Biocast Episode 12 – Endotoxin, Serotonin, and Depression

In Episode 12 I continue on the trail of destruction left in the wake of endotoxin. This episode looks the history of serotonin, the links between serotonin and endotoxin, and the effects of both on brain energy and symptoms of depression. This should be seen as part of a series starting with episode 8 as it references podcasts 8,9,10 and 11.

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Transcript and references:

The Biocast Episode 12 – Endotoxin Serotonin and Depression.

In this episode and going to be continuing on on the theme of the previous podcasts starting at episode 8, and looking at the effects of endotoxin. It would be a good idea to listen to those podcasts first, however give a brief summary of what I’ve discussed so far.

Endotoxin is part of the structure of some bacteria, it is present in the digestive system of humans. As part of the normal metabolism of these bacteria small amounts of endotoxin are released, when these bacteria die larger amounts are released.

Various factors can influence the amount of endotoxin that gets transported from the gastrointestinal system into the rest of the body. Some endotoxin will always be present outside of the gastrointestinal system and at a certain point above this level we will see increases inflammation. An increase of 10 to 50 times more endotoxin can cause sepsis, this is common in pretty extreme situations and some major cause of death in intensive care units. At lower levels, somewhere around 2 to 3 times and increase in endotoxin in the blood we will see other changes that are not immediately life-threatening.

In the previous podcasts I’ve looked at some of the effects of different factors on increasing endotoxin in the blood or liver, for example a high-fat meal or excessive stress. I’ve looked at some of the increases in inflammatory markers associated with endotoxin, and I have looked at some indicators that increased endotoxin in the plasma and liver can cause damage possibly leading to obesity, diabetes, metabolic syndrome, and dementias like Alzheimer’s and Parkinson’s disease.

This podcast then is going to pick up from that point. I am going to look at first the association with increased endotoxin and increased serotonin, and then look at the effects of serotonin or endotoxin on some behaviours in experiments on humans and animals.

Serotonin is derived from the amino acid tryptophan, it is mostly found in the gastrointestinal tract, small amounts are found in the brain, is closely associated with many gastrointestinal problems and it is commonly described in the medical and pharmaceutical literature as a neurotransmitter.

Dr Ray Peat describes some of the effects of serotonin along with the changes in language used to describe it over the years;
“Serotonin’s other names include thrombotonin, thrombocytin, enteramine, and 5-HT, its chemical name (5-hydroxytryptamine). These historical names derive from its role in the intestine and in blood vessels. In 1951, it was discovered that enteramine and thrombotonin were a single substance, and its involvement in circulatory disease, especially hypertension and vascular spasms, was the focus of research. (The increase in the number of “cardiovascular events” recently seen in the study of women using estrogen is what might be expected from something which increases serotonin dominance.) It causes vasoconstriction and vasospasm, and promotes clotting, when it’s released from platelets. Especially when it is released from mast cells, it is considered to be an inflammatory mediator, along with histamine. Edema, bronchoconstriction, immunosuppression, and joint swelling are produced by the release of serotonin from platelets or other cells. As inflammatory mediators, serotonin and histamine are directly involved in asthma, hives, gastrointestinal damage from alcohol, nerve cell damage, edema, and shock.”

That said, lets first take a look at the effect of endotoxin on serotonin.

So the first link included looks at the effect of endotoxin on rabbit blood samples. It found that a relatively low dose of endotoxin would cause serotonin to move from the blood platelets into the blood plasma.
Lipopolysaccharide administration produces time-dependent and region-specific alterations in tryptophan and tyrosine hydroxylase activities in rat brain

The next study looks at the effect of endotoxin on tyrosine hydroxylase, and tryptophan hydroxylase in regions of rat brain. Tyrosine hydroxylase is the enzyme that converts the amino acid l-tyrosine to L-dopa, L-dopa is an important precursor for the neurotransmitter dopamine. Tryptophan hydroxylase is involved in the synthesis of serotonin from tryptophan. Both of these enzymes are described as the rate limiting factors in the synthesis of these neurotransmitters.

The paper cites references that demonstrated long-term isolation would increase tyrosine hydroxylase while auditory stress would increase the activation of tryptophan hydroxylase in certain parts of the brain. The paper suggests that these models of stress may look similar to the addition of endotoxin as a model of stress. Another substance that used in the experiments was NSD 1015, this is a decarboxylase inhibitor and it was used in order to prevent the destruction of the two enzymes in order that they could be measured.

The study found a significant increase in cortical and midbrain concentrations of serotonin but in the striatum their analysis showed no significant effect on serotonin. There was a significant effect on L-dopa only in the midbrain. The paper states that both enzymes are activated in response to peripheral endotoxin, varying with time and region of the brain.

The paper cites references showing increases in serotonin activity in the rat hippocampus, hypothalamus, frontal cortex ,and brainstem of rodents.

So the next paper then takes a step back to the gut and looks at the synthesis of serotonin in the colon.
Indigenous Bacteria from the Gut Microbiota Regulate Host Serotonin Biosynthesis

Tells us that the gastrointestinal tract contains most of the body’s serotonin but that the mechanisms are controlling serotonin synthesis were to this point unclear. The paper mentioned some of serotonins known effects on gastrointestinal diseases immune response and bone development along with cardiac function. Adult germfree mice are known to be quite the paper calls deficient in serum and plasma serotonin controls. These germfree mice have significantly lowered levels of colonic and faecal serotonin. The germfree rodents were found to have lowered levels of the tryptophan hydroxylase one enzyme, which catalyses the conversion from tryptophan to serotonin.

When a crossover of gut bacteria was performed from the germfree mice, that is they transplanted gut bacteria from conventional mice into germfree mice they found that the serum and colon levels of serotonin were increased to those seen in conventional mice. Then in an attempt to reverse the effects on serotonin the mice were giving an antibiotic treatment of four different antibiotics. Significant decreases in serotonin were seen with the antibiotics.

The paper also shows that platelets, also thrombocytes, which are a component of the blood whose function is to stop bleeding, by increasing clotting would uptake serotonin produced in the gut and delivered to sites of clotting around the body. Germfree rodents were seen to have slower clotting time be related to the levels of serotonin in the platelet from the gut. In the previous podcast I looked at endotoxin’s effects on other clotting factors possibly involved in dementia, fibrin and fibrinogen.The paper also noted that metabolites of some bacteria like butyrate and propionate, often said to have a beneficial effect on the gut function, can increase serotonin expression, at least in a cell culture model.
Endotoxin Administration Stimulates Cerebral Catecholamine Release in Freely Moving Rats as Assessed by Microdialysis

The last paper then on the effect of endotoxin on serotonin is a study on rodents. The rodents received either endotoxin or a saline solution and had probes in various parts of their brain record markers of catecholamines, including a breakdown product of serotonin 5HIAA. It seems from my reading so far that the synthesis of serotonin or the release of serotonin from the platelet might be more important than 5H IAA in determining its potential pathological effects, however increased 5HIAA might be an indicator of increased synthesis. The paper explains that concentrations of serotonin could not be measured reliably in this model so they used 5H IAA as a proxy measurement.

They found elevations of 5H IAA in both of the brain regions that were tested, along with significant increases in norepinephrine and dopamine which peaked around two hours and returned to baseline two hours after that in one area of the brain only, the medial hypothalamus.

They also tested the effects of a non-steroidal anti-inflammatory drug called Indomethacin. This is a Cox two inhibitor, similar to aspirin in that regard and it inhibits the production of prostaglandins. Previous experiments had shown no effect from indomethacin on ACTH and corticosteroid after endotoxin treatment. Another experiment showed that indomethacin prevented the increase in catecholamines. In this experiment the indomethacin pretreatment completely prevented any increase in 5HIAA or other catecholamine or measured metabolites.
The Influence of Serotonin on Oxidative Metabolism of Brain Mitochondria

The next paper looks at the effect of serotonin on oxidative phosphorylation in the mitochondria. Mitochondria is organelle in some cells that produces energy, oxidative phosphorylation is the enzymatic process that cells can use to oxidise nutrients to create energy. An interesting point that the paper notes in the beginning is that serotonin is involved in the hypnotic effect of the drug hexobarbital, this was used in the 1950s as an anaesthetic and is classified as a barbiturate, sedative, and hypnotic drug.

So this looked at the effect of serotonin and its metabolites on mitochondria taken from rodent brain cells. It also looked at the relevance of monoamine oxidase in this context. Monoamine oxidase is an enzyme that breaks down monoamines including but not limited to serotonin. This was the method by which they were going to identify any difference in the effect of serotonin and potentially its metabolites.

