Taking the supplement 5-HTP is one way to help supply the brain with serotonin even if the IDO enzyme is breaking down tryptophan. As the video shows, serotonin is made via the following pathway:
Tryptophan ➤ 5-HTP ➤ serotonin
If you take 5-HTP as a supplement, this replenishes the pathway at the 5-HTP step beyond tryptophan, so this bypasses the effects of IDO on tryptophan.
However, according to the video, the cause of depression is not just due to a loss of serotonin, but also due to IDO's activation of the kynurenine pathway, which results in microglial activation (ie, inflammatory immune activation). So taking 5-HTP would only address half the problem caused by IDO.
I've had a neruo-infection from Borrelia and L-Tryptophan has increased my inflammation 10-fold whereas 5htp has helped me tremendously but I had to stop due to heart problems.
**The Quadruple Edged Sword**
Both Microglia and macrophages, in the case of a desseminated CNS infections such as neuroborreliosis, spirochetosis, neuro-syphilis and other neurodegenerative diseases, though not infectious based and thought to be autoimmune disorders in my view will be considered autoimmune with the root etiology being a lose of blood brain barrier cohesion/integrity and the reactivation of latent infectious agents that pass through the BBB. This very well could be a negative feedback loop, as Quinolinic Acid is a potent nmda agonist (cell death) which unfortunately can break down the BBB, which is secreted from the immune system for the purpose of fighting infections. Keep in mind QUIN is needed to produce NAD+ but not at the excessive levels in the brain we see with many neur infections. Borrelia infection which is extremely common, if not treated can cause MS, ALS, and Alzheimer's like "symptoms" among many others, very much like neuro-syphilis, both Borrelia and syphilis are close cousins. There are hundreds of studies illustrating the link between neurodegenerative diseases and desseminated infections.
Quinolinic acid is a potent excitotoxic seen high in the brains of almost all neurodegenerative disease patients, including AIDS complex dimentia, ALS, schizophrenia, psychosis, Huntingtons disease, neuroborreliosis, Babesiosis, Desseminated malaria infections, encephelopathy, Alzheimer's, autism (with high levels of kynurenic acid, which is also modulated by the IDO enzyme like QUIN). and most interesting suicide patients. QUIN can also cause large Lesions in the brain, particularly most susceptible is the hipocampus, lesions on the hipocampus can cause a host of problems including memory disorders.
Moreover, QUIN agonizes the NMDA receptors, which can indirectly increase glutamate another nmda agonist, this can lead to cellular death due to an influx of sustained calcium in the synapse. High levels of QUIN in the brain have also been associated with depression, social isolation, muscle wasting, anxiety and insomnia. More interesting is thte relationship between anti-nmda receptor encephelitis a rare autoimmune disease, where the immune system attacks the NMDA receptors. This very well could be some sort of negative feedback loop, but this is all conjecture.
**Technical**
There is a general consensus that Lyme disease symptoms, whether acute or chronic, are driven largely by inflammation, this could be because of the persistence of the spirochetal forms, dormant cystic forms and their DNA graduals with CNS resivours or an autoimmune reaction caused by post-erradication. In late-stage Lyme disease, the inflammatory cytokines of the early (innate) immune response – particularly tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) – are chronically activated, causing direct damage both within and outside the central nervous system (Habicht 1992; Ramesh et al. 2005; Kisand et al. 2007; Ramesh et al. 2008; Rupprecht et al. 2008). A high percentage of patients in the advanced stages of disease suffer from inflammation of white matter and cerebral hypoperfusion (Fallon & Nields 1994; Fallon et al. 1995; Sumiya et al. 1997; Fallon et al. 1997; Logigian et al. 1997; Plutchok et al. 1999; Heinrich et al. 2003; Fallon et al. 2003; Donta et al. 2006; Fallon et al. 2009). Besides direct damage, chronic inflammation also triggers excessive and imbalanced catabolism of tryptophan, causing tryptophan depletion, neurotoxicity, and a form of immunosuppression -- also found several forms of cancer and HIV infection -- that significantly impairs the effector T cell response required to attack both intracellular and extracellular infection.
