; oxidative stress; β3-adrenoceptor.

Publication types

  • Research Support, Non-U.S. Gov't