Someone on Eurolyme has been posting about his research into inflammation in the brain in Lyme and other chronic diseases. He's given me permission to repost his thoughts here. See below - his name is Anthony. (I've asked him to join this board but he doesn't have time for another board at the moment.)
What he says seems well-informed - perhaps it takes us forward a little?
Jenny
....................................................................................................................
In several psychiatric and neurodegenerative diseases, some of the
> inflammatory components of the immune system are chronically overactivated.
> This stimulates the enzyme IDO, which starts the breakdown process for
> tryptophan. Tryptophan is a precursor of melatonin and serotonin. So if
> tryptophan breakdown is excessively stimulated, it should eventually result
> in depleted tryptophan, and therefore depleted melatonin and serotonin.
> Depleted melatonin would explain the high rate of insomnia in Lyme disease.
>
>>
> Ninety five percent of tryptophan in the brain is broken down in the
> kynurenine pathway for tryptophan metabolism. If there is chronic brain
> inflammation and excessive breakdown of tryptophan, this often causes
> imbalances in tryptophan byproducts. There are three byproducts in
> particular that are most important:
>>
> * 3-hydroxykynurenine
>
> * quinolinic acid
>
> * kynurenic acid
>
>>
> Neurons have multiple receptors, such as receptors for serotonin, dopamine,
> NMDA, etc.
>
>>
> Quinolinic acid activates the NMDA receptor on neurons.
>
>>
> Kynurenic acid inhibits the NMDA receptor on neurons.
>>
>
> Even mild elevations in 3-hydroxykynurenine in the brain cause oxidative
> stress, resulting in cellular damage in the brain.
>>
>
> If quinolinic acid in the brain is highly elevated, this overactivates the
> NMDA receptor on neurons. When the NMDA receptor is constantly activated,
> this allows too much calcium to flow into neurons. Too much calcium inflow
> causes damage and destruction of neurons.
>
>>
> If there is insufficient kynurenic acid in the brain, the NMDA receptor is
> not inhibited enough, so it is constantly activated - much like the scenario
> where there is too much quinolinic acid, i.e., too much calcium inflow into
> neurons, causing their damage and destruction.
>>
>
> If there is too much kynurenic acid in the brain, this causes excessive
> build-up of dopamine around neurons.
>
>>
> High elevation of quinolinic acid in the brain and/or cerebrospinal fluid
> (often accompanied by elevated 3-hydroxykynurenine) is known to occur in
> Lyme disease, chronic depression, Alzheimer's, HIV dementia, ALS, and early
> Huntington's disease.
>
>>
> In Parkinsonism, there is too little kynurenic acid.
>
>>
> In schizophrenia and bipolar disorder, there is too much kynurenic acid.
>
>>
> It is hard to get accurate measurements of these tryptophan byproducts,
> because the most reliable measurements are based on analysis of
> cerebrospinal fluid or post-mortem brain samples. Measurements of these
> byproducts in the blood aren't very reliable. Imbalances in the
> cerebrospinal fluid often don't show up in the blood. But if there are
> imbalances in the blood, there are almost certainly imbalances in the
> cerebrospinal fluid.
>
>>
> In a study of 16 patients who tested positive for Lyme based on antibodies
> in the cerebrospinal fluid, and who had clear clinical signs of central
> nervous system (CNS) infection, 14 of the patients had elevated quinolinic
> acid. The average level of elevation was 15 times higher than healthy
> subjects. The authors concluded that in Lyme with CNS infection, quinolinic
> acid is "dramatically elevated." In this study, there was no tryptophan
> depletion in the cerebrospinal fluid. The authors believed this was because
> the infection was not yet "intense" enough to deplete tryptophan. Source:
> Halperin JJ, Heyes MP. Neuroactive kynurenines in Lyme borreliosis.
> Neurology. 1992 Jan;42(1):43-50.
>
>>
> I haven't found any studies on tryptophan byproducts in chronic pain
> patients, although I haven't focused my research on this area. However, in
> chronic Lyme disease, about 80% of patients have reduced blood flow in the
> brain. This is probably due to inflammation inside the blood vessels in the
> brain (cerebral vasculitis). Fibromyalgia also involves reduced blood flow
> in the brain. In the studies of ketamine for fibromyalgia, reduction of
> symptoms was strongly correlated with increased blood flow in the brain. In
> other words, there was a reduction in the inflammatory immune components
> that trigger excessive breakdown of tryptophan and imbalances in tryptophan
> byproducts. So it would be very surprising if quinolinic acid were not
> elevated, or kynurenic acid was not reduced in fibromyalgia. In one of the
> case reports for ketamine in chronic regional pain syndrome, the remission
> of symptoms was accompanied by significant increase in blood flow in the
> brain. So - probably the same thing.
>
>>
> Elevations in IDO (which activates tryptophan), and in quinolinic acid and
> 3-hydroxykynurenine, are known to suppress the T cell response to infections
> in humans. In mice, this can also cause an autoreactive B cell response.
> This is one way in which Lyme disease very likely suppresses the T cell
> response, and might cause B cell autoimmunity. This is driven by
> inflammation. Since herxing is due to increased inflammation, it very likely
> increases neurotoxicity and immune system dysregulation.
