Artificial Hibernation by Phenothiazines: A Potential Neuroprotective Therapy Against Cerebral Inflammation in Stroke.

Abstract

The inflammatory response to acute cerebral ischemia is a major factor in stroke pathobiology and patient outcome. In the clinical setting, no effective pharmacologic treatments are currently available. Phenothiazine drugs, such as chlorpromazine and promethazine, (C+P) have been widely studied because of their ability to induce neuroprotection through artificial hibernation after stroke. The present study determined their effect on the inflammatory response. Sprague-Dawley rats were divided into 4 groups: (1) sham, (2) stroke, (3) stroke treated by C+P without temperature control and (4) stroke treated by C+P with temperature control (n=8 per group). To assess the neuroprotective effect of C+P, brain damage was measured using infarct volume and neurological deficits. The expression of inflammatory response molecules tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and nuclear factor kappa light chain enhancer of activated B cells (NF-κB) was determined by real-time PCR and Western blotting. TNF-α, IL-1β, ICAM-1, VCAM-1, and NF-κB mRNA and protein expressions were upregulated, and brain damage and neurological deficits were increased after stroke. These markers of cerebral injury were significantly reduced following C+P administration under drug-induced hypothermia, while C+P administration under normal body temperature reduced them by a lesser degree. This study showed an inhibitory effect of C+P on brain inflammation, which may be partially dependent on drug-induced hibernation, as well as other mechanisms of action by these drugs. These findings further suggest the great potential of C+P in the clinical treatment of ischemic stroke.