Intranasal delivery of erythropoietin plus insulin-like growth factor-I for acute neuroprotection in stroke. Laboratory investigation.
OBJECTIVE
Individually, the cytokines erythropoietin (EPO) and insulin-like growth factor-I (IGF-I) have both been shown to reduce neuronal damage significantly in rodent models of cerebral ischemia. The authors have previously shown that EPO and IGF-I, when administered together, provide acute and prolonged neuroprotection in cerebrocortical cultures against N-methyl-D-aspartate-induced apoptosis. The aim of this study was to determine whether intranasally applied EPO plus IGF-I can provide acute neuroprotection in an animal stroke model and to show that intranasal administration is more efficient at delivering EPO plus IGF-I to the brain when compared with intravenous, subcutaneous, or intraperitoneal administration.


METHODS
The EPO and IGF-I were administered intranasally to mice that underwent transient middle cerebral artery occlusion (MCAO). Stroke volumes were measured after 1 hour of MCAO and 24 hours of reperfusion. To evaluate the long-term effects of this treatment, behavioral outcomes were assessed at 3, 30, 60, and 90 days following MCAO. Radiography and liquid scintillation were used to visualize and quantify the uptake of radiolabeled 125I-EPO and 125I-IGF-I into the mouse brain after intranasal, intravenous, subcutaneous, or intraperitoneal administration.


RESULTS
Intranasal administration of EPO plus IGF-I reduced stroke volumes within 24 hours and improved neurological function in mice up to 90 days after MCAO. The 125I-EPO and 125I-IGF-I were found in the brain within 20 minutes after intranasal administration and accumulated within the injured areas of the brain. In addition, intranasal administration delivered significantly higher levels of the applied 125I-EPO and 125I-IGF-I to the brain compared with intravenous, subcutaneous, or intraperitoneal administration.


CONCLUSIONS
The data demonstrate that intranasal EPO plus IGF-I penetrates into the brain more efficiently than other drug delivery methods and could potentially provide a fast and efficient treatment to prevent chronic effects of stroke.
Fletcher
Lauren
L
Department of Neurosurgery, University of Texas Health Science Center San Antonio, San Antonio, Texas 78229, USA.
Kohli
Sanjivan
S
Sprague
Shane M
SM
Scranton
Robert A
RA
Lipton
Stuart A
SA
Parra
Augusto
A
Jimenez
David F
DF
Digicaylioglu
Murat
M
D000208:Acute Disease; D000281:Administration, Intranasal; D000818:Animals; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004359:Drug Therapy, Combination; D004921:Erythropoietin / Q000493:pharmacokinetics*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000493:pharmacokinetics*; D007457:Iodine Radioisotopes; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000493:pharmacokinetics*
D007457:Iodine Radioisotopes; D018696:Neuroprotective Agents; D004921:Erythropoietin; D007334:Insulin-Like Growth Factor I