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A new nerve growth factor-mimetic peptide active on neuropathic pain in rats.

ABSTRACT: 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.

SUBMITTER: Colangelo AM

PROVIDER: S-EPMC6670672 | biostudies-literature | 2008 Mar

REPOSITORIES: biostudies-literature

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A new nerve growth factor-mimetic peptide active on neuropathic pain in rats.

Colangelo Anna Maria AM 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

The Journal of neuroscience : the official journal of the Society for Neuroscience 20080301 11

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 ...[more]

PMID: 18337399

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Project description:Peripheral nerve injury alters the expression of hundreds of proteins in dorsal root ganglia (DRG). Targeting some of these proteins has led to successful treatments for acute pain, but not for sustained postoperative neuropathic pain. The latter may require targeting multiple proteins. Since a single microRNA (miR) can affect the expression of multiple proteins, here, we describe an approach to identify chronic neuropathic pain-relevant miRs. We used two variants of the spared nerve injury (SNI): Sural-SNI and Tibial-SNI and found distinct pain phenotypes between the two. Both models induced strong mechanical allodynia, but only Sural-SNI rats maintained strong mechanical and cold allodynia, as previously reported. In contrast, we found that Tibial-SNI rats recovered from mechanical allodynia and never developed cold allodynia. Since both models involve nerve injury, we increased the probability of identifying differentially regulated miRs that correlated with the quality and magnitude of neuropathic pain and decreased the probability of detecting miRs that are solely involved in neuronal regeneration. We found seven such miRs in L3-L5 DRG. The expression of these miRs increased in Tibial-SNI. These miRs displayed a lower level of expression in Sural-SNI, with four having levels lower than those in sham animals. Bioinformatics analysis of how these miRs could affect the expression of some ion channels supports the view that, following a peripheral nerve injury, the increase of the 7 miRs may contribute to the recovery from neuropathic pain while the decrease of four of them may contribute to the development of chronic neuropathic pain. The approach used resulted in the identification of a small number of potentially neuropathic pain relevant miRs. Additional studies are required to investigate whether manipulating the expression of the identified miRs in primary sensory neurons can prevent or ameliorate chronic neuropathic pain following peripheral nerve injuries. To identify the miRs that were differentially dysregulated between Tibial-SNI and Sural-SNI, we first performed 12 microarrays in a limited number of samples (in four individual DRGs per group: Sham, Tibial-SNI and Sural-SNI; two L3-DRG and two L4-DRG). Then, miRs identified as having differential expression were corroborated with real time qRT-PCR in RNA isolated from individual DRGs (L3, L4 and L5) derived from 4 rats per group (not presented here, but in the manuscript).

Project description:In the present study, the ability of baicalin to relieve neuropathic pain due to spinal nerve ligation in rats was explored, and the relationship between baicalin and ?2-adrenoceptors (?2-AR) was determined. The neuropathic pain model was established by ligating the L5-L6 spinal nerves in Sprague-Dawley rats. Several ?2-AR antagonists were injected into the intramedullary sheath to evaluate the role of baicalin in neuropathic pain. The antagonists included nonselective ?2-AR antagonist idazoxan, ?2a-AR antagonist BRL 44408, ?2b-AR antagonist ARC 239 and ?2c-AR antagonist JP 1302. The rats were divided into an untreated control group, saline group, baicalin group and baicalin + ?2-AR antagonist groups. Paw withdrawal threshold (PWT) was tested to assess the level of pain felt by the rats. The levels of ?2-AR mRNA were tested by reverse transcription-quantitative PCR. Inflammatory factors, including tumor necrosis factor (TNF)-?, interleukin (IL)-6, IL-17 and IL-1?, were analyzed by ELISA. The histopathological changes were assessed by hematoxylin and eosin staining. Flow cytometry was used to examine the percentage of CD4+ peripheral blood mononuclear cells (PBMCs). Compared with the saline group, the PWT value increased after treating with baicalin. However, intrathecal injection of ?2-AR antagonist reversed the antinociceptive effects of baicalin. Compared with the saline group, the expression of ?2a-AR and ?2c-AR mRNA was upregulated significantly in the baicalin group (P<0.05). Levels of ?2-AR mRNA were also decreased in the baicalin + idazoxan group compared with the baicalin group (P<0.05). The levels of TNF-?, IL-6, IL-17 and IL-1? were raised after treatment with baicalin. In addition, baicalin treatment ameliorated the histological damage in the spinal cord. The percentage of CD4+ PBMCs was increased in the saline group compared with the control group (P<0.05). Compared with the baicalin group, the percentage of CD4+ PBMCs was raised after treatment with the ?2-AR antagonists. In conclusion, intrathecal injection of baicalin produced an antiallodynic effect in a spinal nerve ligation-induced neuropathic pain model. The mechanism may be related to the regulation of a2-AR expression.

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A new nerve growth factor-mimetic peptide active on neuropathic pain in rats.

Publications

A new nerve growth factor-mimetic peptide active on neuropathic pain in rats.

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