Brain Derived Growth Factor

Brain derived neurotrophic factor (BDNF) has been shown to prolong survival, protect against glutamate neurotoxicity, and slow disease progression in the wobbler mouse, an early model of ALS. Unfortunately, BDNF did not show benefit in patients with ALS (Anonymous, 1999). 

BDNF was also evaluated in the rat model of PD, and was compared to gUal cell line derived neurotrophic factor (GDNF) results of the study showed that GDNF was more effective than BDNF in the model, but that there were no significant benefits from either of these neuronophic factors (Sun et al., 2005). 

Ciliary neuronophic factor (CNTF) was also shown to protect wobbler mice, to be required for preservation of adult motor neurons in knockout mice, and to reduce immunoreactivity in the spinal cord of ALS patients. This drug advanced as far as Phase III clinical dials, however, no significant difference in survival was observed between CNTF and placebo groups (ALS CNTF Treatment Study Group, 1996 Hurko and Walsh, 2000). 

CNTF has also been investigated in mouse models of PD. Although CNTF had potent neuronophic effects for injured adult rat dopaminergic substantia nigra neurons, it did not prevent the disappearance of the transmitter synthesizing enzyme tyrosine hydroxylase (Hagg and Varon, 1993). Human trials were not conducted. 

---

BDNF (brain-derived neurotrophic factor) is a neuro-trophin, i.e. a target-derived growth factor, which is expressed in the brain predominantly in the hippocampus. It acts through its tyrosine kinase receptor, trkB,... 

FIGURE 2 7-2 Neurotrophin receptors. Neurotrophin family members bind specifically to cognate Trk receptors. The low affinity neurotrophin receptor, p75, promiscuously binds all neurotrophins. BDNF, brain-derived neurotrophic factor NGF, nerve growth factor NT, neurotrophin. 

Barrett GL, Georgiou A, Reid K, Bartlett PF, Leung D. 1998. Rescue of dorsal root sensory neurons by nerve growth factor and neurotrophin-3, but not brain-derived neurotrophic factor or neurotrophin-4, is dependent on the level of the p75 neurotrophin receptor. Neuroscience 85 1321-1328. 

Figure 2.8. Scheme of a chimeric peptide with examples for each of the distinct domains. 0X26, anti-rat transferrin receptor monoclonal antibody (mAh) 84-15, anti-human insulin receptor mAh cHSA, cationized human serum albumin VIP, vasoactive intestinal polypeptide DALDA, dermorphin analogue NGF, nerve growth factor BDNF, brain-derived neurotrophic factor PNA, peptide nucleic acid (3-gal, (3-galactosidase. 

Many cytokines play a regulatory role in processes other that immunity and inflammation. Neurotrophic factors such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) regulate growth, development and maintenance of various neural populations in the central and peripheral nervous system. Erythropoietin stimulates the production of red blood cells from erythroid precursors in the bone marrow. 

Yamada, K. et al. (2002). Role for brain derived neurotrophic factor in learning and memory. Life Sci. 70(7), 735-744. Yamada, M. et al. (1997). The neurotrophic action and signalling of epidermal growth factor. Progr. Neurobiol. 51(1), 19-37. 

The signaling mechanisms activated by neurotrophic factors, which include nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) are fundamentally different from those discussed for G protein-coupled receptors and Ca " (Russell and Duman 2002). The neurotrophic factors bind to specific receptors, TrkA, TrkB, and TrkC (the name Trk is derived from their identification as troponin/receptor kinases from colon carcinoma) (Fig. 2). The Trk receptors contain an extracellular binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. Two neurotrophic factor molecules are required for activation of a Trk receptor dimer, resulting in activation of the tyrosine kinase domains and phosphorylation of substrate proteins as well as autophosphorylation of the Trk receptor itself. 

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). 

---