Neurotrophic factors

K K Jain MD (Dr. Jain is a consultant in neurology and has no relevant financial relationships to disclose.)
Originally released August 27, 1997; last updated August 17, 2017; expires August 17, 2020

Overview

Neurotrophic factors regulate the proliferation, survival, migration, and differentiation of cells in the nervous system. This article is an introduction to the role of neurotrophic factors in the pathophysiology of neurologic disorders and their potential therapeutic applications, which are covered in a series of related articles. Some of the failures of neurotrophic factors in clinical trials are related to the difficulty of delivering them to the site of action in the nervous system. Various approaches to overcome this problem include neurotrophic factor delivery by special devices and gene therapy.

Key points

 

• Neurotrophic factors regulate the proliferation, survival, migration, and differentiation of cells in the nervous system.

 

• Several neurotrophic factors have been identified and investigated for treatment of neurologic disorders.

 

• Besides their role in regeneration, neurotrophic factors also have neuroprotective functions.

 

• Delivery of neurotrophic factors to the central nervous system is a problem as the large molecules do not easily cross the blood-brain barrier.

 

• Apart from direct delivery to the brain, neurotrophic factors can also be delivered by cell and gene therapies.

Historical note and terminology

A "trophic factor" can be generally defined as any molecule that supports the survival of cells. Nerve growth factors are polypeptides that regulate the proliferation, survival, migration, and differentiation of cells in the nervous system. Most of the studies have focused on the effect of growth factors on neuronal survival and maintenance, hence, the term "neurotrophic factors." A neurotrophic factor is synthesized by and released from target cells of the neurons. It is bound to specific receptors, then internalized and transported by retrograde axonal transport to the cell soma where multiple survival-promoting effects are initiated. Neurotrophic factors act via 2 different classes of receptors and activation of various signaling pathways in the target cells (Machalinski et al 2012).

The study of these factors began in the 1930s; 2 decades later, a target-derived soluble protein was shown to influence neuronal survival and was termed "nerve growth factor" (Levi-Montalcini and Hamburger 1953). Nerve growth factor provided the first molecular basis for the concept of neurotrophic signaling between neurons and their targets; however, recognition of the therapeutic potential of nerve growth factor did not take place until the 1960s (Cohen 1960). Another 2 decades passed before the discovery of further nerve growth factors in the 1980s. These discoveries included isolation of brain-derived neurotrophic factor (Barde et al 1982), localization of fibroblast growth factor in neurons of the brain (Pettmann et al 1986), and cloning of brain-derived neurotrophic factor (Leibrock et al 1989). Besides nerve growth factor, a family of nerve growth factor-related polypeptides called “neurotrophins” has been identified along with their specific receptors: neurotrophin-3 (Maisonpierre et al 1990), neurotrophin-4 (Hallbook et al 1991), and neurotrophin-6 (Gotz et al 1994). Other discoveries in this area include cloning of human ciliary neurotrophic factor (Lam et al 1991) and isolation of rat glial cell line-derived neurotrophic factor (Lin et al 1993). Growth factors, termed "cytokines," have also been found to modulate neuronal processes and are sometimes referred to as neuropoietic cytokines or, simply, neurokines. Originally, cytokines were considered to be derived solely from the cells of the immune system, but now they are known to be produced by the cells of the central nervous system also. In this article, the term "neurotrophic factors" will be used in a broad sense to cover all neurotrophins (nerve growth factor and brain-derived neurotrophic factor), growth factors, and other substances that promote survival and repair of the cells of the nervous system.

A practical classification of neurotrophic factors is shown in Table 1.

Table 1. Classification of Neurotrophic Factors, Growth Factors with Neurotrophic Effects

 

• Neurotrophin family

 

- Nerve growth factor (NGF)
- Brain-derived neurotrophic factor (BDNF)
- Neurotrophins: NT-3, NT-4/5, NT-6

• Neuropoietic cytokines (neurokines)

 

- Ciliary neurotrophic factor family (CNTF)
- Leukemia inhibitory factor (LIF) and cholinergic differentiation factor
- Cardiotrophin-1
- Oncostatin M
- Growth promoter activity factor
- Tumor necrosis factor (TNF)

• Ligands for epidermal growth factor receptor family (p185erbB2, p160erbB3, p180erbB4)
• Neuregulins

 

- Neu differentiation factor or heregulin
- Acetylcholine receptor-inducing activity
- Glial growth factors (GGFs)

• Fibroblast growth factors (FGF)
• Transforming growth factors (TGF): (TGF-beta)

 

- Glial cell line-derived neurotrophic factor (GDNF)
- Artemin (a member of GDNF family)
- Neurturin (homologue of GDNF)
- Persephin (identical to GDNF and neurturin)
- Osteogenic protein-1 (OP-1)
- Bone morphogenetic proteins (BMPs) and growth differentiation factors

• Insulin-like growth factors (IGF)
• Platelet-derived growth factor (PDGF)
• Hepatocyte growth factor (HGF)
• Granulocyte-colony stimulating factor (G-CSF)
• Neurotransmitters and neuromodulators
• Serine protease inhibitors: protease nexin-1
• Hedgehog family of inducing proteins
• Proteins involved in synapse formation: agrin, laminin 2, and ARIA (ACh-inducing activity)
• Neuroimmunophilins
• Pigment epithelium-derived factor (PEDF)
• Activity-dependent neurotrophic factors

 

- Activity-dependent neuroprotective protein (ADNP)
- Neuritin (activity-induced neurotrophic factor)

• Angiogenesis growth factor
• Vascular endothelial growth factor (VEGF)
• Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) -- members of a new family of evolutionary conserved neurotrophic factors.
• Peptides designed after biologically active regions of neurotrophic factors

 

- Peptide-6 (designed after CNTF)
- Davunetide (derived from ADNP)

• Substances with nerve growth factor-like properties

 

- Gangliosides
- Cerebrolysin

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