Exploring the Etiological Links behind Neurodegenerative Diseases: Inflammatory Cytokines and Bioactive Kynurenines

Abstract

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.

Single Nucleotide Polymorphisms of Indoleamine 2,3-Dioxygenase 1 Influenced the Age Onset of Parkinson’s Disease

“…The etiology of PD remains poorly understood. Besides genetic disposition, pathological findings are abnormal protein aggregation, elevated oxidative stress, mitochondrial dysfunction, increased glutamate excitotoxicity, alteration of immune response, disturbance of kynurenine pathway (KP) of tryptophan (TRP) metabolism, and among others [5][6][7][8][9][10]. Altered levels of and ratios of kynurenine (KYN) metabolites have been observed in neurologic and psychiatric diseases [3,[11][12][13][14][15][16].…”

“…KYNA has antioxidant properties that scavenges ROS to suppress overshooting inflammation in damaging tissues. Reduced concentrations of KYNA may contribute to tissue damage and inflammatory cell proliferation neurodegenerative diseases [3,10,25,26]. In addition,…”

“…The indoleamine 2,3-dioxygenase IDO1 is one of the first rate-limiting enzymes that converts L-TRP to N-formyl KYN in TRP metabolism, which play a crucial role in governing concentrations of downward bioactive KYN metabolites ( Figure 1) [10]. Activation of IDO1 and the KYN system promotes immunosuppressive effects by inhibition of Natural Killer cells, inhibition of T cell functions, and activation of the regulatory T cells [28].…”

Monitoring the Redox Status in Multiple Sclerosis

“…Years lived with disability begin to increase steeply early in the second decade of life and disability-adjusted life years peak in the sixth decade of life [ 1 ]. MS encompasses a wide range of symptoms from motor and autonomic dysfunctions to psychobehavioral disturbances, including gait difficulties, paresthesia, spasticity, vision problems, dizziness and vertigo, incontinence, constipation, sexual disturbances, pain, cognitive and emotional changes, anxiety, and depression [ 2 , 3 , 4 , 5 ]. Increased risk of depression and painful conditions in chronic illnesses are likely to be mediated by the kynurenine pathway of tryptophan metabolism [ 6 , 7 ].…”

“…As in other neurodegenerative diseases, MS is a clinically classified disease of CNS in which multifactorial factors, including genetic, environmental, socioeconomic, cultural, personal lifestyle, and aging play an initial role to form a causative complex, eventually converging into similar pathognomonic clinical pictures [ 4 ]. Inflammatory and demyelinating attacks are unique manifestations in MS, but different pathomechanisms govern the distinguished clinical courses in each subtype of MS.…”