The Involvement of Neuroinflammation and Kynurenine Pathway in Parkinson's Disease

Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder characterised by loss of dopaminergic neurons and localized neuroinflammation occurring in the midbrain several years before the actual onset of symptoms. Activated microglia themselves release a large number of inflammatory mediators thus perpetuating neuroinflammation and neurotoxicity. The Kynurenine pathway (KP), the main catabolic pathway for tryptophan, is one of the major regulators of the immune response and may also be implicated in the inflammatory response in parkinsonism. The KP generates several neuroactive compounds and therefore has either a neurotoxic or neuroprotective effect. Several of these molecules produced by microglia can activate the N-methyl-D-aspartate (NMDA) receptor-signalling pathway, leading to an excitotoxic response. Previous studies have shown that NMDA antagonists can ease symptoms and exert a neuroprotective effect in PD both in vivo and in vitro. There are to date several lines of evidence linking some of the KP intermediates and the neuropathogenesis of PD. Moreover, it is likely that pharmacological modulation of the KP will represent a new therapeutic strategy for PD.

Central kynurenine pathway shift with age in women

“…Quinolinic acid is neurotoxic in a variety of ways including induction of tau phosphorylation, oxidative stress and excitotoxicity (Guillemin 2012;P erez-De La Cruz et al 2012). It has already been suggested that the kynurenine pathway is part of the underlying causative mechanism of Alzheimer's disease Guillemin et al 2005) and Parkinson's disease (Zinger et al 2011). The parallel trajectories of increased neurodegenerative disease risk with age and elevated inflammation-driven kynurenine pathway, skewed towards the production of quinolinic acid, is consistent with a causal relationship.…”

“…Kynurenine pathway metabolism (Fig. 1) is the major pathway for tryptophan (TRYP) metabolism and is known to be altered in a number of neurodegenerative disorders, including amyotrophic lateral sclerosis (Chen and Guillemin 2009), Parkinson's disease (Zinger et al 2011) and Alzheimer's disease .…”

Physical activity and exercise attenuate neuroinflammation in neurological diseases

“…Although the effects of kynurenine, a neurotoxic Glu agonist, have been studied extensively in MDD, additional research has demonstrated that an imbalance of the kynurenine pathway is also common to SCH, AD and PD (Gong et al, 2011;Kegel et al, 2014;Zinger et al, 2011). Therefore it is reasonable to hypothesize that following PA enhanced skeletal muscle-mediated conversion of the neurotoxin kynurenine, which is capable of crossing the BBB, to kynurenic acid, a compound which does not readily cross the BBB (Olah et al, 2013), could be beneficial in regulating diseases other than MDD.…”

Study of the Activity and Possible Mechanism of Action of a Reversible Inhibitor of Recombinant Human KAT-2: A Promising Lead in Neurodegenerative and Cognitive Disorders

“…Developing KAT isozymes inhibitors is the main strategy to decrease levels of KYNA in the brain, which is beneficial in managing and treating psychiatric disorders [15]. Among the four KATs, KAT2 is the main isozyme responsible (>70%) for KYNA production in the human brain [16], and therefore the inhibition of KAT2 has become the The α-amino group of the external aldimine bond from the previous step is transferred to the PLP, and of the production of KYNA simultaneously allows the formation of pyridoxamine phosphate (PMP); (IV) The regeneration of PLP from PMP is accomplished by converting the co-substrate, α-ketoglutarate, to glutamate by transferring the amino-group of PMP to the α-ketoglutarate, and consequently the PLP-form of the enzyme (I) is regenerated.…”

“…Developing KAT isozymes inhibitors is the main strategy to decrease levels of KYNA in the brain, which is beneficial in managing and treating psychiatric disorders [15]. Among the four KATs, KAT2 is the main isozyme responsible (>70%) for KYNA production in the human brain [16], and therefore the inhibition of KAT2 has become the target of investigations. (S)-4-(Ethyl sulfonyl)benzoylalanine ((S)-ESBA) is the first known reversible KAT2 inhibitor with a reported IC 50 at around 1 to 2 mM [17].…”