The paper found that serotonin could inhibit energy producing reactions in brain mitochondria and suggested that this could impede brain function, use of a monoamine oxidase inhibitor prevented the effects on metabolism suggesting that they were caused by a metabolite of serotonin rather than serotonin itself and in a further experiment serotonin metabolite 3IAAL was found to have similar effects to serotonin alone.
Brain serotonin metabolism in hibernation.

The next study looks at serotonin monoamine oxidase and 5HIAA in ground squirrels. This paper found that when entering into hibernation the animals had increased serotonin with decreased MAO and 5 HIAA and when coming out of hibernation this pattern was reversed and serotonin decreased while its metabolite five HIAA increased and the enzyme responsible for degrading it monoamine oxidase also increased.
A critical review of human endotoxin administration as an experimental paradigm of depression

The next paper going to take a look at is a review of data on endotoxin administration as a model of depression.The paper from 2010 describes major depressive disorder or depression is a debilitating disorder with inadequate treatments where the causes are poorly understood. For psychiatric diagnostics, some of the criteria assessed are alterations are mood, motivation, sleep, energy, psychomotor parameters, self-esteem, hope, cognition, and changes in weight and appetite. Both serotonin and endotoxin are shown independently to affect the latter two, weight and appetite, both known to increase weight and seemingly paradoxically be known to cause anorexia like behaviours.

The paper notes that the common treatments for depression are often targeting monoamines like serotonin and that in the minority of situations were these drugs seem to work the actual mechanisms are still unclear. For example in some cases fluoxetine AKA Prozac can reverse depression and this is said to be due to its effect on serotonin reuptake, however fluoxetine also increases brain allopregnanolone. In rodent models this in itself can reverse behaviours associated with depression. I’ll include some articles on that topic in the references though there are many more.
Elevation of brain allopregnanolone rather than 5-HT release by short term, low dose fluoxetine treatment prevents the estrous cycle-linked increase in stress sensitivity in female rats.
Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits.
Allopregnanolone regulates neurogenesis and depressive/anxiety-like behaviour in a social isolation rodent model of chronic stress.

Cytokines are a group of small proteins that are involved in cell signalling, inflammatory cytokines are involved in increasing inflammation. In the recent podcasts on endotoxin I’ve spoken a little bit about some of the inflammatory cytokines. This paper lists some tables with increased levels of some inflammatory cytokines associated with depression.

It lists the levels of tumour necrosis factor in plasma in depressed verses non-depressed subjects in a number of studies and the overall paradigm seems to be that tumour necrosis factor increases by 60 to 100% in cases of depression. It provides a table showing very large increases in the levels of interleukin-6 in depression. I’ve mentioned both of these inflammatory cytokines in the previous podcasts as both are increased significantly by plasma endotoxin.

The paper notes that some studies show a decrease in inflammatory cytokines from antidepressants suggesting that perhaps antidepressants were acting as anti-inflammatories, and it notes the antidepressant effects of drugs used as anti-inflammatories. For example some Cox two inhibitors have been shown to be superior to placebo’s in cases of antidepressant resistant depression. Cox two inhibitors block the conversion of the polyunsaturated fatty acid arachidonic acid into its inflammatory metabolites. In fact aspirin, which is a Cox two inhibitors has been shown to be as effective as fluoxetine or the other antidepressant imipramine in models of depression in rodents.
Effects of aspirin on immobile behavior and endocrine and immune changes in the forced swimming test: comparison to fluoxetine and imipramine.

It was on to discuss immune induced depressive -like behaviour rodents claiming a vast amount of data exists on the subject. The most common model of this type of depression in rodents is an injection of endotoxin into the abdominal cavity. This produces behaviours which can be analysed to be similar to depression behaviours in humans including, decreases in novelty seeking behaviour, decreases in social behaviours, reduced food intake, sleep disturbance, and anhedonia which is the inability to experience pleasure.

The paper discusses the similarity with the signal of the inflammatory mediators in rodents and monkeys, noting that the depressive like behaviours can continue long after the acute sickness effects of the endotoxin are obvious, citing delayed effects in inflammatory cytokines in the brain for several weeks, previously I’ve talked about a study showing increased inflammatory cytokines in the brain from a peripheral exposure to endotoxin lasting 10 months.

The paper explains all the pathways which I have discussed before with endotoxin binding to CD14 and then toll -like receptor four which activates NFkB, which in turn affects the expression of various things including Cox -2, tumor necrosis factor ,and interleukin-6 and also leading to an increase in inducible nitric oxide synthase. The paper charts some of the pathways from this immune system activation to the brain and then from the brain feeding back into the immune system again, the signals coming from the brain are in part anti-inflammatory and mediated through the HPA axis and vagus nerve, though pro-inflammatory signals are also sent from the brain.

The paper mentions some evidence in humans and animal models that psychogenic and psychological stressors can lead to increased peripheral inflammation. In one of the previous podcasts on the effects of endotoxin on obesity and diabetes I mentioned study that showed destruction of the barrier function of the gastrointestinal system leading to increased plasma endotoxin and the inflammatory cytokines caused by the endotoxin.

The paper explained that it can be difficult to figure out cause and effect regarding the inflammation signals going to and from the brain. The effects of the typhoid vaccine on mood is mentioned in the paper, that it has a subtle effect on mood in the short term with an observed increase in interleukin-6 in the blood along with fatigue and memory impairment.

Low doses of endotoxin cause mild depressive symptoms and increases tumor necrosis factor and interleukin-6 humans, while larger doses cause flulike symptoms, headache, chills, fever, nausea, and myalgia. There is a dose-response relationship between endotoxin and TNF alpha and interleukin-6 and there are also known individual variations in response.

Studies are referenced showing depression as a symptom of acute infection and low-dose endotoxin inducing depressed mood in humans. The depressive effects of endotoxin administration humans are significant after three hours and some of the studies and they correlate with the levels of TNF alpha.The paper describes different methods of subjectively measuring depression, some of them seem to track more closely to endotoxins and inflammation than others.

Experimental subjects exposed to endotoxin were more likely to answer a questionnaire on social interactions saying that they wanted to be alone rather than with other people. In rodents endotoxin decreases exploration of novel environments and engagement in social behaviours, lower neuronal activity is seen in regions of the brain involved in reward when presented with a new environment and sexual behaviour in female relevance is disrupted while in males it is not.

Food intake is suppressed in humans and rodents exposed to endotoxin and higher doses of endotoxin can disrupt sleep in humans, though interestingly the disruption of sleep from experiments with endotoxin seems to show a different pattern and the sleep disruption in idiopathic depression. In rodents endotoxin also disrupts sleep and the effects are mediated by the inflammatory cytokines.

Another factor in the depression diagnosis is fatigue, which is common in infections which are associated with inflammation. Fatigue can be induced in humans by endotoxin and it is associated with increased interleukin-6 but not interleukin-1 TNF. Typhoid vaccination induced slowing of psychomotor abilities is correlated with increased activity of interleukin-6 in a part of the brain called the substantive nigra which I spoke about a little in the previous podcast on endotoxin and dementia. Similar effects were seen in rodent models but in this case the cytokines interleukin-1 and TNF also seemed to trigger fatigue.

Endotoxin -induced cognitive impairment in humans and problems with learning in rodents which was associated with loss of neurons and increased inflammatory cytokines. The paper mentioned the Cox two inhibitor could reduce the effects of endotoxin on cognition in rodent models. Finally the paper mentions increased anxiety markers in rodents and humans.
Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response

Serotonin has been marketed as the happy hormone for many decades now and serotonin modulating drugs certainly seem to have effects on mood and behaviour. Probably the most marketed serotonin themed drugs are the selective serotonin reuptake inhibitors often simply called antidepressants. The next paper takes a look at the serotonin marketing narrative along with these drugs and their effects.

This class of drug was originally marketed as having the effect of keeping serotonin within the synapse, that the increases serotonin in this area would increase happiness by repeatedly stimulating the synaptic receptors. I don’t believe any of this has been proven so far. The paper describes how the synaptic theory of serotonin and depression was derived from observations with drugs that had the effect of either blocking the serotonin transporter or inhibiting the enzyme that breaks down serotonin would decrease depressive symptoms. The theory was then created that depression was caused by reduced monoamine transmission simplified to low serotonin.

Measuring the movement of serotonin within the brain or synapse of a live human is impossible and serotonin does not cross the blood brain barrier so blood measures are not the direct measure of what’s going on in the brain. After discussing many of the problems involved with assessing serotonin in the brain of a live human the paper argues that the ratio of serotonin to its byproduct metabolite 5H IAA is the best marker what it a serotonin transmission. I think transmission just simply means an easy method of exchange of information from one neuron to another, this can be done electrically, or chemically so in this case it would be simply an increased amount of serotonin being passed from one synapse to another.

