Rotenone-induced inner retinal degeneration via presynaptic activation of voltage-dependent sodium and L-type calcium channels in rats

Autor: Masaaki Kageyama, Masaaki Sasaoka, Takashi Ota
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Scientific Reports, Vol 10, Iss 1, Pp 1-16 (2020)
Scientific Reports
ISSN: 2045-2322
DOI: 10.1038/s41598-020-57638-y
Popis: Rotenone, a mitochondrial complex I inhibitor, causes retinal degeneration via unknown mechanisms. To elucidate the molecular mechanisms of its action, we further characterized a rat model of rotenone-induced retinal degeneration. Intravitreal injection of rotenone (2 nmol/eye) damaged mainly the inner retinal layers, including cell loss in the ganglion cell and inner nuclear layers, which were very similar to those induced by 10 nmol/eye N-methyl-D-aspartate (NMDA). These morphological changes were accompanied by the reduced b-wave amplitude of electroretinogram, and increased immunostaining of 2,4-dinitrophenyl, an oxidative stress marker. Rotenone also downregulated expression of neurofilament light-chain gene (Nfl) as a retinal ganglion cell (RGC) marker. This effect was prevented by simultaneous injection of rotenone with antioxidants or NMDA receptor antagonists. More importantly, voltage-dependent sodium and L-type calcium channel blockers and intracellular calcium signaling modulators remarkably suppressed rotenone-induced Nfl downregulation, whereas none of these agents modified NMDA-induced Nfl downregulation. These results suggest that rotenone-induced inner retinal degeneration stems from indirect postsynaptic NMDA stimulation that is triggered by oxidative stress-mediated presynaptic intracellular calcium signaling via activation of voltage-dependent sodium and L-type calcium channels.
Databáze: OpenAIRE
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