Dataset Information

A novel CGRP-neutralizing Spiegelmer attenuates neurogenic plasma protein extravasation.

ABSTRACT:

Background and purpose

Calcitonin gene-related peptide (CGRP) plays an important role in the pathology of migraine, and recent clinical trials suggest the inhibition of CGRP-mediated processes as a new therapeutic option in migraine. In this study, we describe the generation of NOX-L41, a CGRP-neutralizing mirror-image (L-)aptamer (Spiegelmer) and investigate its in vitro and in vivo function.

Experimental approach

A CGRP-binding Spiegelmer was identified by in vitro selection. Binding studies were performed using surface plasmon resonance (SPR), and the inhibitory activity was determined in cell-based assays. The pharmacokinetic profile comparing i.v. and s.c. dosing was analysed in rats. Intravital two-photon microscopy was employed to follow extravasation from meningeal vessels. Finally, in vivo efficacy was tested in a model of electrically evoked meningeal plasma protein extravasation (PPE) in rats.

Key results

We identified NOX-L41, a novel CGRP-neutralizing Spiegelmer. SPR studies showed that NOX-L41 binds to human and rat/mouse CGRP with sub-nanomolar affinities and is highly selective against related peptides such as amylin. In vitro, NOX-L41 effectively inhibited CGRP-induced cAMP formation in SK-N-MC cells. In rats, NOX-L41 had a plasma half-life of 8 h. Pharmacodynamic studies showed that NOX-L41 extravasates from blood vessels in the dura mater and inhibits neurogenic meningeal PPE for at least 18 h after single dosing.

Conclusions and implications

This is the first description of the CGRP-neutralizing Spiegelmer NOX-L41. Preclinical studies confirmed a role for CGRP in neurogenic PPE and provided proof-of-concept for the potential use of this new drug candidate for the treatment or prevention of migraine.

SUBMITTER: Hoehlig K

PROVIDER: S-EPMC4459025 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Publications

A novel CGRP-neutralizing Spiegelmer attenuates neurogenic plasma protein extravasation.

Hoehlig K K Johnson K W KW Pryazhnikov E E Maasch C C Clemens-Smith A A Purschke W G WG Vauléon S S Buchner K K Jarosch F F Khiroug L L Vater A A Klussmann S S

British journal of pharmacology 20150327 12

<h4>Background and purpose</h4>Calcitonin gene-related peptide (CGRP) plays an important role in the pathology of migraine, and recent clinical trials suggest the inhibition of CGRP-mediated processes as a new therapeutic option in migraine. In this study, we describe the generation of NOX-L41, a CGRP-neutralizing mirror-image (L-)aptamer (Spiegelmer) and investigate its in vitro and in vivo function.<h4>Experimental approach</h4>A CGRP-binding Spiegelmer was identified by in vitro selection. Bi ...[more]

PMID: 25659966

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Dataset Information

A novel CGRP-neutralizing Spiegelmer attenuates neurogenic plasma protein extravasation.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

A novel CGRP-neutralizing Spiegelmer attenuates neurogenic plasma protein extravasation.

Similar Datasets

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