UPDATE: THE KYNURENINE PATHWAY: A Key to Neurological Disorders Excuse us Please for being very Premature here but we are just too darn EXCITED about the KYNURENINE Pathway and how Microglia, Astrocytes and Neurons all talk to each other through this Pathway It’s not SEROTONIN (we all know this by now) We might as well lay the groundwork for the Good Stuff to come by reaching agreement on the basic point that theres no convincing body of data that anybody has ever found that Depression is associated to a significant extent with a loss of Serotonin This does not however mean that there no molecular imbalance associated with the various mental disorders such as Depression, BPD, and Schizophrena. Its just that the imbalance is much deeper than the cartoon style metaphor of supposed serotonin deficit that has been fed by the pharma companies to the masses and their ignorant physicians. Speculation about a role of kynurenines in major depressive disorders dates back several decades to the time when the connection between depression, tryptophan and serotonin was first recognized However, the exceptional success of serotonin re-uptake inhibitors as antidepressants, paired with the lack of consistent indications of kynurenine pathway changes in depression, essentially stifled efforts to explore a possible involvement of kynurenine pathway metabolites in pathophysiology. However, studies performed during the past 10 years have led to a significant paradigm shift in this regard, and kynurenine pathway dysfunction is now increasingly recognized as a major player in the development and symptomatology of depressive disorders. Similar in principle to the above-mentioned neuro-immune hypothesis of neurological disorders, the pathophysiological concept is based on the realization that the kynurenine:tryptophan ratio in blood is significantly enhanced in patients with depression and correlates with anxiety and cognitive deficits, but not with neurovegetative or somatic symptoms And, yes, we came across KYNURENINE, this elephant in the Neuroscience room while trying to understand how analysis on the cellular level of microglia, astrocytes and neurons could be better understood by relating to the molecular interactions jointly propelled by these various cell types working in synergy. The Kynurenine pathway is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide (NAD+) from the degradation of the essential amino acid Tryptophan. Disruption in the pathway is associated with certain genetic disorders. Here (below) is one such link which points to this Pathway as of vital interest in a range of cognitive impairments going beyond Depression The common inflammatory etiology of depression and cognitive impairment: a therapeutic target. ncbi.nlm.nih.gov/pubmed/25178630 Chronic inflammation has been shown to contribute to the development of a wide variety of disorders by means of a number of proposed mechanisms. Depression and cognitive impairment are two such disorders which may share a closely linked inflammatory etiology. The ability of inflammatory mediators to alter the activity of enzymes, from key metabolic pathways, may help explain the connection between these disorders. The chronic up-regulation of the kynurenine pathway results in an imbalance in critical neuroactive compounds involving the reduction of tryptophan and elevation of tryptophan metabolites. Such imbalances have established implications in both depression and cognitive impairment. The Kynurenine pathway is an effective mechanism in modulating the immune response and in inducing immune tolerance. This is achieved by accelerating the degradation of Tryptophan and the generation of Kynurenines. The metabolites of the pathway, with their different inherent properties, can also synergize or antagonize the effects of one another. The understanding of pathway, with it loops and interactions and vicissitudes, promises to be fundamental to dealing with a wide range of mental disorders such as depression, bipolar disorder and schizohrenia. So we encourage folks to take a look at Google or PubMed and catch a glimpse of what will be dealing with here. The recently popular QUINOLINIC ACID which potently modulates NMDA Receptors is one of the key products of this pathway along one fork in the process. Quinolinic acid is a downstream product of the kynurenine pathway, which metabolizes the amino acid tryptophan. It acts as an NMDA receptor agonis ncbi.nlm.nih.gov/pubmed/22248144 Quinolinic acid has a potent neurotoxic effect. Studies have demonstrated that quinolinic acid may be involved in many psychiatric disorders, neurodegenerative processes in the brain, as well as other disorders. Very recent research has demonstrated a long-term dysregulation of the kynurenine pathway in the central nervous system of suicide attempters. An increased load of inflammatory cytokines was coupled to more severe symptoms. We therefore suggest that patients with a dysregulated kynurenine pathway are vulnerable to develop depressive symptoms upon inflammatory conditions, as a result the excess production of the NMDA-receptor agonist quinolinic acid. This study provides a neurobiological framework supporting the use of NMDA-receptor antagonists in the treatment of suicidality and depression. ncbi.nlm.nih.gov/pubmed/25124710 Within the brain, quinolinic acid is only produced by activated microglia and macrophages However it is noteworthy that for the Kynurenine Pathway to get down to Quinolinic Acid production by the Microglia, the Astrocytes have to contribute their catabolic action along the way as part of the modulation of neurons by Quinolinic Acid Kynurenic Acid, which is the major Kynurine Pathway, metabolite is synthesized and released by astrocytes and antagonizes NMDAr and α7-nicotinic acetylcholine receptor Kynurenic Acid, which is the major Kynurine Pathway, metabolite is synthesized and released by astrocytes and antagonizes NMDAr and α7-nicotinic acetylcholine receptor If one looks at the chart of the KP Pathway one can see that there is a crucial fork in the road where the Astrocytes must act on the KYNURENINE to catabolize it to Kynurenic Acid., otherwise the pathways runs down to QUINOLINIC ACID. There is good evidence that the kynurenine pathway (KP) and one of its end products, quinolinic acid (QUIN) play a role in the pathogenesis of several major neurological diseases. While QUIN has been shown to be produced in neurotoxic concentrations by macrophages and microglia, the capacity of astrocytes and neurons to produce QUIN is controversial. ncbi.nlm.nih.gov/pubmed/25306914 These researchers (immediately above) found that astrocytes, neurons, and microglia