Corticotropin-releasing factor protects against ammonia neurotoxicity in isolated larval zebrafish brains

Abstract

The physiological roles of corticotropin-releasing factor (CRF) have recently been extended to cytoprotection. Here, to determine whether CRF is neuroprotective in fish, the effects of CRF against high environmental ammonia (HEA)-mediated neurogenic impairment and cell death were investigated in zebrafish. In vivo, exposure of 1 day post-fertilization (dpf) embryos to HEA only reduced the expression of the determined neuron marker neurod1. In contrast, in 5 dpf larvae, HEA increased the expression of nes and sox2, neural progenitor cell markers, and reduced the expression of neurog1, gfap and mbpa, proneuronal cell, radial glia and oligodendrocyte markers, respectively, and neurod1. The N-methyl-d-aspartate (NMDA) receptor inhibitor MK801 rescued the HEA-induced reduction in neurod1 in 5 dpf larvae but did not affect the HEA-induced transcriptional changes in other neural cell types, suggesting that hyperactivation of NMDA receptors specifically contributes to the deleterious effects of HEA in determined neurons. As observed in vivo, HEA exposure elicited marked changes in the expression of cell type-specific markers in isolated 5 dpf larval brains. The addition of CRF reversed the in vitro effects of HEA on neurod1 expression and prevented an HEA-induced increase in cell death. Finally, the protective effects of CRF against HEA-mediated neurogenic impairment and cell death were prevented by the CRF type 1 receptor selective antagonist antalarmin. Together, these results provide novel evidence that HEA has developmental time- and cell type-specific neurotoxic effects, that NMDA receptor hyperactivation contributes to HEA-mediated impairment of determined neurons, and that CRF has neuroprotective properties in the larval zebrafish brain.

Stress hormones mediate developmental plasticity in vertebrates with complex life cycles

“…Components of the CRF signaling system are expressed throughout the body ( Boorse and Denver, 2006 ; Slominski et al, 2013 ). Corticotropin-releasing factor peptides have cytoprotective function, to protect neural, cardiac and other cells from apoptosis ( Alderman et al, 2018 ; Brar et al, 2002 ; Davidson et al, 2009 ; Jonassen et al, 2012 ; Linden et al, 2005 ; Martin et al, 2005 ; Radulovic et al, 2003 ; Szabadfi et al, 2009 ; Tao et al, 2006 ; Williams and Bernier, 2020 ). In tadpoles, CRF is expressed by tail muscle cells and acts in an autocrine manner as a cytoprotective factor for tail muscle cell survival during metamorphosis ( Boorse et al, 2005 ).…”