Kynurenic Acid Inhibits the Electrical Stimulation Induced Elevated Pituitary Adenylate Cyclase-Activating Polypeptide Expression in the TNC.

Tamás Körtési,Zsuzsanna Helyes,Teréz Bagoly,Bernadett Tuka,László Vécsei,Ferenc Fülöp,János Tajti

doi:10.3389/fneur.2017.00745

Abstract

Migraine is a primary headache of imprecisely known mechanism, but activation of the trigeminovascular system (TS) appears to be essential during the attack. Intensive research has recently focused on pituitary adenylate cyclase-activating polypeptide (PACAP) and the kynurenine systems as potential pathogenic factors. We investigated the link between these important mediators and the effects of kynurenic acid (KYNA) and its synthetic analog (KYNA-a) on PACAP expression in the rat trigeminal nucleus caudalis (TNC) in a TS stimulation model related to migraine mechanisms. Adult male Sprague-Dawley rats were pretreated with KYNA, KYNA-a, the NMDA receptor antagonist MK-801, or saline (vehicle). Next, the trigeminal ganglion (TRG) was electrically stimulated, the animals were transcardially perfused following 180 min, and the TNC was removed. In the TNC samples, 38 amino acid form of PACAP (PACAP1-38)-like radioimmunoactivity was measured by radioimmunoassay, the relative optical density of preproPACAP was assessed by Western blot analysis, and PACAP1-38 mRNA was detected by real-time PCR. Electrical TRG stimulation resulted in significant increases of PACAP1-38-LI, preproPACAP, and PACAP1-38 mRNA in the TNC. These increases were prevented by the pretreatments with KYNA, KYNA-a, and MK-801. This is the first study to provide evidence for a direct link between PACAP and the kynurenine system during TS activation.

Highlights

Migraine is a neurovascular primary headache disorder with a complex genetic background [1, 2], the pathomechanism of which is still not fully understood
The real-time polymerase chain reaction (RT-PCR) was performed on a CFX 96 Real-Time System (Bio-Rad, USA) to detect changes in mRNA expression, using forward (5′-CCTACCGCAAAGTCTTGGAC-3′) and reverse (5′-TTGACAGCCATTTGTTTTCG-3′) primers designed for PACAP1–38
In patients suffering from migraines without aura, the development of PACAP1–38-evoked migraine-like attack was independent of the severity of family load [21]

Summary

Introduction

Migraine is a neurovascular primary headache disorder with a complex genetic background [1, 2], the pathomechanism of which is still not fully understood. Calcitonin gene-related peptide (CGRP) is one of the main regulators of the TS, and the recently identified pituitary adenylate cyclase-activating polypeptide (PACAP) plays key roles [3,4,5,6]. To CGRP [8], intravenous administration of the 38 amino acid form of PACAP (PACAP1–38) provoked headache and vasodilatation, both in healthy participants and migraine sufferers, whereas it delayed migraine-like attacks only in migraineurs [9,10,11]. Migraine is a primary headache of imprecisely known mechanism, but activation of the trigeminovascular system (TS) appears to be essential during the attack. Intensive research has recently focused on pituitary adenylate cyclase-activating polypeptide (PACAP) and the kynurenine systems as potential pathogenic factors. Aim: We investigated the link between these important mediators and the effects of kynurenic acid (KYNA) and its synthetic analog (KYNA-a) on PACAP expression in the rat trigeminal nucleus caudalis (TNC) in a TS stimulation model related to migraine mechanisms

Objectives

Methods

Results

Conclusion