Kynurenines and PACAP in Migraine: Medicinal Chemistry and Pathogenetic Aspects

et al. 2019

CMC

Section: Pituitary Adenylate Cyclase-activating Polypeptide (Pacap)mentioning

confidence: 99%

“…Tryptophan, one of the essential amino acids, is the precursor of 5-HT and L-kynurenine under physiological conditions. The kynurenine pathway has been previously presented in details [128,144]. Briefly, it is a complex metabolic pathway with a lot of neuroactive products ending with NAD + [145].…”

Section: Kynurenic Acid (Kyna)mentioning

confidence: 99%

The Therapeutic Impact of New Migraine Discoveries

Vécsei

Lukács

et al. 2019

CMC

“…Based on these observations, early-phase RCTs are currently running to evaluate the efficacy and safety of mAbs targeting PAC1-receptor or PACAP1-38 [158]. Recent preclinical and clinical studies have revealed a new possible aspect of migraine management by influencing the kynurenine pathway [159][160][161][162][163]. Experimental studies with electrically activated trigeminovascular system pointed to a direct link between PACAP and the kynurenine pathway in rats [164].…”

Section: Five-year Viewmentioning

confidence: 99%

Therapeutic strategies that act on the peripheral nervous system in primary headache disorders

Expert Review of Neurotherapeutics

Delia

Nyári

et al. 2019

Introduction: Acute and preventive treatment of primary headache disorders is not completely resolved with regard to efficacy, safety, and tolerability. Hence, peripheral and central neuromodulation can provide therapeutic alternatives in drug-resistant cases. Peripheral targets of neuromodulation include invasive and non-invasive neurostimulation and electrical and chemical nerve and ganglion blockades. Areas covered: A PubMed search of papers published from January 2012 to October 2018 was conducted. The goal of this review was to analyze the efficacy and safety of invasive (implantable) peripheral neurostimulation methods (the occipital nerve, the cervical branch of vagal nerve, the sphenopalatine ganglion) and non-invasive (transcutaneous) peripheral neurostimulation methods (the occipital nerve, the supraorbital nerve, and the cervical and auricular branches of the vagal nerve), based on the results of published clinical trials and case series. Acting also on the peripheral nervous system, peripheral nerve (i.e. greater occipital nerve) and ganglion (i.e. sphenopalatine ganglion) blockades, botulinum neurotoxin type A-hemagglutinin complex therapies, and calcitonin generelated peptide-related monoclonal antibody treatments in this patient population are also discussed. Expert opinion: This review summarizes the latest results on the therapeutic strategies acting on the periphery in primary headache disorders. These therapeutic options are minimally invasive or noninvasive, efficacious, safe, and well tolerated. ARTICLE HISTORY

“…Elevated levels pf PACAP1-38 were found in the ictal phase compared to the interictal phase in migraine patients [109], and the intravenous administration of PACAP1-38 caused delayed migraine-like headache [110]. Although PACAP1-38 seems to play a crucial role in migraine, some aspects of the nociceptive effects of PACAP1-38 in migraine pathophysiology are still unsettled [111,112]. PACAP1-38 causes mast cell degranulation in the dura mater leading to the activation of peripheral trigeminal nerve fibers [113,114].…”

Section: Pituitary Adenylate Cyclase-activating Peptidementioning

confidence: 99%

Migraine, Neurogenic Inflammation, Drug Development - Pharmacochemical Aspects

Lukács

Fülöp

et al. 2017

CMC

Self Cite

Abstract:Background: Migraine is a primary headache disorder. Despite numerous studies conducted with the aim to understand the pathophysiology of migraine, several aspects are still unclear. The trigeminovascular system plays a key role. Neurogenic inflammation is presumed to be an important factor in migraine pathophysiology, mediated by the activation of primary neurons, leading to the release of various pro-inflammatory neuropeptides and neurotransmitters such as Calcitonin Gene-Related Peptide (CGRP), substance P (SP), and vasoactive intestinal peptide (VIP). Nitric oxide (NO), Pituitary adenylate cyclase-activating polypeptide (PACAP) and Glutamate (Glu) also play an important role in the modulation of inflammatory mechanisms. Objective: To review the literature focusing on novel therapeutic targets in migraine, related to neurogenic inflammation. Method: A systematic literature search in the database of PUBMED was conducted regarding therapeutic strategies in migraine, focusing on substances and cytokines released during neurogenic inflammation, published in January 2017. Results: Ongoing phase III clinical studies with monoclonal antibodies against CGRP and CGRP receptors offer promising novel aspects for migraine treatment. Preclinical and clinical studies targeting SP and nitric oxide synthase (NOS) were all terminated with no significant result compared to placebo. New promising therapeutic goal could be PACAP and its receptor (PAC 1 ), and kynurenic acid (KYNA) analogues. Conclusion: Current migraine treatment offers pain relief only for a small proportion of migraine patients and might not be adequate for patients with cardiovascular comorbidity due to side effects. Better understanding of migraine pathophysiology might, therefore, lead to novel therapeutic lines both in migraine attack treatment and prophylaxis.