A new nerve growth factor-mimetic peptide active on neuropathic pain in rats.
Analysis of the structure of nerve growth factor (NGF)-tyrosine kinase receptor A (TrkA) complex, site-directed mutagenesis studies and results from chemical modification of amino acid residues have identified loop 1, loop 4, and the N-terminal region of the NGF molecule as the most relevant for its biological activity. We synthesized several peptides mimicking the two loops (1 and 4) linked together with an appropriate spacer, with or without the N-terminal region. Two peptides named NL1L4 and L1L4 demonstrated good NGF agonist activity at a concentration as low as 3 mum. They induced differentiation of chick dorsal root ganglia and stimulated tyrosine phosphorylation of TrkA, but not TrkB, receptor. In addition L1L4 was able to induce differentiation of PC12 cells. More interestingly, the peptide with the highest "in vitro" activity (L1L4) was shown to reduce neuropathic behavior and restore neuronal function in a rat model of peripheral neuropathic pain, thereby suggesting a potential therapeutic role for this NGF-mimetic peptide.
Colangelo
Anna Maria
AM
Laboratorio di Neuroscienze "R. Levi-Montalcini" and Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, 20126 Milan, Italy.
Bianco
Maria Rosaria
MR
Vitagliano
Luigi
L
Cavaliere
Carlo
C
Cirillo
Giovanni
G
De Gioia
Luca
L
Diana
Donatella
D
Colombo
Daniele
D
Redaelli
Cristina
C
Zaccaro
Laura
L
Morelli
Giancarlo
G
Papa
Michele
M
Sarmientos
Paolo
P
Alberghina
Lilia
L
Martegani
Enzo
E
D000818:Animals; D040761:Biomimetic Materials / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D002642:Chick Embryo; D006801:Humans; D008297:Male; D051379:Mice; D020932:Nerve Growth Factor / Q000819:agonists / Q000494:pharmacology / Q000627:therapeutic use*; D016716:PC12 Cells; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000188:drug therapy / Q000378:metabolism
D010455:Peptides; D020932:Nerve Growth Factor