NEUROTROPHINS AND THEIR RECEPTORS IN NERVE INJURY AND REPAIR

• Published in: Neurochemistry international 1997-04, Vol.30 (4), p.347-374
• Main Authors: EBADI, M, BASHIR, R.M, HEIDRICK, M.L, HAMADA, F.M, EL REFAEY, E, HAMED, A, HELAL, G, BAXI, M.D, CERUTIS, D.R, LASSI, N.K
• Format: Article
• Language: English
• Subjects: Animals; Cytokines - physiology; Humans; Models, Molecular; Nerve Growth Factors - physiology; Nervous System Physiological Phenomena; Receptors, Nerve Growth Factor - physiology; Trauma, Nervous System; Wound Healing - physiology
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/S0197-0186(96)00071-X

Cytokines are a heterogenous group of polypeptide mediators that have been associated with activation of numerous functions, including the immune system and inflammatory responses. The cytokine families include, but are not limited to, interleukins (IL-Iα, IL-Iβ, ILIra and IL-2-IL-15), chemokines (IL-8/NAP-I, NAP-2, MIP-Iα and β, MCAF/MCP-I, MGSA and RANTES), tumor necrosis factors (TNF-α and TNF-β), interferons (INF-α, β and γ), colony stimulating factors (G-CSF, M-CSF, GM-CSF, IL-3 and some of the other ILs), growth factors (EGF, FGF, PDGF, TGFα, TGFβ and ECGF), neuropoietins (LIF, CNTF, OM and IL-6), and neurotrophins (BDNF, NGF, NT-3-NT-6 and GDNF). The neurotrophins represent a family of survival and differentiation factors that exert profound effects in the central and peripheral nervous system (PNS). The 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 such as ciliary neurotrophic factor (CNTF) or fibroblast growth factor (FGF). Responsiveness of neurons to a given neurotrophin is governed by the expression of two classes of cell surface receptor. For nerve growth factor (NGF), these are p75 NTR (p75) and p140 trk (referred to as trk or trkA), which binds both BDNF and neurotrophin (NT)- 4 5 , and trkC receptor, which binds only NT-3. After binding ligand, the neurotrophin-receptor complex is internalized retrogradely transported in the axon to the soma. Both receptors undergo ligand-induced dimerization, which activates multiple signal transduction pathways. These include the ras-dependent pathway utilized by trk to mediate neurotrophin effects such as survival and differentiation. Indeed, cellular diversity in the nervous system evolves from the concerted processes of cell proliferation, differentiation, migration, survival, and synapse formation. Neural adhesion and extracellular matrix molecules have been shown to play crucial roles in axonal migration, guidance, and growth cone targeting. Proinflammatory cytokines, released by activated macrophages and monocytes during infection, can act on neural targets that control thermogenesis, behavior, and mood. In addition to induction of fever, cytokines induce other biological functions associated with the acute phase response, including hypophagia and sleep. Cytokine production has been detected within the central nervous system as a result of brain i