Low-dose, IV ketamine is a promising option for rapid, highly-effective symptom relief, damage reduction, and prevention of T cell suppression in late-stage Lyme disease. Even in low doses, ketamine is a potent anti-inflammatory, inhibiting TNF-alpha and IL-6 (Royblat et al. 1998; Shapira et al. 2004; Bartoc et al. 2006; Yang et al. 2006; Beilin et al. 2007). Ketamine easily crosses the blood-brain barrier (Pai & Heining 2007), and has been shown using brain SPECT scans in human studies to improve cerebral blood flow in patients suffering from cerebral hypoperfusion (Wu et al. 2006; Guedj et al. 2007a; Guedj et al. 2007b).
Phase II clinical trials, small studies, and individual case reports have shown low-dose IV ketamine to be remarkably effective in reducing symptoms of several conditions that appear in late-stage Lyme disease, including refractory depression (Berman et al. 2000; Kudoh et al. 2002; Zarate et al. 2006; Correll & Futter 2006; Liebrenz et al. 2007a; Liebrenz et al. 2007b; Goforth & Holsinger 2007; Paulet al. 2008; Stefanczyk-Sapieha et al. 2008; Matthew et al. 2009), fibromyalgia (Sörensen et al. 1995; Sörensen et al. 1997; Graven-Nielsen et al. 2000; Guedj et al. 2007a; Guedj et al. 2007b), and chronic regional pain syndrome (CRPS) (Harbut & Correll 2002; Correll et al. 2004; Goldberg et al. 2005; Wu et al. 2006; Kiefer et al. 2007; Villanueva-Perez et al. 2007; Jeffreys & Woods 2007; Koffler et al. 2007; Shirani et al. 2008)– although the most advanced cases of refractory CRPS may require anesthetic dosing (Kiefer et al. 2008a; Kiefer et al. 2008b; Becerra et al. 2009).
Case reports have also shown ketamine to be effective inother syndromes that appear in Lyme disease, including status epilepticus, explosive disorder, MS-like syndrome, Parkinsonism, and stroke.
In 2007, Charney et al. reported remarkable and sustained benefits in three highly-refractory depressed patients after four or five ketamine infusions over successive days, with benefits lasting up to 28 days. Kollmar et al. reported in 2008 that a refractory, psychiatric in-patient with ten recent suicide attempts, no response to pharmacological agents, and only partial response to ECT, obtained symptom relief for three days after one low-dose ketamine infusion. Two weeks after the first infusion, she was given a second low-dose infusion, followed by regular dosing with oral memantine. The patient experienced remission shortly after the second infusion. She remained in remission six months later, when her case report was submitted for publication.
**Kynurenine pathway-mediated excitotoxicity and oxidative stress**
Aside from causing direct inflammatory damage, inflammatory cytokines fuel neurotoxicity by activating enzymes that cause excessive or pathogenically imbalanced catabolism of CNS L-tryptophan (TRP) and its metabolites -- known as kynurenines -- via the kynurenine pathway. TRP is one of the ten essential amino acids, is involved in protein synthesis, and acts as a precursor of many biologically active substances (Robotka et al. 2008). When significantly elevated in the CNS, the tryptophan metabolite quinolinic acid (QUIN) is neurotoxic (Guillemin et al. 2005; Halperin & Heyes 1992). And even moderate elevation of the tryptophan metabolite 3-hydroxykynurenine (3-OH-KYN) causes neurotoxicity (Wichers & Maes 2004; Moroni et al. 1999; Okuda et al. 1998). Cerebrospinal fluid levels of QUIN are significantly elevated in disseminated and late-stage Lyme disease -- dramatically in Lyme neuroborreliosis, and to a lesser degree in Lyme encephalopathy without intra-CNS inflammation (Halperin & Heyes 1992). Likewise, increased concentrations of neopterin and of the tryptophan degradation product, L-kynurenine, are detected in the cerebrospinal fluid of patients with acute Lyme neuroborreliosis (Gasse et al. 1994; Fuchs et al. 1991). No studies of CNS levels 3-OH-KYN in B. burgdorferi infection have been published. CNS inflammation and kynurenine imbalances are found in several psychiatric and neurodegenerative syndromes, including depression (Raison et al. 2010; Maes et al. 2009; Myint et al. 2007; Wichers et al. 2005; ), schizophrenia (cites), Parkinsonism (elevated 3-OH-KYN, reduced KYNA) (Mogi et al. 1994a; Mogi et al. 1994b; Blum-Degen et al. 1995; Muller et al. 1998; Mirza et al. 2000; Nagatsu et al. 2000; Hald & Lotharius 2005; Mosley et al. 2006), early-stage Huntington’s disease (elevated 3-OH-KYN and QUIN)(Heyes et al. 1992a; Guidetti & Schwarcz 2003; ), AIDS dementia (elevated QUIN) (Heyes et al. 1992a), autism and autistic spectrum disorders (elevated brain levels of TNF-a, IL-6, IL-8, and IFN-y (cites). . .
