The involvement of kynurenine pathway in neuroinflammation and neurodegeneration: new insight for therapeutic
thesisposted on 28.03.2022, 09:38 by Gloria Castellano González
Mitochondrial dysfunction, glutamate excitotoxicity and neuroinflammation are involved in the pathogenesis of numerous neurological disorders. It has been shown that these deleterious aspects are interconnected and induced through an imbalance in the Kynurenine pathway (KP) metabolism. The KP is the main catabolic route of tryptophan (TRP) that ultimately leads to nicotinamide adenine dinucleotide (NAD+). The KP is activated under inflammatory conditions, which leads to an increase in the KP metabolite, L-‐kynurenine (KYN), in the periphery and central nervous system (CNS). KYN is essential in regulating acute inflammatory responses, by mediating tolerance. However, in the brain, increased levels of KYN can potentially lead to neurotoxic KYN metabolites, predominantly through Kynurenine-‐3-‐monooxigenase (KMO) driven degradation. Therefore, the initial acute anti-‐inflammatory response of KP activation may thereafter contribute to neurodegeneration. Evidence is lacking on how KYN could regulate neuroinflammation in the CNS and why the KP shifts frombeing a protective response from the organism to exacerbate the CNS pathology. The work presented in this thesis demonstrates that increased levels of L-kynurenine (KYN) regulate astrocytic responses to inflammation. Furthermore, abnormalities in kynurenine pathway (KP) metabolite levels can promote neuroinflammatory responses. We also showed that one of the causes of kynurenine-3-monoxygenase (KMO) driven KP dysregulation is mitochondrial dysfunction and that by increasing mitochondrial complex IV activity we could potentially drive KYN degradation through the kynurenine amino transferase (KAT) branch, which promotes the synthesis of neuroprotective metabolites. In conclusion, neurological disorders involving neuroinflammation and mitochondrial impairment, will favour the KMO branch of the KP. This may subsequently lead to the long-‐term effect of KP imbalance, driving the KP towards the neurotoxic metabolites, exacerbating oxidative stress glutamate excitotoxicity and neuroinflammation. Therefore, limiting KMO activity, either with pharmacological inhibitors or by restoring the metabolic balance, could moderate the KP-mediated neurotoxicity, being a potential treatment for neurodegenerative diseases.