Journal of Anesthesia

, Volume 29, Issue 4, pp 609–617 | Cite as

Dietary supplementation with sodium nitrite can exert neuroprotective effects on global cerebral ischemia/reperfusion in mice

  • Takasuke FukudaEmail author
  • Manabu Kakinohana
  • Chitoshi Takayama
  • Masayuki Matsushita
  • Kazuhiro Sugahara
Original Article



Nitrite-derived NO protects against middle cerebral artery occlusion in mice. We developed a new mouse model of global cerebral ischemia and reperfusion (GCI/R) involving reversible occlusion of the major vessels from the aortic arch supplying the brain, and investigated neuroprotection with dietary sodium nitrite supplementation against GCI/R injury.


Mice received drinking water with (nitrite group) or without (control group) sodium nitrite (2 mM) for 5 days and underwent 3-min GCI/R by reversible occlusion of major vessels from the aortic arch (i.e., brachiocephalic, left common carotid, and left subclavian artery). Survival rates and neurological function scores were evaluated for up to 5 days after GCI/R. Histopathological studies were performed to detect neurological degeneration and caspase-3 activation in serial hippocampal sections.


In the control group, 17/30 mice (57 %) survived 5 days after 3-min GCI/R, whereas in the nitrite group 25/30 mice (83 %) survived (p < 0.05). The neurological score at 5 days after GCI in control group was significantly higher than in the nitrite group. Cerebral blood flow (CBF) during GCI was significantly higher in the nitrite group than in the control group, while MABP did not differ significantly between groups. Degenerative changes and caspase-3 activation in hippocampal sections after GCI were observed in the control group but not in the nitrite group. Pretreatment with the NO scavenger c-PTIO abolished the neuroprotective effects of sodium nitrite.


Sodium nitrite supplementation attenuated mortality and neurological impairment after 3-min GCI in mice; an effect likely mediated via vascular mechanisms involving NO.


Nitrite Neuroprotection Global cerebral ischemia and reperfusion 



We thank Masato Tsutsui MD, Ph.D and Mayuko Sakanashi Ph.D for technical assistance for measuring cGMP level.

Financial Disclosure Statement

This work was supported by a Grant-in-aid for scientific research from the Ministry of Education of JAPAN (B) 25293329 to M. K. and Grant-in-aid for challenging exploratory research JAPAN 25670559 to M. K.

Conflict of interest

Takasuke Fukuda, Manabu Kakinohana, Chitoshi Takayama, Masayuki Matsushita, and Kazuhiro Sugahara have no conflicts of interest to disclose.


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Copyright information

© Japanese Society of Anesthesiologists 2015

Authors and Affiliations

  • Takasuke Fukuda
    • 1
    Email author
  • Manabu Kakinohana
    • 1
  • Chitoshi Takayama
    • 2
  • Masayuki Matsushita
    • 3
  • Kazuhiro Sugahara
    • 4
  1. 1.Department of Anesthesiology, Graduate School of MedicineUniversity of the RyukyusNishiharaJapan
  2. 2.Department of Molecular Anatomy, Graduate School of MedicineUniversity of the RyukyusNishiharaJapan
  3. 3.Department of Molecular and Cellular Physiology, Graduate School of MedicineUniversity of the RyukyusNishiharaJapan
  4. 4.University of the RyukyusNishiharaJapan

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