Intranasal delivery of neurotrophic factors BDNF, CNTF, EPO, and NT-4 to the CNS.
Injury to the central nervous system (CNS) generally results in significant neuronal death and functional loss. In vitro experiments have demonstrated that neurotrophic factors such as brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), and neurotrophin-4/5 (NT-4/5) can promote neuronal survival. However, delivery to the injured CNS is difficult as these large protein molecules do not efficiently cross the blood-brain barrier. Intranasal delivery of 70 microg [(125)I]-radiolabeled BDNF, CNTF, NT-4, or erythropoietin (EPO) resulted in 0.1-1.0 nM neurotrophin concentrations within 25 min in brain parenchyma. In addition, not only did these neurotrophic factors reach the CNS, they were present in sufficient concentrations to activate the prosurvival PI3Kinase/Akt pathway, even where lower levels of neurotrophic factors were measured. Currently traumatic, ischemic and compressive injuries to the CNS have no effective treatment. There is potential clinical relevancy of this method for rescuing injured CNS tissues in order to maintain CNS function in affected patients. The intranasal delivery method has great clinical potential due to (1) simplicity of administration, (2) noninvasive drug administration, (3) relatively rapid CNS delivery, (4) ability to repeat dosing easily, (5) no requirement for drug modification, and (6) minimal systemic exposure.
Alcalá-Barraza
Sandra R
SR
Department of Ophthalmology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Lee
Michael S
MS
Hanson
Leah R
LR
McDonald
Abby A
AA
Frey
William H
WH
McLoon
Linda K
LK
D000281:Administration, Intranasal; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002490:Central Nervous System / Q000378:metabolism* / Q000503:physiopathology; D002493:Central Nervous System Diseases / Q000188:drug therapy / Q000503:physiopathology; D016503:Drug Delivery Systems; D008297:Male; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D009414:Nerve Growth Factors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt