4-((3-(1-6-dihyro-6-oxo-9h-purin-9-yl)-1-oxopropyl)amino)benzoic-acid and Peripheral-Nervous-System-Diseases

We report peripheral actions in rats of Neotrofin, a purine derivative of therapeutic interest. Systemic injections mimicked NGF in eliciting sprouting of nociceptive nerves without affecting their regeneration. The sprouting was prevented by anti-NGF treatment, implicating endogenous NGF. We detected no Neotrofin-induced increases in cutaneous NGF levels or in retrograde NGF transport. In contrast, both NGF and phosphorylation of trkA increased significantly in DRGs, with a marginal appearance of phosphorylated trkA in axons. We conclude that the DRG effects of Neotrofin are responsible for its induction of sprouting. Neotrofin also induced a striking phosphorylation of axonal erk 1 and 2, which was, however, unaffected by anti-NGF treatment. We suggest that this NGF-independent MAP kinase activation is involved in nonsprouting functions of Neotrofin such as neuroprotection. Unlike injected NGF, Neotrofin did not induce hyperalgesia, supporting its candidacy as a treatment for peripheral neuropathies like those induced by diabetes and anticancer chemotherapy.

Topics: Aminobenzoates; Animals; Antibodies; Binding Sites; Female; Ganglia, Spinal; Glycoproteins; Hyperalgesia; Hypoxanthine; Hypoxanthines; Lectins; Mitogen-Activated Protein Kinases; Nerve Growth Factor; Nerve Regeneration; Neuronal Plasticity; Neurons, Afferent; Nociceptors; Peripheral Nerves; Peripheral Nervous System Diseases; Phosphorylation; Purines; Rats; Rats, Wistar; Receptor, trkA; Reflex