datadragon
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quinolinic acid, a metabolite of kynurenine is an endogenous excitotoxin that could cause selective loss of orexin neurons as compared to MCH neurons by activating glutamate NMDA receptors. In addition, quinolinic acid-induced decrease of orexin neurons was prevented by an inhibitor of poly(ADP-ribose) polymerases. These results provide the first evidence concerning cytotoxic consequences onto orexin neurons, and indicate that NMDA receptor-mediated injury may contribute to the selective loss of these neurons in the hypothalamus, a prominent neuropathological feature found in narcolepsy patients. https://pubmed.ncbi.nlm.nih.gov/14751771/
Interesting a bit up I mentioned that monoamine neurotransmitters such as dopamine, noradrenaline, and serotonin (5-HT) hyperpolarize and inhibit orexin neurons via alpha 2-adrenergic and 5-HT1A receptors as well so it seems any dysregulation in the kynurenine pathway and the kyn/trp ratio is but one factor so far of several that seems to have a lowering effect either way on orexin neurons.
This study that came out in 2019 mirrors the idea that IFN-a induced persistent fatigue which does not abate post-treatment, that is, once there is no longer immune activation from IFN-α. It mentions that in a study of chronic-activated Epstein-barr virus (CAEBV), higher fever was significantly associated with a higher kynurenine/tryptophan (Kyn/TRP) ratio and lower Tryptophan, while there were trends towards associations between a higher KYN/TRP ratio and severe tiredness and night sweats (Bellmann-Weiler et al., 2008). This suggests that inflammation-induced activation of IDO may be relevant for the persistence of symptoms, including fatigue, following an immune trigger and differs with the lower tryptophan and increased kynurenine. Levels of the KYN/TRP ratio and 3-HK were lower in this study in CFS patients than controls, while the tryptophan levels were similar to controls. This lower KYN/TRP ratio in CFS (and the lack of association with PF) is somewhat in opposition to a study of somatization which observed higher levels of the KYN/TRP ratio. Again differences among some studies which didnt make sense initially. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350004/
other kynurenine metabolites, quinolinic, and picolinic acids, can also enhance IFN-γ-dependent iNOS expression https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808205/
Interesting a bit up I mentioned that monoamine neurotransmitters such as dopamine, noradrenaline, and serotonin (5-HT) hyperpolarize and inhibit orexin neurons via alpha 2-adrenergic and 5-HT1A receptors as well so it seems any dysregulation in the kynurenine pathway and the kyn/trp ratio is but one factor so far of several that seems to have a lowering effect either way on orexin neurons.
This study that came out in 2019 mirrors the idea that IFN-a induced persistent fatigue which does not abate post-treatment, that is, once there is no longer immune activation from IFN-α. It mentions that in a study of chronic-activated Epstein-barr virus (CAEBV), higher fever was significantly associated with a higher kynurenine/tryptophan (Kyn/TRP) ratio and lower Tryptophan, while there were trends towards associations between a higher KYN/TRP ratio and severe tiredness and night sweats (Bellmann-Weiler et al., 2008). This suggests that inflammation-induced activation of IDO may be relevant for the persistence of symptoms, including fatigue, following an immune trigger and differs with the lower tryptophan and increased kynurenine. Levels of the KYN/TRP ratio and 3-HK were lower in this study in CFS patients than controls, while the tryptophan levels were similar to controls. This lower KYN/TRP ratio in CFS (and the lack of association with PF) is somewhat in opposition to a study of somatization which observed higher levels of the KYN/TRP ratio. Again differences among some studies which didnt make sense initially. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350004/
other kynurenine metabolites, quinolinic, and picolinic acids, can also enhance IFN-γ-dependent iNOS expression https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808205/
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