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Memantine Alleviates Brain Injury and Neurobehavioral Deficits after Experimental Subarachnoid Hemorrhage

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Abstract

Subarachnoid hemorrhage (SAH) causes brain injury via glutamate excitotoxicity, which leads to an excessive Ca2+ influx and this starts an apoptotic cascade. Memantine has been proven to reduce brain injury in several types of brain insults. This study investigated the neuro-protective potential of memantine after SAH and explored the underlying mechanisms. An endovascular perforation rat model of SAH was used and Sprague–Dawley rats were randomized into sham surgery, SAH + vehicle, and SAH + memantine groups. The effects of memantine on SAH were evaluated by assessing the neuro-behavioral functions, blood–brain barrier (BBB) permeability and neuronal cell preservation. The mechanisms of action of memantine, with its N-methyl-d-aspartate (NMDA) antagonistic characteristics on nitric oxide synthase (NOS) expression and peroxynitrite formation, were also investigated. The apoptotic cascade after SAH was suppressed by memantine. Neuronal NOS (nNOS) expression, peroxynitrite formation, and subsequent oxidative/nitrosative stress were also reduced. Memantine effectively preserved BBB integrity, rescued neuronal injury, and improved neurological outcome in experimental SAH. Memantine has neuro-protective potential in experimental SAH and may help combat SAH-induced brain damage in the future.

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Acknowledgements

This study was supported by grants from the National Cheng Kung University Hospital Medical Center (Grant NCKUH-10005022 and NCKUH-10102001). The authors thank Li-Ching Lin and Lung Yu for technical support. The authors are also grateful to Ming-Tai Yu, and Ya-Chun Hsiao for services on image acquisition and analysis from the FACS-like Tissue Cytometry in the Center of Clinical Medicine, National Cheng Kung University Hospital. The authors also thank Jia-Ling Wu and Liang-Yi Wang of the Biostatistics Consulting Center, National Cheng Kung University Hospital, for statistical consulting services.

Conflicts of interest

The authors declare no competing financial interests.

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Authors and Affiliations

  1. Institute of Clinical Medicine, National Cheng Kung University, Tainan, 704, Taiwan

    Chih-Yuan Huang, Liang-Chao Wang, Hao-Kuang Wang, Chia-Hsin Pan, Ya-Yun Cheng, Yan-Shen Shan, Chung-Ching Chio & Kuen-Jer Tsai

  2. Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan

    Chih-Yuan Huang, Liang-Chao Wang & Yan-Shen Shan

  3. Department of Neurosurgery, E-Da Hospital, Kaohsiung, Taiwan

    Hao-Kuang Wang

  4. Department of Neurosurgery, Chi Mei Medical Center, Tainan, Taiwan

    Chung-Ching Chio

  5. Center of Clinical Medicine, National Cheng Kung University Hospital, Tainan, Taiwan

    Kuen-Jer Tsai

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  1. Chih-Yuan Huang
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Supplemental Figure 1

Memantine attenuated cellular apoptosis after SAH in a dose-dependent manner. The dosage of memantine that improved cellular apoptosis in SAH animals, 1 day after SAH, was investigated. Data are mean ± SEM from sham animals, vehicle-treated animals and animals treated with different dosage of memantine. Administration of 10 mg/kg memantine failed to reduce cellular apoptosis after SAH. 20mg/kg and 30 mg/kg loading of memantine led to a statistically significant protection of brain after SAH (P<0.05). (GIF 29 kb)

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Huang, CY., Wang, LC., Wang, HK. et al. Memantine Alleviates Brain Injury and Neurobehavioral Deficits after Experimental Subarachnoid Hemorrhage. Mol Neurobiol 51, 1038–1052 (2015). https://doi.org/10.1007/s12035-014-8767-9

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