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: Xiaokun Geng, Fengwu Li, James Yip, Changya Peng, Omar Elmadhoun, Jiamei Shen, Xunming Ji, Yuchuan Ding
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 54 Issue 10 Pg. 8140-8150 (Dec 2017) ISSN: 1559-1182 [Electronic] United States
• PMID: 27896650 (Publication Type: Journal Article)

Chemical References

• Neuroprotective Agents
• Promethazine
• Chlorpromazine

Topics

• Animals
• Chlorpromazine (administration & dosage)
• Dose-Response Relationship, Drug
• Drug Therapy, Combination
• Ischemic Attack, Transient (metabolism, pathology, prevention & control)
• Male
• Neuroprotective Agents (administration & dosage)
• Oxidative Stress (drug effects, physiology)
• Promethazine (administration & dosage)
• Rats
• Rats, Sprague-Dawley
• Severity of Illness Index
• Stroke (metabolism, pathology, prevention & control)