title: A novel stroke therapy of pharmacologically induced hypothermia after focal cerebral ischemia in mice.
abstract: Compelling evidence from preclinical and clinical studies has shown that mild to moderate hypothermia is neuroprotective against ischemic stroke. Clinical applications of hypothermia therapy, however, have been hindered by current methods of physical cooling, which is generally inefficient and impractical in clinical situations. In this report, we demonstrate the potential of pharmacologically induced hypothermia (PIH) by the novel neurotensin receptor 1 (NTR1) agonist ABS-201 in a focal ischemic model of adult mice. ABS-201 (1.5-2.5 mg/kg, i.p.) reduces body and brain temperature by 2-5°C in 15-30 min in a dose-dependent manner without causing shivering or altering physiological parameters. Infarct volumes at 24 h after stroke are reduced by ∼30-40% when PIH therapy is initiated either immediately after stroke induction or after 30-60 min delay. ABS-201 treatment increases bcl-2 expression, decreases caspase-3 activation, and TUNEL-positive cells in the peri-infarct region, and suppresses autophagic cell death compared to stroke controls. The PIH therapy using ABS-201 improves recovery of sensorimotor function as tested 21 d after stroke. These results suggest that PIH induced by neurotensin analogs represented by ABS-201 are promising candidates for treatment of ischemic stroke and possibly for other ischemic or traumatic injuries.
authors.affiliation: Department of Anesthesiology, Emory University School ofMedicine, Atlanta, Georgia 30322, USA.
authors.forename: Ko-Eun
authors.initials: KE
authors.lastname: Choi
authors.forename: Casey L
authors.initials: CL
authors.lastname: Hall
authors.forename: Jin-Mei
authors.initials: JM
authors.lastname: Sun
authors.forename: Ling
authors.initials: L
authors.lastname: Wei
authors.forename: Osama
authors.initials: O
authors.lastname: Mohamad
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Dix
authors.forename: Shan P
authors.initials: SP
authors.lastname: Yu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002545:Brain Ischemia / Q000150:complications / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D002544:Cerebral Infarction / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control / Q000628:therapy*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D007036:Hypothermia, Induced / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009048:Motor Skills / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000737:chemistry; D009496:Neurotensin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry; D018028:Receptors, Neurotensin / Q000819:agonists*
chemical_list: C575024:ABS-201; D018696:Neuroprotective Agents; D009842:Oligopeptides; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; D009496:Neurotensin