Nicotinamide blocks N-methyl-N-nitrosourea-induced photoreceptor cell apoptosis in rats through poly (ADP-ribose) polymerase activity and Jun N-terminal kinase/activator protein-1 pathway inhibition.
Nicotinamide (NAM) blocks N-methyl-N-nitrosourea (MNU)-induced photoreceptor cell apoptosis in rats, though the underlying molecular mechanisms remain unclear. Activation of the nuclear enzyme poly (ADP-ribose) polymerase (PARP) in response to DNA damage plays a pivotal role in apoptosis. Thus, the role of NAM in the regulation of PARP and Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) was investigated by Western blot analyses. During 7 days after the intraperitoneal injection of MNU (60 mg/kg), rat retinas exhibited DNA fragmentation characteristic of apoptosis and activation of PARP, phosphorylation of JNK and c-Jun, induction of AP-1 (c-Jun and c-Fos) and Bax, as well as photoreceptor cell loss. However, when NAM (1000 mg/kg, subcutaneously) was given immediately after MNU, it was found that PARP activation was diminished, the phosphorylation of JNK and c-Jun was suppressed, and the induction of c-Jun, c-Fos and Bax was suppressed. This resulted in the retinal structure being protected. Therefore, NAM blocked MNU-induced photoreceptor cell apoptosis by inhibiting both PARP activity and the JNK/AP-1 signalling pathway.
Uehara
Norihisa
N
Department of Pathology II, Kansai Medical University, 10-15 Fumizono, Moriguchi, Osaka 570-8506, Japan. ueharan@takii.kmu.ac.jp
Miki
Katsuaki
K
Tsukamoto
Reiko
R
Matsuoka
Yoichiro
Y
Tsubura
Airo
A
D000477:Alkylating Agents; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western / Q000379:methods; D005260:Female; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008770:Methylnitrosourea; D009536:Niacinamide / Q000494:pharmacology*; D010786:Photoreceptor Cells / Q000201:enzymology / Q000473:pathology*; D011065:Poly(ADP-ribose) Polymerases / Q000032:analysis / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014803:Vitamin B Complex / Q000494:pharmacology*
D000477:Alkylating Agents; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014803:Vitamin B Complex; D009536:Niacinamide; D008770:Methylnitrosourea; D011065:Poly(ADP-ribose) Polymerases