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Delivery of Neurotrophic Factors to the Central Nervous System: Pharmacokinetic Considerations
Abstract
Neurotrophic factors are proteins with considerable potential in the treatment of central nervous system (CNS) diseases and traumatic injuries. However, a significant challenge to their clinical use is the difficulty associated with delivering these proteins to the CNS. Neurotrophic factors are hydrophilic, typically basic, monomeric or dimeric proteins, mostly in the size range of 5 to 30 kDa. Neurotrophic factors potently support the development, growth and survival of neurons, eliciting biological effects at concentrations in the nanomolar to femtomolar range. They are not orally bioavailable and the blood-brain and blood-cerebrospinal fluid barriers severely limit their ability to enter into and act on sites in the CNS following parenteral systemic routes of administration. Most neurotrophic factors have short in vivo half-lives and poor pharmacokinetic profiles. Their access to the CNS is restricted by rapid enzymatic inactivation, multiple clearance processes, potential immunogenicity and sequestration by binding proteins and other components of the blood and peripheral tissues. The development of targeted drug delivery strategies for neurotrophic factors will probably determine their clinical effectiveness for CNS conditions. Achieving significant CNS target site concentrations while limiting systemic exposure and distribution to peripheral sites of action will lessen unwanted pleiotropic effects and toxicity. Local introduction of neurotrophic factors into the CNS intraparenchymally by direct injection/infusion or by implantation of delivery vectors such as polymer matrices or genetically modified cells yields the highest degree of targeting, but is limited by diffusion restrictions and invasiveness. Delivery of neurotrophic factors into the cerebrospinal fluid (CSF) following intracerebroventricular or intrathecal administration is less invasive and allows access to a much wider area of the CNS through CSF circulation pathways. However, diffusional and cellular barriers to penetration into surrounding CNS tissue and significant clearance of CSF into the venous and lymphatic circulation are also limiting. Unconventional delivery strategies such as intranasal administration may offer some degree of CNS targeting with minimal invasiveness. This review presents a summary of the neurotrophic factors and their indications for CNS disorders, their physicochemical characteristics and the different approaches that have been attempted or suggested for their delivery to the CNS. Future directions for further research such as the potential for CNS disease treatment utilising combinations of neurotrophic factors, displacement strategies, small molecule mimetics, chimaeric molecules and gene therapy are also discussed.
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“This is likely because of the limited number of routes to reach the brain, such as blood-brain barrier and extraneuronal/perineuronal routes along the trigeminal or olfactory nerves.10, 49, 50, 51, 52, 53”
From Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial (2016) · cites this paper as [49]
Citations
Cites
Initial sequencing and analysis of the human genome
International Human Genome Sequencing Consortium, Whitehead Institute for Biomedical Research, C. F. G. R., Lander, E. S., Linton, L. M., Birren, B., Nusbaum, C., Zody, M. C., Baldwin, J., Devon, K., Dewar, K., et al. (2001) · Nature · doi:10.1038/35057062 · Cited by 24,216
The sequence of the human genome
Venter, J. C., Adams, M. D., Myers, E. W., Li, P. W., Mural, R. J., Sutton, G. G., Smith, H. O., Yandell, M., Evans, C. A., Holt, R. A., et al. (2001) · Science · doi:10.1126/science.1058040 · Cited by 13,909
