During the development of the vertebrate nervous system, up to 50 percent or more of many types of neurons normally die soon after they form synaptic connections with their target cells. This massive cell death is thought to reflect the failure of these neurons to obtain adequate amounts of specific neurotrophic factors that are produced by the target cells and that are required for the neurons to survive. This neurotrophic strategy for the regulation of neuronal numbers may be only one example of a general mechanism that helps to regulate the numbers of many other vertebrate cell types, which also require signals from other cells to survive. These survival signals seem to act by suppressing an intrinsic cell suicide program, the protein components of which are apparently expressed constitutively in most cell types.

https://science.sciencemag.org/content/sci/262/5134/695.full.pdf

Programmed cell death and the control of cell survival: lessons from the nervous system

The development and maintenance of the nervous system depends on proteins known as neurotrophic factors. Although the prototypical neurotrophic factor, nerve growth factor (NGF), has been intensively studied for decades, the discovery and characterization of additional such factors has been impeded by their low abundance. Sequence homologies between NGF and the recently cloned brain-derived neurotrophic factor (BDNF) were used to design a strategy that has now resulted in the cloning of a gene encoding a novel neurotrophic factor, termed neurotrophin-3 (NT-3). The distribution of NT-3 messenger RNA and its biological activity on a variety of neuronal populations clearly distinguish NT-3 from NGF and BDNF, and provide compelling evidence that NT-3 is an authentic neurotrophic factor that has its own characteristic role in vivo.

https://science.sciencemag.org/content/sci/247/4949/1446.full.pdf

Neurotrophin-3: a neurotrophic factor related to NGF and BDNF

Prostaglandin synthase 2.

Diffusion in the extracellular space (ECS) of the brain is constrained by the volume fraction and the tortuosity and a modified diffusion equation represents the transport behavior of many molecule...

/pdf/diffusion-in-brain-extracellular-space-4beypnugcc.pdf

Diffusion in brain extracellular space.

Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants.

The present invention relates to nucleic acid sequences encoding ciliary neurotrophic factor (CNTF) and to the proteins, peptides, and derivatives produced therefrom. In various embodiments of the invention, the nucleic acid sequences, proteins, and peptides of the invention may be used in the treatment of a variety of neurological diseases and disorders, including Alzheimer's disease. In a specific embodiment of the invention, CNTF may be used to support the growth of spinal cord neurons, thereby providing a method of treating spinal cord damage caused by trauma infarction, infection, nutritional deficiency or toxic agents. The present invention also relates to a novel method for producing substantially pure CNTF. The invention also relates to pharmaceutical compositions comprising effective amounts of CNTF gene products which may be used in the diagnosis and treatment of a variety of neurological diseases and disorders. The present invention relates to the cloning sequencing and expression of CNTF and provides, for the first time, a means for producing human CNTF utilizing human CNTF-encoding nucleic acid sequences. Furthermore, the CNTF nucleic acid sequences of the invention may be utilized to identify nucleic acid sequences encoding CNTF or CNTF-homologous molecules in a variety of species and tissues.

Ciliary neurotrophic factor

The present invention relates to nucleic acid sequences encoding brain derived neurotrophic factor (BDNF), as well as BDNF protein produced in quantity using these nucleic acid sequences, as well as fragments and derivatives thereof. In addition, the invention relates to pharmacologic compositions and therapeutic uses of BDNF, having provided, for the first time, the means to generate sufficient quantities of substantially pure BDNF for clinical use. In a specific embodiment, BDNF may be used to promote the survival of substantia nigra dopaminergic neurons and basal forebrain cholinergic neurons, thereby providing a method for treating, respectively, Parkinson's disease and Alzheimer's disease. The invention also relates to antibodies directed toward BDNF or fragments thereof, having provided a method for generating sufficient immunogen. Further, by permitting a comparison of the nucleic acid sequences of BDNF and NGF, the present invention provides for the identification of homologous regions of nucleic acid sequence between BDNF and NGF, thereby defining a BDNF/NGF gene family; the invention provides a method for identifying and isolating additional members of this gene family.

Brain derived neurotrophic factor

From the brain-derived neurotrophic factor

The present invention relates to a method for regulating levels of nerve growth factor in the central nervous system, and is based on the discovery that in vivo synthesis of nerve growth factor may be regulated by various cytokines. In specific embodiments, intracerebroventricular injection of interleukin 1, fibroblast growth factor, or TGFβ1 increase synthesis of nerve growth factor and its mRNA. The methods of the present invention may be useful in the treatment of various neurologic diseases or disorders, including Alzheimer's disease.

Regulation of nerve growth factor synthesis in the central nervous system

The present invention relates to methods of treatment of motor neuron disorders, such as amyotrophic lateral sclerosis (Lou Gehrig's disease) comprising administering, to a subject in need of such treatment, an effective amount of a neurotrophic factor termed fibroblast growth factor 5 (FGF-5), which supports the survival, growth and/or differentiation of motor neurons. A combination of FGF-5 and a second agent, preferably CNTF, may be also used in the treatment of motor neuron disease. Also disclosed are methods of promoting the survival, growth and/or differentiation of motor neurons in vitro, methods of diagnosis, and assay systems which may be used to identify agents which have FGF-5-like activity and which may be useful in the treatment of motor neuron diseases. The present invention additionally provides pharmaceutical compositions comprising FGF-5 alone or in combination with a second agent which supports the survival, growth and/or differentiation of motor neurons, and a pharmaceutically acceptable carrier.

Dan Lindholm

Papers

Ciliary neurotrophic factor

Brain derived neurotrophic factor

From the brain-derived neurotrophic factor

Regulation of nerve growth factor synthesis in the central nervous system

Treatment of motor neuron diseases with fibroblast growth factor-5 (fgf-5)