Intranasal administration of insulin-like growth factor-I bypasses the blood-brain barrier and protects against focal cerebral ischemic damage.
BACKGROUND
Insulin-like growth factor-I (IGF-I) has been shown to protect against stroke in rats when administered intracerebroventricularly. However, this invasive method of administration is not practical for the large number of individuals who require treatment for stroke. Intranasal (IN) delivery offers a noninvasive method of bypassing the blood-brain barrier (BBB) to deliver IGF-I and other neurotrophic factors to the brain. Here, we demonstrate for the first time the therapeutic benefit of IN IGF-1 in rats following middle cerebral artery occlusion (MCAO).


METHODS
A blinded, vehicle-controlled study of IN IGF-I was performed using the intraluminal suture occlusion model. Rats were randomly divided into vehicle-control, 37.5 and 150 microg IGF-I-treated groups. Treatments occurred at 10 min after onset of 2 h of MCAO, and then 24 and 48 h later. Four neurologic behavioral tests were performed 4, 24, 48 and 72 h after the onset of MCAO. Corrected infarct volumes were evaluated 72 h after the onset of MCAO.


RESULTS
Treatment with the 150 microg IGF-I significantly reduced the infarct volume by 63% vs. control (p=0.004), and improved all the neurologic deficit tests of motor, sensory, reflex and vestibulomotor functions (p<0.01). However, the 37.5 microg dose of IGF-I was ineffective.


CONCLUSIONS
While IGF-I does not cross the BBB efficiently, it can be delivered to the brain directly from the nasal cavity following IN administration, bypassing the BBB. IN IGF-I markedly reduced infarct volume and improved neurologic function following focal cerebral ischemia. This noninvasive, simple and cost-effective method is a potential treatment for stroke.
Liu
X F
XF
Stroke Lab, Alzheimer's Treatment and Research Center, Department of Neurology, Regions Hospital, 640 Jackson Street, Saint Paul, MN 55101-2595, USA. Liuxx159@tc.umn.edu
Fawcett
J R
JR
Thorne
R G
RG
DeFor
T A
TA
Frey
W H
WH
D000281:Administration, Intranasal; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D009069:Movement Disorders / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D009460:Neurologic Examination; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010291:Paresis / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D011187:Posture / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D012678:Sensation Disorders / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology
D018696:Neuroprotective Agents; D007334:Insulin-Like Growth Factor I