Remote ischemic perconditioning is effective alone and in combination with intravenous tissue-type plasminogen activator in murine model of embolic stroke.
OBJECTIVE
Remote ischemic conditioning is cardioprotective in myocardial infarction and neuroprotective in mechanical occlusion models of stroke. However, there is no report on its therapeutic potential in a physiologically relevant embolic stroke model (embolic middle cerebral artery occlusion) in combination with intravenous tissue-type plasminogen activator (tPA).


METHODS
We tested remote ischemic perconditioning therapy (RIPerC) at 2 hours after embolic middle cerebral artery occlusion in the mouse with and without intravenous tPA at 4 hours. We assessed cerebral blood flow up to 6 hours, neurological deficits, injury size, and phosphorylation of Akt (Serine(473)) as a prosurvival signal in the ischemic hemisphere at 48 hours poststroke.


RESULTS
RIPerC therapy alone improved the cerebral blood flow and neurological outcomes. tPA alone at 4 hours did not significantly improve the neurological outcome even after successful thrombolysis. Individual treatments with RIPerC and intravenous tPA reduced the infarct size (25.7% and 23.8%, respectively). Combination therapy of RIPerC and tPA resulted in additive effects in further improving the neurological outcome and reducing the infarct size (50%). All the therapeutic treatments upregulated phosphorylation of Akt in the ischemic hemisphere.


CONCLUSIONS
RIPerC is effective alone after embolic middle cerebral artery occlusion and has additive effects in combination with intravenous tPA. RIPerC may be a simple, safe, and inexpensive combination therapy with intravenous tPA.
Department of Neurology, Georgia Health Sciences University, 1120 15 Street, CA 1014, Augusta, GA 30912, USA. mhoda@georgiahealth.edu
Md Nasrul
MN
Hoda
Shahneela
S
Siddiqui
Samuel
S
Herberg
Sudharsan
S
Periyasamy-Thandavan
Kanchan
K
Bhatia
Sherif S
SS
Hafez
Maribeth H
MH
Johnson
William D
WD
Hill
Adviye
A
Ergul
Susan C
SC
Fagan
David C
DC
Hess
D061605:Administration, Intravenous; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000503:physiopathology; D003131:Combined Modality Therapy; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012039:Regional Blood Flow / Q000502:physiology; D020521:Stroke / Q000209:etiology* / Q000473:pathology / Q000628:therapy*; D015912:Thrombolytic Therapy / Q000379:methods*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
D005343:Fibrinolytic Agents; D051057:Proto-Oncogene Proteins c-akt; D010959:Tissue Plasminogen Activator