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Research ArticleNEUROPHARMACOLOGY

The Cognition-Enhancer Nefiracetam Inhibits Both Necrosis and Apoptosis in Retinal Ischemic Models in Vitro and in Vivo

Mutsumi Ueda, Ryousuke Fujita, Takehiko Koji and Hiroshi Ueda
Journal of Pharmacology and Experimental Therapeutics April 2004, 309 (1) 200-207; DOI: https://doi.org/10.1124/jpet.103.061127
Mutsumi Ueda
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Ryousuke Fujita
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Takehiko Koji
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Hiroshi Ueda
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Abstract

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.

Footnotes

  • Parts of this study were supported by grants-in-aid and special coordination funds from the Ministry of Education, Culture, Sports, Science and Technology.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • DOI: 10.1124/jpet.103.061127.

  • ABBREVIATIONS: DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; PI, propidium iodide; BDNF, brain-derived neurotrophic factor; LOG, low oxygen and low glucose; LD, low-density; HD, high-density; BSS, buffered salt solution; WST-8, 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt; PBS, phosphate-buffered saline; FITC, fluorescein isothiocyanate; GCL, ganglion cell layer; ONL, outer nuclear layer; INL, inner nuclear layer; TEM, transmission electron microscopy; PI 3-kinase, phosphoinositide 3-kinase; ERK, extracellular signal-regulated kinase; PD98059, 2′-amino-3′-methoxyflavone.

    • Received October 5, 2003.
    • Accepted December 5, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 309 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 309, Issue 1
1 Apr 2004
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Research ArticleNEUROPHARMACOLOGY

The Cognition-Enhancer Nefiracetam Inhibits Both Necrosis and Apoptosis in Retinal Ischemic Models in Vitro and in Vivo

Mutsumi Ueda, Ryousuke Fujita, Takehiko Koji and Hiroshi Ueda
Journal of Pharmacology and Experimental Therapeutics April 1, 2004, 309 (1) 200-207; DOI: https://doi.org/10.1124/jpet.103.061127

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Research ArticleNEUROPHARMACOLOGY

The Cognition-Enhancer Nefiracetam Inhibits Both Necrosis and Apoptosis in Retinal Ischemic Models in Vitro and in Vivo

Mutsumi Ueda, Ryousuke Fujita, Takehiko Koji and Hiroshi Ueda
Journal of Pharmacology and Experimental Therapeutics April 1, 2004, 309 (1) 200-207; DOI: https://doi.org/10.1124/jpet.103.061127
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