expressed IDO but only microglia were able to produce detectable amounts of QUIN. The rate-limiting enzymes of KYN formation from TRYis IDO in astrocytes, microglia, microvascular endothelial cells and macrophages and TDO in liver, kidney and brain However, astrocytes and neurons had the ability to catabolize QUIN. This study also provides the first evidence of IDO expression and lack of production of QUIN in culture of primary human neurons. There has been a flurry of interest in Ketamine as an anti-depressant,for example, and this is yet another example of a more superficial approach where the ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, is found to have rapid anti-depressant effects at the NMDA receptor, where the Quinolinic Acid produced by Microglia also impacts. ncbi.nlm.nih.gov/pubmed/23982301 In this research on depression research (immediately below) Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulategyrus: evidence for an immune-modulated glutamatergic neurotransmission? ncbi.nlm.nih.gov/pubmed/21831269 Their results add a novel link to the immune hypothesis of depression by providing evidence for an upregulation of microglial QUIN in brain regions known to be responsive to infusion of NMDA antagonists such as ketamine. Further work in this area could lead to a greater understanding of the pathophysiology of depressive disorders and pave the way for novel NMDA receptor therapies or immune-modulating strategy Kynurenic Acid (which is produced by Astrocytes in that OTHER FORK) acts as an antiexcitotoxic and anticonvulsant, most likely through acting as an antagonist at excitatory amino acid receptors. Because of this activity, it may influence important neurophysiological and neuropathological processes. As a result, kynurenic acid has been considered for use in therapy in certain neurobiological disorders. Conversely, increased levels of kynurenic acid have also been linked to certain pathological conditions. High levels of KynurenicAcid have been identified in patients suffering from tick-borne encephalitis,[8] schizophrenia and HIV-related illnesses. In all these situations increased levels were associated with confusion and psychotic symptoms. Kynurenic acid acts in the brain as a glycine-site NMDAr antagonist, key in glutamatergic neurotransmission system, which is thought to be involved in the pathophysiology and pathogenesisof schizophrenia. So we have here a FORK IN THE ROAD, where insufficient production of Kynurenic Acid (KYNA) by Astrocytes can lead to production of the Neurotoxic GUINOLINIC ACID and symptoms of Depression ...and where excessive production production of Kynurenic Acid by the Astrocytes can lead to psychotic disorders and schizophrenia. KYNA and QUINOLINIC Acid, we should note, do not cross the blood-brain barrier 42 and must be formed locally within the brain. One can only wonder about how the cyclic nature of BIPOLAR DISORDER arises. Elevated levels of Kynurenic Acid (KYNA) have now been found in the cerebrospinal fluid of patients with bipolar disorder. Elevated levels of KYNA have previously been observed in patients with schizophrenia, both in the cerebrospinal fluid (CSF)1 and postmortem prefrontal cortex Interestingly, KYNA tonically modulates midbrain dopamine activity, indicating a potential role of this compound in dopamine-related diseases. ncbi.nlm.nih.gov/pmc/articles/PMC2861136/ As we watch the burgeoning interest in Ketamine as an anti-depressant we cannot help but be curious about how that interacts with the Kynurenine Pathway. Ketamine, is psychotomimetic drug which produces schizophrenia-like symptoms in normal individuals and exacerbates psychotic features in patients with schizophrenia The observation of Ketamines functioning as a NMDA receptor antagonist led to the idea that excessive KYNA (by reducing NMDA receptor activity) or an increased ratio of KYNA on one hand, and 3-HK and its downstream metabolites on the other, might play a role in schizophrenia pathology The issue of the balance within the Kynurenine Pathway and how the various cell types driving that pathway interact to produce that balance must provoke curiosity. Hopefully this little morsel thus far serves as an appetizer....to whet the scientific palate...to attempt to truy understand the underlying mechanisms of Depression and other neurological disorders (and, yes, there is more to come on this topic) And just for the Record as am epilogue on the dumbed down SEROTONIN metaphor: of Depression causation, the psychiatric profession has finally come clean and confessed on a national media outlet that there is no evidence to support the Serotonin Theory of Depression. madinamerica/2012/01/psychiatrys-grand-confession/ On NPR’s Morning Edition there is a segment about the chemical imbalance theory, and virtually all the psychiatrists who are interviewed acknowledge that the there was never any evidence in support of the idea that low serotonin causes depression. But then, amazingly, they go on to say that it is perfectly fine to tell patients that serotonin imbalance causes depression even though they know this isn’t the case. Several years ago in PLoS Medicine we wrote a long piece about the serotonin theory and the disconnect between what research psychiatrists say in professional journals and textbooks and what the advertisements say. While the advertisements presented the theory as scientific fact, the scientific sources clearly did not. Given the enormous marketing programs that pushed this theory combined with the media’s lack of skepticism, we were sympathetic to the general public who could hardly be faulted for thinking that theory had some foundation in fact. We pointed out to the reporter that we weren’t attacking a sacred cow but that instead we were pointing out the mainstream psychiatry didn’t even accept this theory. We urged the reporter to contact the FDA, NIMH, APA, etc and ask them about the science behind the advertisements. He did, and as expected, an expert from the FDA explained that the theory was really just a metaphor. The problem is that patients who heard their physician explain the serotonin theory thought they were hearing real science. They weren’t told it was a metaphor and hence thought it was a fact. According to many ratinal observers, it was the pharmaceutical companies who espoused the theory, and not well-informed, practicing clinicians, because the psychiatry community has known all along that the theory is not true. Any and all comments are more than welcome as we continue this voyage of discovery and the KYNURENINE PATHWAY
Posted on: Tue, 06 Jan 2015 20:19:50 +0000
Trending Topics
Recently Viewed Topics
© 2015