Parkinsonism typically involves CNS inflammation (Mirza et al. 2000), with increased levels of TNF-alpha, IL-1 beta, IL-3, and IL-6 in CSF, and in the postmortem striatum and substantia nigra.50-56 Likewise, elevated levels of 3-OH-KYN are found in the CSF, and in the postmortem brain.59-66 Excitotoxic overactivation of the NMDA receptors in Parkinsonism is mediated in large part by low levels of kynurenic acid, a tryptophan metabolite that is the only known endogenous NMDA receptor antagonist. (Ogawa et al. 1992; Stone 2001a; Erhardt et al. 2009; Stone 1993; Stone 2001b; Sas et al 2007; Németh et al. 2006; Borlangan et al. 2000).Kynurenic acid and 3-OH-KYN are both synthesized from N-formylkynurenine (N-formyl-KYN), but involving different enzymes.
**Tryptophan/Kynurenine Pathway**
Tryptophan is metabolized in several pathways. The most widely known is the serotonergic pathway, which is active in platelets and neurons, and yields 5-hydroxy-TRP, and then serotonin. TRP is also the precursor of the pineal hormone, melatonin. But ninety five percent of TRP within the brain is catabolized through the kynurenine pathway (Robotka et al. 2008). In this pathway, the enzyme indoleamine-2,3-dioxygenase (IDO) catalyzes the first step in tryptophan degradation. (See figure 1). Elevated TNF-alpha increases production of the cytokine IFN-gamma, which exerts a powerful stimulus on IDO. Excessive or pathogenically imbalanced catabolism through the kynurenine pathway results in production of neurotoxic levels of 3-OH-KYN and QUIN (Robotka et al. 2008; Vamos et al. 2009; Guillemin et al. 2003; Guillemin et al. 2001), and insufficient levels of the only known endogenous NMDA receptor antagonist, kynurenic acid (KYNA).
**IDO Enzyme**
In the human brain, IDO is expressed in microglia (Guillemin et al. 2003; Wichers et al 2005; Vamos et al. 2009) and in part in the astrocytes (Guillemin et al. 2001; Vamos et al. 2009). Infiltrating macrophages and resident microglia are the major source of QUIN within the brain (Heyes et al. 1992b; Espey et al. 1997; Guillemin et al. 2001; Guillemin et al. 2005). Although the kynurenine pathway is fully expressed in both microglia and macrophages, for unknown reasons, macrophages have a much greater capacity of producing QUIN than microglia (Guillemin et al. 2003; Guillemin et al. 2005). Human astrocytes are not able to produce QUIN, but are capable by themselves of producing L-kynurenine, which is the substrate for 3-OH-KYN synthesis. IDO activation by infiltrating macrophages is particularly damaging because IL-4, which downregulates IDO activity, is found in low levels in the brain [verify with more research] (Wesselingh et al. 1993). The role of 3-OH-KYN in brain physiology is unknown, but in primate lenses it appears to play a role in protecting the retina from UV radiation (Vamos et al. 2009; Vasquez et al. 2002). Even relatively low levels of 3-OH-KYN may cause neurotoxicity by inducing oxidative stress and neuronal apoptosis (Wichers et al. 2004; Moroni et al. 1999; Okuda et al. 1998). QUIN acts as an agonist at the N-methyl-D-aspartate (NMDA) receptor subgroup containing subunits NR2A and NR2B. Significant elevation of CNS QUIN causes a form of neurotoxicity -- known as excitotoxicity -- by over-activating NMDA receptors in the brain hippocampus. This allows excessive influx of calcium into neurons (Robotka et al. 2008; Vamos et al. 2009), inhibits glutamate uptake into the synaptic vesicle, leading to excessive microenvironment glutamate concentrations (Robotka et al. 2008; Vamos et al. 2009), and promotes lipid peroxidation (Robotka et al. 2008; Rios & Santamaria 1991; Behan & Stone 2002). Elevated QIUN might also potentiate its own neurotoxicity and that of other excitatory amino acids in the context of energy depletion (Robotkaet al. 2008; Schurr & Rigor 1993; Bordelon et al. 1997; Schuck et al. 2006). Moreover, 3-OH-KYN and QUIN appear to cause neurotoxicity in a synergistic manner: co-injection of these kynurenines into the striatum of rats causes substantial neuronal loss in doses that cause no or minimal neurodegeneration when injected alone (Robotka et al. 2008; Guidetti et al. 1991).
