PT  - JOURNAL ARTICLE
AU  - Mutsumi Ueda
AU  - Ryousuke Fujita
AU  - Takehiko Koji
AU  - Hiroshi Ueda
TI  - The Cognition-Enhancer Nefiracetam Inhibits Both Necrosis and Apoptosis in Retinal Ischemic Models in Vitro and in Vivo
AID  - 10.1124/jpet.103.061127
DP  - 2004 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 200--207
VI  - 309
IP  - 1
4099  - http://jpet.aspetjournals.org/content/309/1/200.short
4100  - http://jpet.aspetjournals.org/content/309/1/200.full
SO  - J Pharmacol Exp Ther2004 Apr 01; 309
AB  - The retinal ischemic-reperfusion stress (130 mm Hg, 45 min) caused neuronal damage throughout all cell layers and reduced the thickness of retinal layer by 30% at 7 days after the stress of mouse retina. The intravitreous injection of 100 pmol of nefiracetam, a cognition-enhancer, completely prevented the damage when it was given 30 min before and 3 h after the stress. Partial prevention was observed when it was given 24 h after the stress, or low dose (10 pmol) nefiracetam was given 30 min before the stress. However, aniracetam had no effect. In the retinal cell line N18-RE-105, the ischemic-reperfusion stress by 2 h culture under the serum-free condition with low oxygen (less of 0.4% O2) and low glucose (1 mM) caused necrosis or apoptosis in the low-density (0.5 × 104 cell/cm2)or high-density (5 × 104 cell/cm2) culture, respectively. The necrosis showed membrane disruption, loss of electron density, and mitochondrial swelling, whereas apoptosis showed nuclear fragmentation and condensation in transmission electron microscopical analyses and in experiments using specific cell death markers. Nefiracetam inhibited both necrosis and apoptosis, whereas brain-derived neurotrophic factor (BDNF) inhibited only apoptosis. The cell-protective actions of nefiracetam were abolished by nifedipine and ω-conotoxin GVIA, L-type and N-type calcium channel blocker, but not by PD98059 or wortmannin, extracellular signal-regulated kinase 1/2 or phosphoinositide 3-kinase inhibitor, respectively, whereas those of BDNF were abolished by PD98059 and wortmannin, but not by nifedipine and ω-conotoxin GVIA. All these findings suggest that nefiracetam inhibit necrosis and apoptosis occurred in the ischemic/hypoxic neuronal injury through an increase in Ca2+ influx. The American Society for Pharmacology and Experimental Therapeutics