KYNA analogue SZR72 modifies CFA-induced dural inflammation- regarding expression of pERK1/2 and IL-1β in the rat trigeminal ganglion

Abstract

BackgroundNeurogenic inflammation has for decades been considered an important part of migraine pathophysiology. In the present study, we asked the question if administration of a novel kynurenic acid analogue (SZR72), precursor of an excitotoxin antagonist and anti-inflammatory substance, can modify the neurogenic inflammatory response in the trigeminal ganglion.MethodsInflammation in the trigeminal ganglion was induced by local dural application of Complete Freunds Adjuvant (CFA). Levels of phosphorylated MAP kinase pERK1/2 and IL-1β expression in V1 region of the trigeminal ganglion were investigated using immunohistochemistry and Western blot.FindingsPretreatment with one dose of SZR72 abolished the CFA-induced pERK1/2 and IL-1β activation in the trigeminal ganglion. No significant change was noted in case of repeated treatment with SZR72 as compared to a single dose.ConclusionsThis is the first study that demonstrates that one dose of KYNA analog before application of CFA can give anti-inflammatory response in a model of trigeminal activation, opening a new line for further investigations regarding possible effects of KYNA derivates.

Topical dura mater application of CFA induces enhanced expression of c-fos and glutamate in rat trigeminal nucleus caudalis: attenuated by KYNA derivate (SZR72)

“…The synthesis procedure has previously been presented [15, 17]. The KYNA analogue (SZR72, N-(2-N,N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride) has the following structural properties: the presence of a water-soluble side-chain, the inclusion of a new cationic centre, and side-chain substitution in order to enhance brain penetration [17]. …”

“…The operation has been described in details earlier [16, 17]. Briefly, animals were deeply anesthetized and a handheld drill was used to remove a 3x3 mm large portion of the parietal bone, cooled by saline irrigation to avoid local healing.…”

“…We have recently developed an animal model for long-term trigeminovascular activation following application of Complete Freund’s Adjuvant (CFA) onto the surface of the dura mater [16]. We found activation of satellite glial cells and neurons of the trigeminal ganglion (IL-1, pERK1/2) that were abolished by the KYNA-analogue, SZR72 [17] possibly acting on peripheral and central gluatamate receptors (30). The present study was designed to examine whether dural application of CFA can cause activation of the central part of the trigeminalvascular system,: the TNC and C 1 -C 2 regions of the spinal cord.…”

The Therapeutic Impact of New Migraine Discoveries

“…One possibility could be the use of a prodrug such as L-kynurenine or its derivates [153][154][155]; whereas shifting the pathway towards the production of KYNA with different enzyme inhibitors would represent another possible therapeutic strategy [156][157]. During the last years, our research group has synthesized several different KYNA derivates that have proven to be effective in animal models of cerebral ischemia [158], Huntington's disease [159], epilepsy [160], and rat models of trigeminovascular activation [68,[161][162]. The chemical structures of these KYNA analogues have been previously presented.…”

Migraine, Neurogenic Inflammation, Drug Development - Pharmacochemical Aspects

“…This effect was mitigated by a novel KYNA derivate [142]. In another experimental model, CFA was injected into the temporomandibular joint of rat, inducing inflammation in the TG, which was subsequently mitigated by KYNA and KYNA derivate [143].…”