Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases (NDs), presenting a broad range of symptoms from motor dysfunctions to psychobehavioral manifestations. A common clinical course is the proteinopathy-induced neural dysfunction leading to anatomically corresponding neuropathies. However, current diagnostic criteria based on pathology and symptomatology are of little value for the sake of disease prevention and drug development. Overviewing the pathomechanism of NDs, this review incorporates systematic reviews on inflammatory cytokines and tryptophan metabolites kynurenines (KYNs) of human samples, to present an inferential method to explore potential links behind NDs. The results revealed increases of pro-inflammatory cytokines and neurotoxic KYNs in NDs, increases of anti-inflammatory cytokines in AD, PD, Huntington’s disease (HD), Creutzfeldt–Jakob disease, and human immunodeficiency virus (HIV)-associated neurocognitive disorders, and decreases of neuromodulatory KYNs in AD, PD, and HD. The results reinforced a strong link between inflammation and neurotoxic KYNs, confirmed activation of adaptive immune response, and suggested a possible role in the decrease of neuromodulatory KYNs, all of which may contribute to the development of chronic low grade inflammation. Commonalities of multifactorial NDs were discussed to present a current limit of diagnostic criteria, a need for preclinical biomarkers, and an approach to search the initiation factors of NDs.

Kynurenines are the products of tryptophan metabolism. Among them, kynurenine and kynurenic acid are generally thought to have neuroprotective properties, while 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid are considered neurotoxic. They participate in immunoregulation and inflammation and possess pro- or anti-excitotoxic properties, and their involvement in oxidative stress has also been suggested. Consequently, it is not surprising that kynurenines have been closely related to neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis and multiple sclerosis. More information about the less-known metabolites, picolinic and cinnabarinic acid, evaluation of new receptorial targets, such as aryl-hydrocarbon receptors, and intensive research on the field of the immunomodulatory function of kynurenines delineated the high importance of this pathway in general homeostasis. Emerging knowledge about the kynurenine pathway provides new target points for the development of therapeutical solutions against neurodegenerative diseases.

The trigeminal ganglion (TG) plays a central role in cranial pain. Administration of complete Freund’s adjuvant (CFA) into the temporomandibular joint (TMJ) elicits activation of TG. Kynurenic acid (KYNA) is an endogenous excitatory amino acid receptor blocker, which may have an anti-inflammatory effect. We hypothesize that KYNA may reduce CFA-induced activation within the TG. A local inflammation was induced by administration of CFA into the TMJ in rats. KYNA and kynurenic acid amide 2 (KYNAA2) were intraperitoneally administered. We investigated changes of mitogen-activated protein kinases (MAPKs as ERK1/2, p38 and SAPK/JNK), NF-κB, CaMKII and DREAM, in addition to calcitonin gene-related peptide (CGRP) and its receptor components calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) in the TG, with immunohistochemistry and Western blot at 2 and 10 days post-CFA injection. We showed CFA-induces increases in pERK1/2, pp38, CaMKII, NF-κB and DREAM immunohistochemistry after 2 and 10 days. KYNAA2 displayed stronger effects on MAPKs than KYNA. Increased expression of CaMKII, NF-κB and DREAM were found in the neurons. Western blot showed significantly increase in pERK expression at 10 days post-CFA, which decreased after 10 days of KYNA treatment. Two days post-CFA, a significantly increase in pp38 expression was found, which decreased after 2 days of KYNA and KYNAA2 treatment. The CFA-induced inflammatory model for the TG activation provided a time-related expression of MAPK (pERK1/2, pp38) and NF-κB. It involves both the neuronal and glial activation, which points to possible neuron-glia interactions during this process. The administration of the endogenous NMDA-receptor antagonists, KYNA and its derivative KYNAA2, resulted in the inhibition of the induced signaling system of the TG, which further points the importance of the glutamate receptors in this mechanism.