Pitavastatin prevents NMDA-induced retinal ganglion cell death by suppressing leukocyte recruitment

Toru Nakazawa, Hidetoshi Takahashi, Kazuaki Nishijima, Masahiko Shimura, Nobuo Fuse, Makoto Tamai, Ali Hafezi-Moghadam, Kohji Nishida

Research output: Contribution to journalArticlepeer-review

72 Citations (Scopus)

Abstract

Excitotoxicity is a major cause of retinal ganglion cell (RGC) death during ischemic diseases such as vessel occlusion and diabetic retinopathy. However, the underlying mechanisms are not well understood. Statins, inhibitors of the HMG-CoA reductase, have neuroprotective effects in addition to their original role in lowering cholesterol. We hypothesize that pitavastatin, a recently introduced potent statin, is protective against N-methyl-d-aspartic acid (NMDA)-induced RGC death. Pitavastatin, administered by gavage, abolished NMDA-induced loss of RGCs. To elucidate the mechanisms underlying the neuroprotective effect of pitavastatin, we investigated its impact on inflammation. NMDA increased the expression of interleukin-1β and TNF-α, and endothelial adhesion molecules, including ICAM-1, and induced leukocyte accumulation in the retinal vessels. Pitavastatin significantly reduced NMDA-induced leukocyte accumulation and up-regulation of endothelial adhesion molecules, whereas cytokine expression was unaffected. Systemic blockade of ICAM-1 in wild-type mice or absence of CD18 in gene-deficient (CD18-/-) mice significantly suppressed NMDA-induced leukocyte accumulation and RGC death. These findings suggest a novel and causative role for inflammatory leukocyte recruitment in NMDA-induced excitotoxicity. Furthermore, we show the novel neuroprotective effect of statins against excitotoxicity-induced RGC death. Statins or other anti-inflammatory agents may thus have therapeutic benefits in excitotoxicity-associated neuronal diseases through blockade of leukocyte recruitment.

Original languageEnglish
Pages (from-to)1018-1031
Number of pages14
JournalJournal of Neurochemistry
Volume100
Issue number4
DOIs
Publication statusPublished - 2007 Feb

Keywords

  • Cluster of differentiation 18
  • Excitotoxicity
  • Leukocyte recruitment
  • Retina
  • Statin

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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