QUIN-induced damage is also potentiated by reactive oxygen radicals (Behan et al. 2002; Stone & Darlington 2002). Because KYNA is an NMDA receptor antagonist, insufficient levels of this kynurenine are functionally similar to elevated levels of QUIN. Glutamate, like QUIN, is an NMDA receptor agonist. In the mammalian CNS, glutamate is the main excitatory neurotransmitter, and is essential for normal brain functions (Ozawa et al. 1998). Glutamate accumulation into synaptic vesicles is the initial critical step for physiologic glutamatergic neurotransmission (Özkan & Ueda 1998). However, overstimulation of the glutamatergic system, which occurs when extracellular glutamate levels increase over the physiological range, is involved in many acute and chronic brain diseases due to excitotoxicity (Maragakis & Rothstein 2004). elevated extracellular QUIN stimulates synaptosomal glutamate release (Tavares et al. 2002) and inhibits glutamate uptake into astrocytes (Tavares et al. 2002). Moreover, extracellular elevation of excitotoxic QUIN results in overlapping glutamate excitotoxicity. Elevated extracellular QUIN and glutamate are found in ., including epilepsy (
Meldrum 1994), amyotrophic lateral sclerosis (ALS) (Spreux-Varoquaux et al., 2002), probably Parkinsonism (Maragakis & Rothstein 2004), perhaps Huntington’s (Maragakis & Rothstein 2004). In order to avoid excessive increases of extracellular glutamate and glutamatergic excitotoxicity, glutamate must be taken up from synaptic cleft to the cytosol of glial and neuronal cells to be stored into synaptic vesicles on neuronal terminals (Robinson & Dowd, 1997; Anderson and Swanson, 2000; Fykse & Fonnum, 1996; Wolosker et al., 1996). The most significant mechanism for maintaining extracellular glutamate levels below neurotoxic concentrations is uptake by astrocytes. (Rothstein et al., 1996). However, elevated extracellular QUIN stimulates synaptosomal glutamate release (Tavares et al. 2002) and inhibits glutamate uptake into astrocytes (Tavares et al. 2002). Thus, excessive extracellular concentration of excitotoxic QUIN results in overlapping glutamate excitotoxicity.
**IDO/kynurenine pathway-mediated immune dysregulation**
Suppression of CD4+ and CD8+ effector T cells and/or induction of T regulatory cells
caused by overactivation of IDO and concomitant activation of the kynurenine pathway is
likely to be a significant immunosuppressive mechanism in advanced Lyme disease, and
may also contribute to autoimmune reactions.
A simplified overview of some key components in the adaptive immune response helps
in understanding the potential effects of IDO/kynurenine pathway-mediated dysregulation of the immune system.During the early (innate) immune response, macrophages and dendritic cellsphagocytize extracellular pathogens and also cells that are infected by microbial pathogens (intracellular infection). Dendritic cells are an important link between the innate and adaptive immune response. They present antigen-derived molecules from phagocytized microbes to T cells in the peripheral lymphoid organs, i.e., the lymph nodes, the spleen, and the mucosal and cutaneous immune systems. For this reason, they are one of the most important types of antigen presenting cells (APCs).Dendritic cells carrying class I major histocompatibility (MHC-I) molecules from phagocytized intracellular microbes are recognized only by cytotoxic CD8+ T cells. Cytotoxic T cells recognize and attack only intracellular infections. [How are CD8+ Tregs differentiated? By characteristics of dendritic cells carrying MHC-I molecules?]Dendritic cells carrying MHC-II molecules from phagocytized extracellular microbes are recognized only by CD4+ T cells. Depending, among other things, on characteristics of the dendritic cells that deliver MHC-II molecules to the peripheral lymphoid organs, CD4+ T cells differentiate into T helper 1 (Th1) cells, T helper 2 (Th2) cells, T helper 17 (Th17) cells, or T regulatory cells (Tregs). Th1 lymphocytes produce inflammatory cytokines that assist macrophages in phagocytosis of cells harboring intracellular infection.
