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The Journal of Neuroscience, March 12, 2008, 28(11):2698-2709; doi:10.1523/JNEUROSCI.5201-07.2008

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Neurobiology of Disease
A New Nerve Growth Factor-Mimetic Peptide Active on Neuropathic Pain in Rats

Anna Maria Colangelo,^1 * Maria Rosaria Bianco,^2 * Luigi Vitagliano,^3 * Carlo Cavaliere,² Giovanni Cirillo,² Luca De Gioia,¹ Donatella Diana,³ Daniele Colombo,¹ Cristina Redaelli,¹ Laura Zaccaro,³ Giancarlo Morelli,³ Michele Papa,² Paolo Sarmientos,⁴ Lilia Alberghina,¹ and Enzo Martegani¹

¹Laboratorio di Neuroscienze "R. Levi-Montalcini" and Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, 20126 Milan, Italy, ²Laboratorio di Morfologia delle Reti Neuronali, Dipartimento di Medicina Pubblica Clinica e Preventiva, Seconda Università di Napoli, 80138 Naples, Italy, ³Centro Interuniversitario di Ricerca sui Peptidi Bioattivi and Dipartimento delle Scienze Biologiche, Università di Napoli "Federico II" and Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche, 80138 Naples, Italy, and ⁴Primm srl, 20132 Milan, Italy

Correspondence should be addressed to either of the following: Enzo Martegani, Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy, Email: enzo.martegani{at}unimib.it; or Paolo Sarmientos, Primm srl, Via Olgettina 58, 20132 Milan, Italy, Email: paolo.sarmientos{at}primm.it

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 µM. 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.

Key words: NGF; bioactive peptides; NMR structure; neuropathic pain; gliosis; TrkA

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Received June 6, 2007; revised Jan. 8, 2008; accepted Jan. 8, 2008.

Correspondence should be addressed to either of the following: Enzo Martegani, Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy, Email: enzo.martegani{at}unimib.it; or Paolo Sarmientos, Primm srl, Via Olgettina 58, 20132 Milan, Italy, Email: paolo.sarmientos{at}primm.it

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