Therapeutic potential of the neurotrophins and neurotrophin-CNTF combinations in peripheral neuropathies and motor neuron diseases.

Although they are clearly critical in ontogeny, a broader role is emerging for neurotrophic factors in the maintenance and regeneration of the mature nervous system. This is due to recent success in the molecular characterization of a significant number of novel neurotrophic factors, including the neurotrophin family members brain-derived neurotrophic factor (BDNF), neurotrophin (NT)-3 and NT-4/5, and ciliary neurotrophic factor (CNTF). Availability of these factors, elucidation of their receptor structure and creation of mutant mice lacking in expression of these factors has rapidly led to an understanding of their mechanisms of action and neuronal specificity. Thus, in addition to classical target-derived roles it now appears that, in the adult, neurotrophic factors may also function in autocrine/paracrine modes to maintain neuronal survival, regulate phenotype and orchestrate regenerative sprouting. Furthermore, two or more neurotrophic factors may act synergistically in these functions. This chapter reviews recent studies on: (a) the specificity of NT-3 for proprioceptive sensory neurons in vitro, and the ability of NT-3 to attenuate deficits arising from large-fibre sensory neuropathy; and (b) synergistic actions of BDNF and CNTF towards motor neurons in vitro and the ability of BDNF-CNTF co-treatment to arrest motor neuron disease in the Wobbler mutant mouse. The clinical potential of NT-3 in peripheral neuropathies and of BDNF-CNTF co-treatment in motor neuron disease is highlighted.