Delayed neuroprotective effect of insulin-like growth factor-i after experimental transient focal cerebral ischemia monitored with mri.
OBJECTIVE
Insulin-like growth factor (IGF) treatment has been shown to have trophic and neuroprotective effects in vitro and in vivo in different lesion models. IGF-I has potent neuroprotective effects after hypoxic-ischemic injury and global ischemia. The role of IGF-I in focal cerebral ischemia is only partially understood. Therefore, in the present study, we evaluated, by applying MRI monitoring, whether a clinically relevant systemic administration of IGF-I can achieve a long-lasting neuroprotective effect.


METHODS
Male Wistar rats underwent transient occlusion of the right middle cerebral artery for 1 hour by using the suture occlusion model. Animals then were intraventricularly treated with 33.33 microg IGF-I/d for 3 days (group A, the IGF-I group [n=13]; group B, the placebo group [n=14]) or subcutaneously treated with 200 microg IGF-I/d for 7 days (group D, the IGF-I group [n=10]; group E, the placebo group [n=10]). Groups C and F served as sham-operated controls (n=5 and n=3, respectively). Treatment was begun 30 minutes after occlusion of the middle cerebral artery. Subcutaneously treated animals underwent MRI studies (diffusion-weighted imaging, perfusion imaging, and T2-weighted imaging) beginning 60 minutes after vessel occlusion at 6 hours and at days 1, 2, 5, and 7 after ischemia. The animals were weighed and neurologically assessed daily (rating scale ranged from 0, indicating no deficit, to 5, indicating death). On the third day (intraventricular trial) and on the seventh day (subcutaneous trial), animals were euthanized, and brain sections were stained with triphenyltetrazolium chloride.


RESULTS
The mean infarct volume was 52.9+/-25.2 mm(3) in intraventricularly treated animals versus 146.4+/-62.2 mm(3) in control animals (P<0.01) and 42.2+/-17.9 mm(3) in subcutaneously IGF-I-treated animals versus 73.1+/-38.1 mm(3) in control animals (P<0.05). Apparent diffusion coefficient-derived lesion volume at 60 minutes after occlusion was 40.4+/-23.7 mm(3) versus 38.3+/-19.3 mm(3) (P=NS), increased to 168.3+/-49.55 mm(3) versus 105.5+/-33.8 mm(3) (P<0.05) at 24 hours, and then decreased to 55.8+/-30.3 mm(3) versus 23.3+/-20.2 mm(3) (P<0.05) for control and IGF-I-treated animals, respectively. The T2-weighted-derived ischemic lesion volume at 24 hours after occlusion was 236+/-49.2 mm(3) versus 115.9+/-56.8 mm(3) (P<0.05) and decreased to 115.9+/-26.2 mm(3) versus 75.7+/-35.8 mm(3) (P<0.05) at day 7 for control and IGF-I-treated animals, respectively. The relative regional cerebral blood volume was reduced to 50% before reperfusion in all regions of interest except for region of interest 1 (vessel territory of anterior cerebral artery), recovered during reperfusion, but was not different between the control and the growth factor-treated group at any imaging time point. There was no significant difference in weight loss. There was less neurological deficit after ischemia in intraventricularly and subcutaneously IGF-I-treated animals compared with control animals (P<0.05).


CONCLUSIONS
Continuous treatment with intraventricularly and subcutaneously administered IGF-I achieved a long-lasting neuroprotective effect as early as 24 hours after ischemia as measured by MRI. Therefore, IGF-I may represent a new approach to the treatment of focal cerebral ischemia.
Schäbitz
W R
WR
Department of Neurology, University of Heidelberg, Heidelberg, Germany. wolf_schaebitz@med.uni-heidelberg.de
Hoffmann
T T
TT
Heiland
S
S
Kollmar
R
R
Bardutzky
J
J
Sommer
C
C
Schwab
S
S
D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D015918:Infusion Pumps, Implantable; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage*; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D009460:Neurologic Examination / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D016896:Treatment Outcome
D018696:Neuroprotective Agents; D007334:Insulin-Like Growth Factor I