title: Neuroprotection by Chlorpromazine and Promethazine in Severe Transient and Permanent Ischemic Stroke.
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.
authors.affiliation: China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, 101100, China.|Department of Neurosurgery, Wayne State University School of Medicine, 550 E Canfield, Detroit, MI, 48201, USA.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Geng
authors.affiliation: China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, 101100, China.
authors.forename: Fengwu
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Wayne State University School of Medicine, 550 E Canfield, Detroit, MI, 48201, USA.
authors.forename: James
authors.initials: J
authors.lastname: Yip
authors.affiliation: Department of Neurosurgery, Wayne State University School of Medicine, 550 E Canfield, Detroit, MI, 48201, USA.
authors.forename: Changya
authors.initials: C
authors.lastname: Peng
authors.affiliation: Department of Neurosurgery, Wayne State University School of Medicine, 550 E Canfield, Detroit, MI, 48201, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Elmadhoun
authors.affiliation: China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, 101100, China.
authors.forename: Jiamei
authors.initials: J
authors.lastname: Shen
authors.affiliation: China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, 101100, China. jixm@ccmu.edu.cn.|Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China. jixm@ccmu.edu.cn.
authors.forename: Xunming
authors.initials: X
authors.lastname: Ji
authors.affiliation: China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, 101100, China. yding@med.wayne.edu.|Department of Neurosurgery, Wayne State University School of Medicine, 550 E Canfield, Detroit, MI, 48201, USA. yding@med.wayne.edu.
authors.forename: Yuchuan
authors.initials: Y
authors.lastname: Ding
mesh_terms: D000818:Animals; D002746:Chlorpromazine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D002546:Ischemic Attack, Transient / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011398:Promethazine / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D020521:Stroke / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
chemical_list: D018696:Neuroprotective Agents; D011398:Promethazine; D002746:Chlorpromazine
keywords: Brain metabolism; Hibernation-like therapeutic effect; Ischemia/reperfusion; ROS