IDO and kynurenine pathway activation have multiple protective functions in immune system regulation. On the one hand, induction of IDO plays an important role in the innate immune response during early stages of several infections (Njau et al. 2009; Müller et al. 2008; Hainz et al. 2007; Popov & Schultze 2008). On the other hand, elevation of IDO and kynurenine pathway activation may play a role in protecting the fetus from immune system attack by fostering feto-maternal tolerance (Sedlmayr 2007).
**HIV- and cancer-like immunosuppression by overactivation of IDO and kynurenine pathway**
In several forms of cancer and in several chronic infectious diseases, overactivation of inflammatory cytokines and IDO, depletion of tryptophan, and synthesis of kynurenines – individually or in combination – suppress the adaptive immune response by affecting
either T cells, antigen-presenting cells, or both. (MacKenzie et al. 2007). Elevated IDO appears to play a role in upregulating Tregs in human lymphatic filariasis (Babu et al. 2006), a significant role in CD4+ T cell dysregulation in chronic human HCV infection (Larrea et al. 2007), causes significant suppression of CD4+ and cytotoxic T cells in the peripheral blood in chronic human HBV (Chen et al. 2009), appears to downregulate CD4+ effector T cells, increase Tregs, and increase the rate of apoptosis in CD8+ Tcells in SIV infection (Boasso et al. 2007; Boasso et al. 2009), inhibits CD4+ T-cell proliferation that characterizes HIV disease progression, and appears to limit proliferative and cytotoxic capacity of CD8+ T cells in HIV infection (Boasso et al. 2007b; Boasso et al. 2007c; Persidsky et al. 2006).
This same form of immunosuppression occurs in several malignancies, including breast cancer (Mansfield et al. 2009)
; acute myeloid leukemia (Curti et al. 2007; Curti et al. 2008; Chamuleau et al. 2008), ovarian carcinoma (Inaba et al. 2009, lung cancer Suzuki et al. 2009), endometrial cancer (Ino et al. 2008), pancreatic cancer (Witkiewicz et al. 2008), hepatocellular carcinoma (Pan et al. 2008), cutaneous melanoma (Polak et al. 2007). The mechanisms involved in IDO/kynurenine pathway-mediated immunosuppression are being studied intensively, and are partially understood.
Human dendritic cells that differentiate under elevated-IDO and/or low-tryptophan conditions show a reduced capacity to stimulate T helper (Th) cells (CD4+), and favor induction of Tregs (Brenk et al. 2009; Chen et al. 2008; Hill et al. 2007). The reduced proliferation of CD4+ T cells and increased induction of Tregs would be systemic (Brenk et al. 2009), and therefore measurable in the peripheral serum. Similarly, in human fibroblasts, elevated IDO and kynurenine pathway activation suppresses proliferation of CD8+ T cells, and to a lesser extent CD4+ T helper cells (Forouzandeh et al. 2008). The molecular effect of tryptophan depletion and/or exposure to tryptophan catabolites on CD8+ T cells appear to be associated with limited proliferative response and ability to exhibit cytotoxic function (Boasso et al. 2007b). The reduced proliferation of CD8+ cytotoxic T cells is only partially measurable in peripheral serum, because it also occurs in the local microenvironment where elevated IDO activates the kynurenine pathway (Brenk et al. 2009; Chen et al. 2008; Hill et al. 2007).
Liu et al. have recently shown that while elevated IDO significantly reduced the number of proliferating CD3+ and CD8+ T cells in an experimental rat lung allograft, those levels were still significantly higher than found in normal lungs. Yet the CD8+ T cells that did proliferate were significantly stripped of their cytotoxic capacity in microenvironments with elevated IDO, despite remaining viable (Liu et al. 2009).
