Combination therapy of moderate hypothermia and thrombolysis in experimental thromboembolic stroke--an MRI study.
Thrombolysis (T) is limited by reperfusion-associated injury and the short therapeutic window after stroke onset. The present study investigates whether hypothermia alone or in combination with thrombolysis has beneficial effects after experimental thromboembolic stroke. Wistar rats (n = 60) were subjected to thromboembolic occlusion (TE) of the middle cerebral artery (MCA). Thrombolysis (T) was performed with intravenous recombinant tissue-plasminogen activator (rt-PA) 1 h (early T) or 3 h (late T) after TE. Hypothermia (Hy) was applied for 4 h at 33 degrees C started 1 h after TE. Experimental groups included control (C), early thrombolysis (ET), late thrombolysis (LT), hypothermia (Hy), early thrombolysis plus hypothermia (ET+Hy), and late thrombolysis plus hypothermia (LT+Hy). Animals were investigated by MRI and silver infarct staining (SIS) to assess the cerebral infarct size. All animals of group Hy survived, in contrast to 40% in group C (P < 0.05). ET+HY and LT+Hy showed a trend towards better survival as compared to ET and LT alone. PWI parameters were not significantly different between ET versus ET+HY and LT versus LT+Hy, but rt-PA administration led to improved cerebral perfusion in MRI. Significant differences in infarct volumes (T2/SIS) were found after 24 h in all treatment groups versus the control group (P < 0.05). The lesion volume calculated from T2 was significantly smaller in ET (16% +/- 5%), ET+Hy (10 +/- 4%), and LT+Hy (20% +/- 9%) after 5.5 h (10.8% +/- 4.8%) versus C (42% +/- 15%), (P < 0.05). These data indicate that hypothermia improves survival and decreases infarct volume. However, there were no significant differences between the use of rt-PA alone or in combination with hypothermia. Further studies are needed to confirm these effects, also several days after stroke onset.
Kollmar
Rainer
R
Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. Rainer_Kollmar@med.uni-heidelberg.de
Henninger
Nils
N
Bardutzky
Jürgen
J
Schellinger
Peter D
PD
Schäbitz
Wolf-Rüdiger
WR
Schwab
Stefan
S
D000818:Animals; D001921:Brain / Q000098:blood supply / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D007036:Hypothermia, Induced / Q000379:methods*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000175:diagnosis / Q000628:therapy*; D020767:Intracranial Thrombosis / Q000150:complications / Q000175:diagnosis / Q000628:therapy*; D008279:Magnetic Resonance Imaging; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000627:therapeutic use; D020521:Stroke / Q000150:complications / Q000175:diagnosis / Q000628:therapy*; D015996:Survival Rate; D015912:Thrombolytic Therapy / Q000379:methods*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use; D016896:Treatment Outcome
D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator