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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.

journal_name

Mol Neurobiol

journal_title

Molecular neurobiology

authors

Geng X,Li F,Yip J,Peng C,Elmadhoun O,Shen J,Ji X,Ding Y

doi

10.1007/s12035-016-0280-x

subject

Has Abstract

pub_date

2017-12-01 00:00:00

pages

8140-8150

issue

10

eissn

0893-7648

issn

1559-1182

pii

10.1007/s12035-016-0280-x

journal_volume

54

pub_type

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