In patients with chronic hepatitis B, elevated IDO is responsible for immunotolerance against HBV, closely correlates with HBV viral load, and is negatively correlated with CD4 (+) and CD8 (+) T cells, and with the ratio of CD4/CD8 (Liu et al. 2009). In patients with chronic hepatitis C -- which is characterized by weak T-cell responses -- IDO expression in liver tissue, and serum kynurenine tryptophan ratio -- a reflection of IDO activity -- are significantly elevated (Larrea et al. 2007). In hepatitis C-infected chimpanzees, hepatic IDO expression decreased in animals that cured the infection, while it remained high in those that progressed to chronicity (Larrea et al. 2007). Elevated IDO and kynurenine-tryptophan ratio are strongly correlated to viral load and immunosuppressive regulatory T cell (Treg) levels in the spleen and gut during progressive simian immunodeficiency virus (SIV) infection (Boasso et al. 2007). Elevated IDO and depleted tryptophan also induce suppression of cytotoxic T-cells in mice infected with malaria (Tetsutani et al. 2007).
Inhibition of IDO as an adjunct to treatment has proven remarkably effective in animal studies of SIV and HIV infection, and several forms of cancer. In SIV-infected monkeys experiencing only a partial response to retroviral therapy, partial blockade of IDO with retroviral therapy reduced plasma and lymph node SIV to undetectable levels (Boasso et al. 2009). In a murine model of HIV-1 encephalitis, the IDO inhibitor 1-methyl-DL-tryptophan (1-MT) enhances the generation of HIV-1-specific cytotoxic T lymphocytes, leading to elimination of HIV-1-infected macrophages in brains of the treated mice (Potula et al. 2005). In mouse models of transplantable melanoma and breast cancer, 1-MT, in combination with chemotherapeutic agents, significantly inhibited tumor growth and enhanced survival of treated mice (Hou et al. 2007). Yet because of its poor solubility, 1-MT has restricted clinical application (Hou et al. 2007, van der Sluijs et al. 2006, Popov et al. 2008). Inhibition of IFN-gamma, with resulting inhibition of IDO, also reverses T cell unresponsiveness in mice injected with staphylococcal enterotoxin A (Kim et al. 2009).
This same immunosuppressive mechanism is likely occurring in advanced Lyme disease of long-term duration, since tryptophan is depleted, IDO is very likely overactivated, and CNS QUIN is significantly elevated – “dramatically” so in neuroborreliosis where “the severity of the infection and [inflammatory] immune stimulation [was not yet] intense.” (Halperin & Heyes 1992). [Cite studies on Th1/Th2, Treg, and CD8+ ratios in chronic Lyme]. Because cytotoxic T cells, natural killer cells, and macrophages play a central role in attacking intracellular infection, systemic or local microenvironment suppression/deactivation of CD8+ and CD4+ Th1 lymphocytes may largely explain the persistence of intracellular B. burgdorferi. Likewise, suppression of CD4+ Th2 cells would help explain the persistence of extracellular B. burgdorferi.
This could also explain the poor sensitivity of the CD57+ NK T-cell count as a diagnostic and prognostic indicator, despite its apparent specificity in Lyme disease and/or TBIs.
Moreover, because lysis of B. burgdorferi provokes inflammation (cites), antibiotics are likely to cause further activation of IDO and the kynurenine pathway, which would compromise the immune response against both intracellular and extracellular infection. Of course, antimicrobials can be effective in Lyme disease that is not too far advanced, as demonstrated by Halperin & Heyes (1992). But in cases of long-term infection, this would help explain why advanced Lyme disease is incurable using antimicrobials without a targeted, anti-inflammatory adjunct. Plenty of anecdotal evidence for herx-like reactions in treating babesiosis. Look for studies on this in treating babesiosis and malaria. Elevated IDO and depleted tryptophan induce suppression of cytotoxic T-cells in mice infected with malaria (Tetsutani et al. 2007).
**Suppressing TNF-alpha and IDO as well as NMDA Receptor**
Inflammation may have a protective role and promote regeneration of damaged neurons. We do not yet know how to achieve a "balanced" inflammation. Because some novel anti-inflammatory treatment might have detrimental consequences, carefully monitoring disease progress in patients treated with this category of drugs is indispensable (Aktas et al. 2007; Bransfield ). However, as inflammation, IDO activation, and CNS QUIN levels subside, so do Lyme disease symptoms. Since short-course, low-dose ketamine infusions suppress inflammation for days or weeks, and if ketamine is infused only symptomatically, the immune balance should not be skewed in an anti-inflammatory direction for any extended period. Role of tryptophan starvation in controlling specific infections. Higher degree of tryptophan depletion required to deactivate T cells than to fight off these infections.
