Intranasal delivery of neurotrophic factors BDNF, CNTF, EPO, and NT-4 to the CNS

Sandra R. Alcalá-Barraza; Michael S. Lee; Leah R. Hanson; Abby A. McDonald; William H. Frey; Linda K. McLoon

doi:10.3109/10611860903318134

Intranasal delivery of neurotrophic factors BDNF, CNTF, EPO, and NT-4 to the CNS

Sandra R. Alcalá-Barraza, Michael S. Lee, Leah R. Hanson, Abby A. McDonald, William H. Frey, Linda K. McLoon

Ophthalmology & Visual Neurosciences

Research output: Contribution to journal › Article › peer-review

146 Scopus citations

Abstract

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 μg [¹²⁵I]-radiolabeled BDNF, CNTF, NT-4, or erythropoietin (EPO) resulted in 0.1-1.0nM neurotrophin concentrations within 25min 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.

Original language	English (US)
Pages (from-to)	179-190
Number of pages	12
Journal	Journal of Drug Targeting
Volume	18
Issue number	3
DOIs	https://doi.org/10.3109/10611860903318134
State	Published - Apr 2010

Bibliographical note

Funding Information:
This work was supported by EY11374 from the National Eye Institute, Prevent Blindness America, the Glaucoma Foundation, the Minnesota Lions and Lionesses, the Lew Wasserman Mid-Career Merit Award from Research to Prevent Blindness (RPB), and an unrestricted grant to the Department of Ophthalmology from RPB Inc.

Keywords

Blood-brain barrier
Brain-derived neurotrophic factor
Central nervous system (CNS)
Ciliary neurotrophic factor
Distribution
Erythropoietin
Insulin growth factor-1
Nasal drug delivery
Neurotrophic factor
Neurotrophin-4/5
Protein delivery

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title = "Intranasal delivery of neurotrophic factors BDNF, CNTF, EPO, and NT-4 to the CNS",

abstract = "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 μg [125I]-radiolabeled BDNF, CNTF, NT-4, or erythropoietin (EPO) resulted in 0.1-1.0nM neurotrophin concentrations within 25min 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.",

keywords = "Blood-brain barrier, Brain-derived neurotrophic factor, Central nervous system (CNS), Ciliary neurotrophic factor, Distribution, Erythropoietin, Insulin growth factor-1, Nasal drug delivery, Neurotrophic factor, Neurotrophin-4/5, Protein delivery",

author = "Alcal{\'a}-Barraza, {Sandra R.} and Lee, {Michael S.} and Hanson, {Leah R.} and McDonald, {Abby A.} and Frey, {William H.} and McLoon, {Linda K.}",

note = "Funding Information: This work was supported by EY11374 from the National Eye Institute, Prevent Blindness America, the Glaucoma Foundation, the Minnesota Lions and Lionesses, the Lew Wasserman Mid-Career Merit Award from Research to Prevent Blindness (RPB), and an unrestricted grant to the Department of Ophthalmology from RPB Inc.",

year = "2010",

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language = "English (US)",

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T1 - Intranasal delivery of neurotrophic factors BDNF, CNTF, EPO, and NT-4 to the CNS

AU - Alcalá-Barraza, Sandra R.

AU - Lee, Michael S.

AU - Hanson, Leah R.

AU - McDonald, Abby A.

AU - Frey, William H.

AU - McLoon, Linda K.

N1 - Funding Information: This work was supported by EY11374 from the National Eye Institute, Prevent Blindness America, the Glaucoma Foundation, the Minnesota Lions and Lionesses, the Lew Wasserman Mid-Career Merit Award from Research to Prevent Blindness (RPB), and an unrestricted grant to the Department of Ophthalmology from RPB Inc.

PY - 2010/4

Y1 - 2010/4

N2 - 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 μg [125I]-radiolabeled BDNF, CNTF, NT-4, or erythropoietin (EPO) resulted in 0.1-1.0nM neurotrophin concentrations within 25min 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.

AB - 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 μg [125I]-radiolabeled BDNF, CNTF, NT-4, or erythropoietin (EPO) resulted in 0.1-1.0nM neurotrophin concentrations within 25min 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.

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KW - Distribution

KW - Erythropoietin

KW - Insulin growth factor-1

KW - Nasal drug delivery

KW - Neurotrophic factor

KW - Neurotrophin-4/5

KW - Protein delivery

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SN - 1061-186X

VL - 18

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EP - 190

JO - Journal of Drug Targeting

JF - Journal of Drug Targeting

IS - 3

ER -

Intranasal delivery of neurotrophic factors BDNF, CNTF, EPO, and NT-4 to the CNS

Abstract

Bibliographical note

Keywords

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