>
>>
> Anthony
>
>
>
>
>
What he says seems well-informed - perhaps it takes us forward a little?
Jenny
....................................................................................................................
In several psychiatric and neurodegenerative diseases, some of the
> inflammatory components of the immune system are chronically overactivated.
> This stimulates the enzyme IDO, which starts the breakdown process for
> tryptophan. Tryptophan is a precursor of melatonin and serotonin. So if
> tryptophan breakdown is excessively stimulated, it should eventually result
> in depleted tryptophan, and therefore depleted melatonin and serotonin.
> Depleted melatonin would explain the high rate of insomnia in Lyme disease.
>
>>
> Ninety five percent of tryptophan in the brain is broken down in the
> kynurenine pathway for tryptophan metabolism. If there is chronic brain
> inflammation and excessive breakdown of tryptophan, this often causes
> imbalances in tryptophan byproducts. There are three byproducts in
> particular that are most important:
>>
> * 3-hydroxykynurenine
>
> * quinolinic acid
>
> * kynurenic acid
>
>>
> Neurons have multiple receptors, such as receptors for serotonin, dopamine,
> NMDA, etc.
>
>>
> Quinolinic acid activates the NMDA receptor on neurons.
>
>>
> Kynurenic acid inhibits the NMDA receptor on neurons.
>>
>
> Even mild elevations in 3-hydroxykynurenine in the brain cause oxidative
> stress, resulting in cellular damage in the brain.
>>
>
> If quinolinic acid in the brain is highly elevated, this overactivates the
> NMDA receptor on neurons. When the NMDA receptor is constantly activated,
> this allows too much calcium to flow into neurons. Too much calcium inflow
> causes damage and destruction of neurons.
>
>>
> If there is insufficient kynurenic acid in the brain, the NMDA receptor is
> not inhibited enough, so it is constantly activated - much like the scenario
> where there is too much quinolinic acid, i.e., too much calcium inflow into
> neurons, causing their damage and destruction.
>>
>
> If there is too much kynurenic acid in the brain, this causes excessive
> build-up of dopamine around neurons.
>
>>
> High elevation of quinolinic acid in the brain and/or cerebrospinal fluid
> (often accompanied by elevated 3-hydroxykynurenine) is known to occur in
> Lyme disease, chronic depression, Alzheimer's, HIV dementia, ALS, and early
> Huntington's disease.
>
>>
> In Parkinsonism, there is too little kynurenic acid.
>
>>
> In schizophrenia and bipolar disorder, there is too much kynurenic acid.
>
>>
> It is hard to get accurate measurements of these tryptophan byproducts,
> because the most reliable measurements are based on analysis of
> cerebrospinal fluid or post-mortem brain samples. Measurements of these
> byproducts in the blood aren't very reliable. Imbalances in the
> cerebrospinal fluid often don't show up in the blood. But if there are
> imbalances in the blood, there are almost certainly imbalances in the
> cerebrospinal fluid.
>
>>
> In a study of 16 patients who tested positive for Lyme based on antibodies
> in the cerebrospinal fluid, and who had clear clinical signs of central
> nervous system (CNS) infection, 14 of the patients had elevated quinolinic
> acid. The average level of elevation was 15 times higher than healthy
> subjects. The authors concluded that in Lyme with CNS infection, quinolinic
> acid is "dramatically elevated." In this study, there was no tryptophan
> depletion in the cerebrospinal fluid. The authors believed this was because
> the infection was not yet "intense" enough to deplete tryptophan. Source:
> Halperin JJ, Heyes MP. Neuroactive kynurenines in Lyme borreliosis.
> Neurology. 1992 Jan;42(1):43-50.
>
>>
> I haven't found any studies on tryptophan byproducts in chronic pain
> patients, although I haven't focused my research on this area. However, in
> chronic Lyme disease, about 80% of patients have reduced blood flow in the
> brain. This is probably due to inflammation inside the blood vessels in the
> brain (cerebral vasculitis). Fibromyalgia also involves reduced blood flow
> in the brain. In the studies of ketamine for fibromyalgia, reduction of
> symptoms was strongly correlated with increased blood flow in the brain. In
> other words, there was a reduction in the inflammatory immune components
> that trigger excessive breakdown of tryptophan and imbalances in tryptophan
> byproducts. So it would be very surprising if quinolinic acid were not
> elevated, or kynurenic acid was not reduced in fibromyalgia. In one of the
> case reports for ketamine in chronic regional pain syndrome, the remission
> of symptoms was accompanied by significant increase in blood flow in the
> brain. So - probably the same thing.
>
>>
> Elevations in IDO (which activates tryptophan), and in quinolinic acid and
> 3-hydroxykynurenine, are known to suppress the T cell response to infections
> in humans. In mice, this can also cause an autoreactive B cell response.
> This is one way in which Lyme disease very likely suppresses the T cell
> response, and might cause B cell autoimmunity. This is driven by
> inflammation. Since herxing is due to increased inflammation, it very likely
> increases neurotoxicity and immune system dysregulation.
>
>>
> Anthony
>
>
>
>
>