Improved Therapeutic Benefits by Combining Physical Cooling With Pharmacological Hypothermia After Severe Stroke in Rats.

Abstract

BACKGROUND AND PURPOSE:

Therapeutic hypothermia is a promising strategy for treatment of acute stroke. Clinical translation of therapeutic hypothermia, however, has been hindered because of the lack of efficiency and adverse effects. We sought to enhance the clinical potential of therapeutic hypothermia by combining physical cooling (PC) with pharmacologically induced hypothermia after ischemic stroke.

METHODS:

Wistar rats were subjected to 90-minute middle cerebral artery occlusion by insertion of an intraluminal filament. Mild-to-moderate hypothermia was induced 120 minutes after the onset of stroke by PC alone, a neurotensin receptor 1 (NTR1) agonist HPI-201 (formally ABS-201) alone or the combination of both. The outcomes of stroke were evaluated at 3 and 21 days after stroke.

RESULTS:

PC or HPI-201 each showed hypothermic effect and neuroprotection in stroke rats. The combination of PC and HPI-201 exhibited synergistic effects in cooling process, reduced infarct formation, cell death, and blood-brain barrier damages and improved functional recovery after stroke. Importantly, coapplied HPI-201 completely inhibited PC-associated shivering and tachycardia.

CONCLUSIONS:

The centrally acting hypothermic drug HPI-201 greatly enhanced the efficiency and efficacy of conventional PC; this combined cooling therapy may facilitate clinical translation of hypothermic treatment for stroke.

• Authors: Jin Hwan Lee, Ling Wei, Xiaohuan Gu, Soonmi Won, Zheng Zachory Wei, Thomas A Dix, Shan Ping Yu
• Journal: Stroke (Stroke) Vol. 47 Issue 7 Pg. 1907-13 (07 2016) ISSN: 1524-4628 [Electronic] United States
• PMID: 27301934 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2016 The Authors.

Chemical References

• ABS-201
• Ice
• Neuroprotective Agents
• Oligopeptides
• Receptors, Neurotensin
• neurotensin type 1 receptor

Topics

• Animals
• Cell Death
• Double-Blind Method
• Drug Evaluation, Preclinical
• Heart Rate (drug effects)
• Hypothermia, Induced (methods)
• Ice
• In Situ Nick-End Labeling
• Infarction, Middle Cerebral Artery (pathology, therapy)
• Male
• Motor Activity
• Neurons (pathology)
• Neuroprotective Agents (therapeutic use)
• Oligopeptides (therapeutic use)
• Rats
• Rats, Wistar
• Receptors, Neurotensin (agonists)
• Recovery of Function