By reducing CNS inflammation, ketamine should counteract IDO/tryptophan/kynurenine-mediated induction of Tregs,suppression of CD4+ and CD8+ effector T cells. Autoimmunity in Lyme-MS, Lyme-arthritis after “adequate” antibiotic therapy...Only one in vivo mouse study so far to support this, but possibility that lysis-induced inflammation can trigger or exacerbate autoimmune response by further activating IDO and kynurenine pathway... ..
Long-term, daily use of high-dose ketamine -- urinary tract damage, ulcerative cystitis, disabling frequent urination... Controlled effectively by author by Class IV 7.5 W, 980 nm medical near-infrared laser.Mimicry of schizophrenicsymptoms by blockage of NMDA receptor should not be an issue in Lyme disease if usedsymptomatically, since NMDA receptor is overactivated. However, since the NMDA receptor is generallyunderactivated in schizophrenia, and because the Halperin & Heyes study showing dramatically elevated quinolinic acid (NDMA receptor antagonist) in Lyme neuroborreliosis involved a small and heterogeneous group of patients, ketamine should be used very cautiously in Lyme-schizophrenia.
Symptom reduction, neuroprotection, etc. . . . Because ketamine aids in cerebral delivery of IV antibiotics by ameliorating cerebral hypoperfusion, and may also ameliorate a major form of immunosuppression, the duration of antibiotic treatment and time to cure should be decreased in Lyme disease patients using ketamine. Ketamine also offers hope for late-stage patients who cannot tolerate antibiotic-induced symptom exacerbation.
**IDO Inducers**
Amyloid peptide Aβ 1-42 – induces lDO expression and a significant increase in the production of QUIN by human macrophages and microglia in Alzheimer’s. (Guillemin et al. 2003).
Interferon-β (IFN-β) – in multiple sclerosis, pharmacologically relevant concentrations of IFN-beta are able to induce the kynurenine pathway in human macrophages. (Amirkhani et al. 2005; Gullemin et al. 2001)
Interferon-γ (IFN- γ) – very potetently activates IDO
Nef (Smith et al. 2001)
Tat (Smith et al. 2001)
Tumor necrosis factor-α (TNF- α) – strongly stimulates IFN- γ
(see above)
**IDO and QUIN inhibitors as well as indirect inhibitors of toxic metabolites downstream of IDO enzyme**
•Kynurenine 3-monooxygenase drug targets (Regulator: Determines Neurotoxicity and Neuroprotection potential. Can metabolize neurotoxic 3-hydroxy-L-kynurenine which is downstream; Deficency due to cytokines can cause a shift to Kynurenic Acid; although neuroprotetive it can cause cognitive deficits including issues w/ visospatial working memory and predictive pursuit; inhibitors help neurodegenerative diseases and excitotoxicity but have potential cognitive side effects due to an increase in KYN Acid)
(QUIN causes brain lesions. So my thinking is that the body effort to combat the excitotoxicity w/ a greater production in KYN acid. KYN Acid is elevated in Schizophrenia, Autism and to a lesser degree Aspergers Syndrome.)
* Rosmarinic Acid (Found in Lemon Balm) IDO inhibitor possibly due to COX-2 inhibition; unsure how potent)
* Curcumin (Safest bet; not sure how potent at reducing QUIN)
* COX-2 inhibitors (Not that potent; potential side effects; down-regulates indoleamine 2,3-dioxygenase [IDO], leading to a reduction in kynurenine levels as well as reducing proinflammatory cytokine activity)
* Norharmane (B-Carboline; found in Syrian Rue psychedelic, very POTENT at inhibiting QUIN but of course with potential side effects; safety issues)
* NMDA Antagonists (Magnesium, Low dose Ketamine, memantine; does nothing to inhibit QUIN production but can protect against its excitotoxicity due to NMDA antagonism; 2-amino-5-phosphonopentanoic acid, MK-801 and memantine, can partially decrease QUIN toxicity; (iii) kynurenic acid can decrease LDH release in a linear manner, whereas picolinic acid does the same but non-linearly; and (iv) 1-methyl tryptophan is effective in decreasing QUIN release by the rodent microglial cell line BV-2 and thus protects NSC-34 from cell death. There is currently a lack of effective treatment for ALS and our in vitro results provide a novel therapeutic strategy for ALS patients.
