During nerve development, neurotrophins help nerve cells decide if they are going to live or die. Neurotrophins are small proteins secreted in the nervous system at extremely low concentrations. Low levels of a neurotrophin are needed to keep nerve cells alive. However, in some cases, presence of a neurotrophin can have the opposite effect, initiating cell-death. During development of the nervous system, levels of neurotrophins control unwanted nerve cells. Later, neurotrophins stimulate the growth of new dendrites and to cause unwanted dendrites to die back from crowded areas.
Neurotrophins are proteins with closely related structures that are known to support the survival of different classes of embryonic neurons. Neurotrophins is a generic term that describes a number of neurotrophic factors enhancing neuronal differentiation, inducing proliferation, influencing synaptic functions, and promoting the survival of neurons that are normally destined to die during different phases of the development of the central and peripheral nervous system.
Neurotrophins (neurotrophic factors) are proteins which induce the survival of neurons and are found in the blood stream. Neurotrophins are capable of signaling particular cells to survive, differentiate, or grow. Neurotrophins are secreted by target tissues and prevent neurons from initiating programmed cell death - thus enabling the neurons to survive. Neurotrophins induce differentiation of progenitor cells to form neurons.
Growth factors such as basic-FGF or LIF due to their trophic activities on a number of neurons are frequently also counted among the neurotrophin group.
BDNF, NGF and NT-3 are referred to as the NGF protein family as NGF is the founder member of this family of proteins. The multifunctional Pan-Neurotrophin-1 (PNT-1) protein efficiently activates all trk receptors and displays multiple neurotrophic specificities.
Another neuronal survival factor is NSE (neuron-specific enolase). Other factors with neurotrophic activities normally not classified as neurotrophins and often possessing a broader spectrum of functions are EGF, HBNF (heparin binding neurite-promoting factor), IGF-2, acidic-FGF and FGF-basic, PDGF, NSE (neuron-specific enolase), and Activin-A.
Exogenous delivery of the neurotrophic factors, brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3), promotes the function, sprouting and re-growth of 5-HT-containing neurones in the brains of adult rats. Infusions of BDNF into the dorsal nucleus produce an antidepressant effect. Environmental stressors such as immobilization induce depression and decrease BDNF mRNA. Antidepressants increase BDNF mRNA in the brain, via 5-HT2A and beta-adrenoceptor subtypes and prevent the stress-induced decreases in BDNF mRNA. Treatments of depression might work by increasing endogenous brain levels of BDNF or NT-3, which in turn could promote monoamine-containing neuron growth and function. Drugs that selectively stimulate the production of neurotrophins could represent a new generation of antidepressants.
A distinction is made between Neurite promoting factor (NPF) & Neuronal differentiation factor depending upon their bioactivities. Neurite promoting factor (NPF) doesn’t promote neuronal survival or general growth but are required to induce outgrowth of axonal or dendritic processes. NPF activity include NGF, S100, GMF-beta (glial maturation factor), proteoglycans, merosin, fibronectin, collagens, cell adhesion molecules, & laminin.
Neuronal differentiation factors influence transmitter phenotypes without affecting neuronal survival. Members of a neurotrophic gene family are involved during the development in adult nervous system as indicated by in vitro assays using recombinant neurotrophic factors and distributions of their mRNAs and proteins.
80% of neurons in the nervous system undergo cell death during normal vertebral development in order to ensure adequate the #s of neurons that establish appropriate innervation densities with effector organs or other neuronal populations.
Sparing neurons from programmed death influence development. Neurotrophins support neuronal survival up to the time of naturally-occuring cell death and then become ineffective. This mechanism involves a switch in the type of neurotrophin receptor expressed by the neuron. Other neurotrophins have profound effects on neuronal progenitor cells and can increase the number of neurons in a population destined to have a specific phenotype. Neurotrophins affect electrical synapse activity which increase expression of neurotrophin genes.
Transgenic mice carrying null mutations of various genes encoding neurotrophins or their receptors revealed a broad spectrum of activities of neurotrophins in the nervous system. Studies and investigations of neurotrophin receptors will aid in defining the roles of neurotrophins in the mature central nervous system. It is already clear that the development, maintenance, and plasticity of the nervous system involves careful spatial and temporal control of expression of multiple neurotrophins, their receptors, and other factors.
Neurotrophins are of potential clinical interest since they influence the functional activities and survival of distinct neuronal populations within the peripheral and central nervous system. Neurotrophins are currently under investigation as therapeutic agents for the treatment of neurodegenerative disorders and nerve injury either individually or in combination with other trophic factors.
A number of diseases, such as Alzheimer's disease, stroke, and cancer, may cause neural damage in part through the misfunction of neurotrophins. Current therapeutic strategies are to fight these diseases using neurotrophic factors to help and control any loss of nerve function. Unfortunately, neurotrophins do not last very long in the body when injected to the body and show significant side effects. Today, researchers are looking for drugs that “fool” cells into thinking that they are receiving signals from neurotrophins.