N-Methyl-N-Nitrosourea-Induced Photoreceptor Degeneration Is Inhibited by Nicotinamide via the Blockade of Upstream Events before the Phosphorylation of Signalling Proteins

Abstract EN

N-methyl-N-nitrosourea (MNU), a known carcinogen, is generally used in animal models to chemically induce photoreceptor degeneration.

It has been reported that nicotinamide (NAM) exerts a protective effect on MNU-induced photoreceptor degeneration.

We investigated the molecular mechanisms on MNU-induced photoreceptor degeneration.

Intraperitoneal MNU injection (75 mg/kg) in rats induced selective photoreceptor degeneration in 7 days.

NAM administration completely inhibited photoreceptor degeneration.

Photoreceptor layer abnormality was observed within 6 hours after MNU injection, whereas it was restored in the NAM-treated retina, as detected by optical coherence tomography.

One day following MNU administration, phosphorylation of the cell death-associated signalling proteins c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38) increased, while the apoptosis-related proteins, full-length poly(ADP-ribose) polymerase (PARP) and apoptosis-inducing factor (AIF), were depleted.

These changes were not observed in the NAM-treated retinas.

Cell survival signalling, such as extracellular signal-regulated kinase (ERK), Akt, and cAMP response element binding protein (CREB) phosphorylation, increased in the MNU- but not in the NAM-treated rat retinas.

Increased phosphorylated ERK (p-ERK) levels were observed within 6 hours after MNU administration, suggestive of cell survival signalling activation.

This did not occur in NAM-treated retinas.

These results indicate that NAM regulates upstream cellular events prior to the activation of cell death-related signalling events, such as JNK and p38 phosphorylation.