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Neuroprotection by Chlorpromazine and Promethazine in Severe Transient and Permanent Ischemic Stroke

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An Erratum to this article was published on 28 June 2017

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Abstract

Previous studies have demonstrated depressive or hibernation-like roles of phenothiazine neuroleptics [combined chlorpromazine and promethazine (C + P)] in brain activity. This ischemic stroke study aimed to establish neuroprotection by reducing oxidative stress and improving brain metabolism with post-ischemic C + P administration. Sprague-Dawley rats were subjected to transient (2 or 4 h) middle cerebral artery occlusion (MCAO) followed by 6 or 24 h reperfusion, or permanent (28 h) MCAO without reperfusion. At 2 h after ischemia onset, rats received either an intraperitoneal (IP) injection of saline or two doses of C + P. Body temperatures, brain infarct volumes, and neurological deficits were examined. Oxidative metabolism and stress were determined by levels of ATP, NADH, and reactive oxygen species (ROS). Protein kinase C-δ (PKC-δ) and Akt expression were determined by Western blotting. C + P administration induced a neuroprotection in both transient and permanent ischemia models evidenced by significant reduction in infarct volumes and neurological deficits post-stroke. C + P induced a dose-dependent reduction in body temperature as early as 5 min post-ischemia and lasted up to 12 h. However, reduction in body temperature either only slightly or did not enhance C + P-induced neuroprotection. C + P therapy improved brain metabolism as determined by increased ATP levels and NADH activity, as well as decreased ROS production. These therapeutic effects were associated with alterations in PKC-δ and Akt protein expression. C + P treatments conferred neuroprotection in severe stroke models by suppressing the damaging cascade of metabolic events, most likely independent of drug-induced hypothermia. These findings further prove the clinical potential for C + P treatment and may direct us closer towards the development of an efficacious neuroprotective therapy.

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  • 28 June 2017

    An erratum to this article has been published.

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Authors and Affiliations

  1. China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, 101100, China

    Xiaokun Geng, Fengwu Li, Jiamei Shen, Xunming Ji & Yuchuan Ding

  2. Department of Neurosurgery, Wayne State University School of Medicine, 550 E Canfield, Detroit, MI, 48201, USA

    Xiaokun Geng, James Yip, Changya Peng, Omar Elmadhoun & Yuchuan Ding

  3. Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China

    Xunming Ji

Authors
  1. Xiaokun Geng
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  2. Fengwu Li
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  3. James Yip
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  4. Changya Peng
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Correspondence to Xunming Ji or Yuchuan Ding.

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All experimental procedures were approved by the Institutional Animal Investigation Committee of Capital Medical University in accordance with the National Institutes of Health (USA) guidelines for care and use of laboratory animals.

Sources of Funding

This work was partially supported by American Heart Association Grant-in-Aid (14GRNT20460246), Merit Review Award (I01RX-001,964-01) from the US Department of Veterans Affairs Rehabilitation R&D Service, National Natural Science Foundation of China (81501141), and Beijing NOVA program (xx2016061) as well as National Outstanding Youth Science Fund of China (no. 81325007).

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An erratum to this article is available at https://doi.org/10.1007/s12035-017-0656-6.

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Geng, X., Li, F., Yip, J. et al. Neuroprotection by Chlorpromazine and Promethazine in Severe Transient and Permanent Ischemic Stroke. Mol Neurobiol 54, 8140–8150 (2017). https://doi.org/10.1007/s12035-016-0280-x

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