Neurotrophic factors types

Each neurotrophic factor influences the growth and development of a specific group of neuronal types, with some cells being sensitive to several such factors. Many sustain specific neuronal populations whose death underlines various neurodegenerative diseases. This raises the possibility that these regulatory molecules may be of benefit in treating such diseases. Results from early clinical trials have been at best mixed, but many remain optimistic that neurotrophic factors may provide future effective treatments for some currently incurable neurodegenerative conditions. 

AC VIII, adenylyl cyclase type VIII BDNF, brain-derived neurotrophic factor CamKII, calcium-calmodulin kinase II GIRK2, G protein-activated inward rectifying potassium 2 MAOA, monoamine oxidase A n.d., not determined NCAM, neural cell adhesion molecule nNOS, neuronal nitric oxide synthase Petl, ETS domain transcription factor tPA, serine protease tissue-plasminogen activator (tPA). t/ > Increase/decrease in anxiety-related behavior. No effect. 

Ampakines are drugs that potentiate currents mediated by AMPA-type glutamate receptors. In behavioral tests, ampakines are effective in correcting behaviors in various animal models of schizophrenia and depression. They protect neurons against neurotoxic insults, in part by mobilizing growth factors such as brain-derived neurotrophic factor (BDNF). 

Neurotropic factors of dopaminergic neurons may represent a potential neuroprotective therapy for Parkinson s disease. Apart from nerve growth factor (NGF), the family of the neurotrophins subsumes at the present time BDNF, neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5). However, the concept of neurotrophic factors as specific, target-derived molecules, each acting on distinct neuronal types, has to be modified because of their high degree of pleiotropism and a... 

Some neurons are more sensitive than others to the effects of a variety of toxicants that is, they display a selective vulnerability to neurotoxicants. For example, mitochondrial respiratory complex inhibitors such as cyanide and 3-nitropropionic acid are toxic to all cell types yet within the CNS, neurons in the basal ganglia (a group of regions that collectively control motor behavior) appear to be particularly sensitive to these agents. In most cases, selective vulnerability to neurotoxicants arises because of a unique combination of factors that predispose a cell type or region to particular insults. These factors may include the presence of certain ion channels, receptors or uptake sites, the activity level of xenobiotic metabolizing or antioxidant enzymes, the expression profile of neurotrophic factors or their receptors, and so on. Three CNS sites highly vulnerable to neurotoxicant effects are described separately below. 

The neurotrophin receptor p75 was first identified as a nerve growth factor (NGF)-binding protein and was subsequently shown to interact with each of the other neurotrophic factors, BDNF, neurotrophin-3, and neurotrophin-4/-5. It also modulates the activity of several members of the tropomyosin-related receptor tyrosine kinase family (Trk) (reviewed in Chao, 2003). p75, a member of the tumor necrosis factor superfamily, is a type I transmembrane protein with four cysteine-rich domains in its extracellular region and a Death domain in its cytoplasmic protein (Fig. 11). 

Wild-type, but not mutant Htt, stimulates transcription of brain-derived neurotrophic factor (BDNF), and neuronal restrictive silencer element (NRSE) is the target of wild-type Htt activity on the BDNF promoter II (Zuccato et al., 2003). 

The neurotrophin family includes NGF, BDNF, neurotrophin-3 (NT-3), NT-4/5, and NT-6. All neurotrophins are capable of binding to the p75 receptor each neurotrophin also binds to a specific Trk receptor. Trk is the receptor for NGF TrkB is the receptor for BDNF and NT-4, while TrkC is the receptor for NT-3. Neurotrophins secreted by cells protect neurons from apoptosis (Korsching, 1993 Lewin and Barde, 1996). Similarly, ciliary neurotrophic factor (CNTF), a structurally related type I cytokine and GDNF, structurally related to TGF-[3, each constitute a sub-family of neurotrophic factors. 

The increased number of new ly generated cells in the SGZ follow ing hfe-style modulators, is thought to be due to the increase in cell survival and has been linked to increased protein levels for both BDNF and neurotrophin 3 (NT-3) (Lee et al., 2000, 2002 Duan et al., 2001). Ciliary neurotrophic factor (CNTF) is an acidic protein involved in type-2 astrocyte differentiation. Injection of CNTF into the mouse brain stimulates precursor cell proliferation w ith the CNTF receptor alpha expressed on GFAP-positive cells of the SVZ (Fmsley and Hagg, 2003). 

Soontomniyomkij V, Wang G, Pittman CA, Wiley CA, Achim CL (1998) Expression of brain-derived neurotrophic factor protein in activated microglia of human immunodeficiency virus type 1 encephahtis. Neuropathol Appl Neurobiol 24 453 60. 

Chen ZY, Patel PD, Sant G, Meng CX, Teng KK, Hempstead BL et al (2004) Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci 24 4401-4411... 

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