* Nicotinylalanine (Inhibitor of Kynurenine Hysroxylase, which reduces QUIN production in favor of Kynurenic Acid, potential cognitive side effects)
* 1-Methyltryptophan (Racemic compound that weakly inhibits indoleamine dioxygenase,[20] but is also a very slow substrate.[21] The specific racemer 1-methyl-D-tryptophan [known as indoximod] is in clinical trials for various cancers.)
* Epacadostat and navoximod (GDC-0919) (potent inhibitors of the indoleamine 2,3-dioxygenase enzyme and are in clinical trials for various cancers.[22] BMS-986205 is also in clinical trials for cancer.[23]
* Interleukin 4 (IL-4) and Nitric Oxide (IDO-1 downregulation; however, it should be noted that nitric oxide does not inhibit IDO-1 in microglia cells.
* Astrocytes (Neuroprotective by minimizing QUIN accumulation and maximizing synthesis of KYNA) (Mycoplasma, Borrelia Burgdorferi the casuative agent of Lyme Disease have an affinity towards destroying these glial cells)
What increases the production of QUIN?
* Interferon-γ (IFN-γ) and to a lesser extent IFN-β, IFN-α, tumour necrosis factor α (TNF-α), platelet activating factor, cytotoxic T-lymphocyte antigen 4, HIV-1 proteins Nef and Tat and amyloid beta peptide 1–42 can lead to upregulation of the cellular expression of IDO-1 with consequent increased QUIN production, among others.
* Niacin is an indirect IDO-1 inhibitor. Instead of taking tryptophan, niacin is used to shift tryptophan metabolism away from the kynurenine pathway.
https://www.ncbi.nlm...les/PMC3195227/
* Cytokines may also act synergistically to increase QUIN production. For example, this happens with TNF-α and IFN-γ leading to enhanced IDO-1 activity and increased QUIN by secretion from macrophages. Seen in neurobrreliosis, CNS Lyme Disease.
* Presence of infiltrating macrophages and/or activated microglia, astrocytes become indirectly and paradoxically neurotoxic through the production of large concentrations of KYN that can be secondarily metabolized as extra substrate by neighbouring monocytic cells to synthesize QUIN.
http://onlinelibrary...12.08485.x/full
>QUIN is produced and released by infiltrating macrophages and activated microglia, the very cells that are prominent during neuroinflammation.
>QUIN acts as a neurotoxin, gliotoxin, proinflammatory mediator, pro-oxidant molecule and can alter the integrity and cohesion of the Blood Brain Barrier.
Lose of BBB integrity is probably how I got neuroborreliosis in the first place.
It is well known that activated resident microglia and infiltrating macrophages are the major source of QUIN within the brain
Neurons within the hippocampus, striatum and neocortex are sensitive to QUIN, but cerebellar and spinal cord neurons are less sensitive. These differences in regional sensitivity most likely relate to differences in NMDAR configuration [78–83]. We recently demonstrated that, by using a combination of three NMDAR antagonists, we could fully protect motor neurons from QUIN excitotoxicity.
QUIN can increase glutamate release by neurons, inhibit its uptake by astrocytes and inhibit astroglial glutamine synthetase leading to excessive microenvironment glutamate concentrations and neurotoxicity.
Dysfunctional states of distinct steps of the L-Tryptophan catabolism / kynurenine pathway (e.g. kynurenine, kynurenic acid, quinolinic acid, anthranilic acid, 3 -Hydroxykynurenine) have been described for a number of disorders, e.g.
Quinolinic acid is also elevated in Lyme disease and other illnesses.
https://www.ncbi.nlm...pubmed/1531156/
https://www.ncbi.nlm...ubmed/23548271/
Elevated kynurenine and related metabolites suppress the immune system.
https://www.ncbi.nlm...les/PMC5063567/
https://www.ncbi.nlm...ubmed/20941617/
HIV dementia
Tourette syndrome
Tic disorders
Psychiatric disorders (e.g. Schizophrenia, major depression, anxiety disorders)
Multiple sclerosis
Huntington's disease
Encephalopathies
Lipid metabolism
Liver fat metabolism
Systemic lupus erythematosus
Glutaric aciduria
Vitamin B6 deficiency
Eosinophilia-myalgia syndrome
Neuroborreliosis
**IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity.**
http://www.ncbi.nlm....pubmed/15494706
**Theanine inhibits the kynurenine pathway**
http://eprints.ru.ac.za/2336/
