Introduction to Nerve Growth Factor


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Introduction to Nerve Growth Factor 

There are two antibodies related to NGF.

1. Fulranumab

Recombinant monoclonal antibody to NGF.Fulranumabis a human monoclonal antibody designed for the treatment of pain.  

2. Tanezumab

Recombinant monoclonal antibody to NGF. Tanezumab (INN, codenamed RN624) is a monoclonal antibody against nerve growth factor, as a treatment for pain.  

What is NGF?

Nerve growth factor (NGF) can promote the growth, development, differentiation and maturation of central and peripheral neurons, maintain the normal function of the nervous system, and accelerate the repair of nervous system injury. NGF is widely distributed in various tissues and organs of the body (including the brain). The concentration of NGF in target tissues is related to the density of sympathetic and sensory nerves in target areas and the content of mRNA.

Structural characteristics of NGF

NGF has two types: 7SNGF and 2.5SNGF. 7SNGF is composed of three subunits, alpha, beta and gamma, in the proportion of alpha 2 beta1 gamma 2. Of them, the beta subunit is the active region of NGF, which can fully reflect the physiological effects of NGF. It is a dimer composed of 118 amino acid residues and bound by non-covalent bonds. The gamma subunit comprises 229 amino acid residues, which is an arginine-specific ester peptidase that hydrolyzes NGF precursors to produce active NGF. The alpha subunit can inhibit the activity of gamma subunit.2.5SNGF is a general term for the combination of beta-NGF and its modifiers obtained from the purification of beta-NGF from the submandibular gland of mice. Its structure is basically the same as that of the beta subunit, so it is also called beta-NGF.

Receptors of NGF

NGF exerts its biological effects by binding to receptors on the cell surface. There are two kinds of receptors: high affinity receptors and low affinity receptors. The high affinity receptor, known as TrkA receptor, has a molecular weight of 140 KD and consists of 790 amino acids. It is a tyrosine protein kinase receptor encoded by the proto-oncogene trk.The tertiary structure of TrkA consists of extracellular, transmembrane and intracellular tyrosine kinase. There are eight repetitive regions of leucine outside the cell, which are connected with a group of cysteine residues in series before and after each. The constant region of C2 immunoglobulin, which serves as the domain of NGF,lies next to the cell membrane.Asa member of the superfamily of tumor necrosis factor receptors, p75 is a low affinity receptor of NGF, with the molecular weight of 75KD. Its tertiary structure is also divided into three parts: the glycosylated extracellular part, the transmembrane part and the intracellular part lacking intrinsic catalytic activity. The extracellular part containing four cysteine repeats is the binding site of NGF. Its mediated biological effects include: enhancing the affinity between NGF and TrkA; regulating the signal transduction of TrkA; participating in apoptosis; regulating the retrograde transport of neurotransmitters, the growth of axons and the formation of nerve plexus.

Distribution of NGF and its receptors

NGF is widely distributed. In the central nervous system, NGF mainly distributes in cholinergic neurons in hippocampus, cerebral cortex, septum, Broca oblique zone, olfactory bulb and striatum. The granular cell layer in the dentate gyrus of hippocampus, the vertebral cell layer and cerebral cortex in the CA1-CA3 area are the highest.In the central nervous system, the content of NGF mRNA is positively correlated with the distribution density of cholinergic neurons in the tissues. Peripherally, NGF is mainly distributed in sympathetic or sensory nerves such as submandibular gland, heart, iris, skin and vas deferens. NGF can be synthesized by fibroblasts, smooth muscle cells, skeletal muscle cells, glia, cardiomyocytes, immune cells and adipocytes.

NGF receptors are also widely distributed. Experiments show that NGF receptors can be expressed in the tissues and cells of the three embryonic layers. In the nervous system, it mainly distributes in the basal forebrain, striatum, septum, lateral geniculate body, superior colliculus and almost all cholinergic neurons, peripheral sensory neurons and sympathetic neurons. In non-nerve cells, it mainly distributes in melanocytes, mast cells, neutrophils, submandibular gland cells, myoepithelial cells, adventitia, basic cells of oral mucosa and hair follicles.

Biological effects of NGF

1. NGF and nervous system

It plays an important nutritional role in the nervous system and promotes the differentiation and growth of neurons. The results showed that NGF could induce mitosis of sensory ganglion and sympathetic neurons in chicken embryos, and increase organelles such as nucleolus, rough endoplasmic reticulum, golgi body and microfilament microtubules. In addition, NGF can promote the repair of damaged neurons and determine the growth direction of axons.

2. NGF and Tumors

NGF and its receptors are expressed not only in normal tissues, but also in various tumors, such as pancreatic cancer, cervical cancer, preceding adenocarcinoma and neuroblastoma. NGF can promote or inhibit tumors, depending on their types. For example,it has the capacity to inhibit the proliferation of small cell lung cancer and reverse its phenotype to a benign direction. NGF can also promote the differentiation and maturation of cancer cells and make them develop in a benign way in morphology, thus inhibiting the growth of tumors.

3. NGF and immune response

NGF is expressed in a variety of immune cells, such as monocytes, macrophages, neutrophils, helper lymphocytes and B lymphocytes. NGF can regulate the proliferation and differentiation of immune cells and participate in immune and inflammatory reactions. For instance, itis able to promote lymphocyte proliferation and differentiation by regulating cellular and humoral immunity.CD4+T lymphocytes can express NGF and TrkA receptors, while NGF has biological effects on CD4+T lymphocytes through TrkA receptors. NGF may regulate other immune cells, as well. For example, it can mediate the chemotaxis of mast cells, which can be neutralized by polyclonal antibodies to NGF.NGF may also promote the proliferation and differentiation of human umbilical cord blood basophils, neutrophils and mouse macrophages. A large number of studies have shown that the concentration of NGF in inflammation is high, but the specific role of NGF in the inflammation process remainsunclear, which needs to be further studied.

In summary, NGF is a multi-functional neurofactor, capable of regulating both the nervous system and the non-nervous system, and its role in the non-nervous system is a hotspot of current research.

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