Molecular Mechanisms of Depression: Perspectives on New Treatment Strategies
Lang, U. E., & Borgwardt, S. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350094 · Cited by 8,526
Neurogenesis in the adult human hippocampus
Eriksson, P. S., Perfilieva, E., Björk-Eriksson, T., Alborn, A.-M., Nordborg, C., Peterson, D. A., & Gage, F. H. (1998) · Nature Medicine · doi:10.1038/3305 · Cited by 6,369
The Nerve Growth Factor 35 Years Later
Levi‐Montalcini, R. (1987) · Science · doi:10.1126/science.3306916 · Cited by 3,109
Mechanism of Action and In Vivo Role of Platelet-Derived Growth Factor
Heldin, C., & Westermark, B. (1999) · Physiological Reviews · doi:10.1152/physrev.1999.79.4.1283 · Cited by 2,521
Berg, H. C. (1984) · Princeton University Press eBooks · doi:10.1515/9780691279886 · Cited by 2,417
Proteomics to study genes and genomes
Pandey, A., & Mann, M. (2000) · Nature · doi:10.1038/35015709 · Cited by 2,399
Transplantation of Embryonic Dopamine Neurons for Severe Parkinson's Disease
Freed, C. R., Greene, P. E., Breeze, R. E., Tsai, W.-Y., DuMouchel, W., Kao, R., Dillon, S., Winfield, H., Culver, S., Trojanowski, J. Q., et al. (2001) · New England Journal of Medicine · doi:10.1056/nejm200103083441002 · Cited by 2,366
Hillery, A. M., Lloyd, A. W., & Swarbrick, J. (2016) · CRC Press eBooks · doi:10.1201/b12801 · Cited by 2,031
Research works printed but not linked: 15
- Walsh, 1995, Biol Technol, 13, 1167
- Desai, 1999, Mor Mortal Wkly Rep CDC Surveill Summ, 48, 7
- Foldi, 1996, Lymphology, 29, 1
- Kuo, 1991, J Chromatogr B Biomed Sci Appl, 543, 463
- Tanaka, 1997, Res Commun Mol Pathol Pharmacol, 96, 267
- Frystyk, 1995, Am J Physiol, 269, E840
- Fung, 1998, Cancer Res, 58, 672
- Penn, 1997, Neurosurgery, 40, 94
- Apfel, 1996, Ciba Found Symp, 196, 98
- de Vries, 1996, J Pharmacol Exp Ther, 277, 1418
- Venero, 1996, Mol Pharmacol, 49, 303
- DeSesso, 1993, Qual Assur, 2, 213
- Bojsen-Moller, 1971, J Anat, 110, 25
- Kaechi, 1993, J Pharmacol Exp Ther, 264, 321
- Tuszynski, 1996, Gene Ther, 3, 305
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Kosaka, H., Okamoto, Y., Munesue, T., Yamasue, H., Inohara, K., Fujioka, T., Anme, T., Orisaka, M., Ishitobi, M., Jung, M., et al. (2016) · Translational Psychiatry · doi:10.1038/tp.2016.152 · Cited by 117
Hallschmid, M. (2021) · Journal of Neuroendocrinology · doi:10.1111/jne.12934 · Cited by 113
Wu, H., Zhou, Y., Wang, Y., Tong, L., Wang, F., Song, S., Xu, L., Liu, B., Yan, H., & Sun, Z. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.717192 · Cited by 90
Ionescu, I. A., Dine, J., Yen, Y.-C., Buell, D. R., Herrmann, L., Holsboer, F., Eder, M., Landgraf, R., & Schmidt, U. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2011.317 · Cited by 87
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Metadata
- Authors
- Thorne, R. G., & Frey, W. H.
- Affiliations
- Regions Hospital (US)
- Venue
- Clinical Pharmacokinetics
- Published
- 2001
- Volume
- 40
- Issue
- 12
- Pages
- 907-946
- ISSN
- 0312-5963 (ISSN-L)
- OpenAlex
- W1973304468
- Cited by
- 487
- References
- 310
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 19 · 2023: 20 · 2022: 21 · 2021: 24 · 2020: 31 · 2019: 17 · 2018: 24 · 2017: 17 · 2016: 26 · 2015: 26 · 2014: 26 · 2013: 28 · 2012: 20
- FWCI
- 1.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Pharmacokinetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Keywords
- neurotrophic factors, brain drug delivery, blood-brain barrier, blood-CSF barrier, intrathecal administration, intracerebroventricular administration, intranasal drug delivery, intraparenchymal injection, gene therapy, small molecule mimetics, central nervous system disorders, traumatic brain injury, pharmacokinetics, immunogenicity
- MeSH terms
- Animals, Central Nervous System Diseases, Drug Combinations, Humans, Nerve Growth Factors
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