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

[ Vol. 16 , Issue. 3 ]

Author(s):

Longfei Guan, Sichao Guo, James Yip, Kenneth B. Elkin, Fengwu Li, Changya Peng, Xiaokun Geng* and Yuchuan Ding*   Pages 232 - 240 ( 9 )

Abstract:


Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords:

Inflammation, ischemia/reperfusion, pharmacological hypothermia, brain metabolism, phenothiazines, stroke.

Affiliation:

Department of Neurosurgery, Wayne State University School of Medicine, Detroit, Michigan, MI, Department of Neurosurgery, Wayne State University School of Medicine, Detroit, Michigan, MI, Department of Neurosurgery, Wayne State University School of Medicine, Detroit, Michigan, MI, Department of Neurosurgery, Wayne State University School of Medicine, Detroit, Michigan, MI, China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, Department of Neurosurgery, Wayne State University School of Medicine, Detroit, Michigan, MI, China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, Department of Neurosurgery, Wayne State University School of Medicine, Detroit, Michigan, MI



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