Neotrofin, a novel purine that induces NGF-dependent nociceptive nerve sprouting but not hyperalgesia in adult rat skin.
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.
Holmes
Michael
M
Department of Psychiatry and Behavioural Neurosciences, McMaster University Medical Center, Hamilton, Ontario, Canada L8N 3Z5.
Maysinger
Dusica
D
Foerster
Anne
A
Pertens
Evi
E
Barlas
Cia
C
Diamond
Jack
J
D062365:Aminobenzoates / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006023:Glycoproteins; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D019271:Hypoxanthine / Q000494:pharmacology* / Q000627:therapeutic use; D007042:Hypoxanthines; D037102:Lectins / Q000378:metabolism / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009416:Nerve Regeneration / Q000187:drug effects* / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D009619:Nociceptors / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010525:Peripheral Nerves / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D020917:Receptor, trkA / Q000187:drug effects / Q000378:metabolism; D012018:Reflex / Q000187:drug effects / Q000502:physiology
D062365:Aminobenzoates; D000906:Antibodies; D006023:Glycoproteins; D007042:Hypoxanthines; D037102:Lectins; D011687:Purines; C473590:isolectin B4-binding glycoprotein, mouse; C086241:4-((3-(1,6-dihyro-6-oxo-9H-purin-9-yl)-1-oxopropyl)amino)benzoic acid; D019271:Hypoxanthine; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D020928:Mitogen-Activated Protein Kinases