Nerve growth factor synthesis and its regulatory mechanisms: an approach to therapeutic induction of nerve growth factor synthesis.

Nerve growth factor (NGF) is a protein necessary for the differentiation and maintenance of peripheral sympathetic neurons, certain sensory neurons, and cholinergic neurons of the basal forebrain. NGF is synthesized in target areas of NGF-responsive neurons. This protein binds to specific cell surface receptors on the nerve terminals and is retrogradely transported to the cell bodies of the neurons, during which various physiological functions are expressed. In spite of its physiological importance, the regulatory mechanisms of NGF synthesis are unknown. We approached this problem from an in vitro cellular aspect and in turn applied the knowledge obtained to in vivo studies on the regulation of NGF synthesis. Nonneuronal cells, such as astroglial cells, fibroblast cells, and Schwann cells, synthesize and secrete NGF in cultures. NGF synthesis by these cells is growth dependent, suggesting that the expression of some genes relevant to cell growth is associated with upregulation of NGF synthesis. To elucidate neuronal influences, we tested various neurotransmitters and found that catecholamines and their analogues have stimulatory effects on NGF synthesis of nonneuronal cells. From the results of a structure-activity relationship, alkylcatechol compounds with an alkyl group at position 4 of the catechol ring show a potent stimulatory activity in vitro. Evidence that NGF has a potent protective activity on neuronal degeneration both in the central nervous system (CNS) and peripheral nervous system (PNS) is accumulating. NGF is a macromolecule that cannot pass through the blood-brain barrier, suggesting a limited availability of this protein for therapeutic use in diseases with neuronal degeneration in the CNS. We considered that compounds with a low molecular weight that elicit stimulatory activity on NGF synthesis are much more useful and practical for therapeutic purposes. Therefore, we investigated alkylcatechol compounds and their diacetyl derivatives, and found them to be able to induce NGF synthesis in the rat PNS in vivo. This is the first step in developing an agent capable of inducing NGF synthesis for therapeutic use in the future. The physiological and/or therapeutic significance of NGF induction is discussed.