The paper mentioned variations in the SERT gene, variations of which will in theory lead to increased serotonin in the synapse by reducing reuptake, these variations are associated with an increased risk of depression in response to stressors, contradicting the low serotonin hypothesis. This variation of this gene that leads to increased serotonin is also associated with an increased risk of anxiety.
The jugular vein brings blood directly from the brain, so it is the part of the body were you would find the least contamination with peripheral or non-brain derived serotonin, so this may be the closest thing we could get you a sample of brain serotonin as things stand. In another study on humans, looking at the levels of 5HIAA in samples of blood from the jugular vein of depressed humans the levels were found to be increased and with treatment of SSRI drugs the levels of 5HIAA decreased 12 weeks later. Increased levels of 5HIAA were also found in patients diagnosed with panic disorder.

Further on the paper mentions the drug tianeptine AKA stablon. This drug has a number of effects that might alter depressive symptoms but the paper focuses on the fact that it is serotonin reuptake enhancer, that is to say it will limit the amount of synoptic action a given amount of serotonin can produce, or lowering the effect of serotonin in this context. It is comparable to other antidepressants in its ability to lower symptoms of depression in some people, again contradicting the low serotonin narrative.

The paper references articles showing of increased serotonin transmission in infection which is known to cause depressive symptoms, the serotonin/5HIAA ratio were specifically analysed in the hippocampus and hypothalamus. In rodent models of depression using situations of inescapable shock increased cellular serotonin is measured in various parts of the brain and his evidence is used to suggest that this increase is caused by increased serotonin transmission.

Similar patterns are seen in rodent models of chronic social defeat, chronic mild stress, chronic restraint and stress, maternal separation and social isolation. The paper mentions that neonatal exposure to SSRIs leads to increased serotonin transmission in the adult animal in the hypothalamus which is accompanied by depressive behavioural profile.

Rodents with a couple of different variations of genetic mutations that would lead to higher synaptic serotonin express higher levels of depressive behaviour.After presenting this information the paper goes on to argue that the serotonergic system was probably first evolved to regulate cellular energy activity via the mitochondria, effectively controlling the metabolism of every organ and metabolic process in the body through various serotonin receptors of which it lists 14 in seven different classes.

The paper puts forward an argument that serotonin is involved in regulating major metabolic pathways for generating ATP from glucose. Serotonin can regulate aerobic glycolysis and as we seen already it affects levels of oxidative phosphorylation. Oxidative phosphorylation is more efficient but aerobic glycolysis generate ATP at a faster rate.

Serotonin affects blood glucose homeostasis, fat storage and metabolism, it can affect energy distribution through the vascular system contracting or dilating vessels.The paper details a long list of interactions between serotonin and energy production in various parts of the body, altering oxidative phosphorylation and glycolysis for example. Exercise depletes glycogen in the brain and skeletal muscle of rodents while increasing serotonin in the same regions, both normalise with recovery. The paper then suggests that some of the seemingly contradictory effects of serotonin are due to its state dependent effects, that is that in a different energetic state serotonin can have a different effect on a region function.

The paper argues that the effects of SSRIs are due to a compensatory reaction to the drug rather than their stated pharmacological properties. SSRIs change the ratio of intracellular to extracellular serotonin in the brain within minutes or hours of the administration. This changes the energy homeostasis of various regions. In rodents this increase in extracellular serotonin promotes glycolysis in the hippocampus and inhibits oxidative phosphorylation in the mitochondria of the rodent liver and brain.

With SSRIs there is a claimed therapeutic delay, that is that the effects of the drug are not supposed to be felt immediately but after a period of weeks, this coincides with the amount of time that it takes for the balance of intra-and extracellular serotonin to normalise from the initial effects of the drug. Another property of SSRIs and antidepressant medications in general claimed by the authors is that they actually decrease the synthesis of total serotonin. Effects of SSRIs on the serotonin 5-HT one a receptor over the same time period are explained as adaptive response to restore energy homeostasis in response to the administration of the drug.

Another potentially important time-dependent effect of SSRIs is that they initially increase glutamatergic transmission, this is seen to increase the effect of the neurotransmitter glutamate which is excitatory and in excess may be involved in many brain related problems. The paper lists a number of other cases involving antidepressant drugs for their acute effects are known to be the opposite of their chronic effects, further supporting the argument that any therapeutic effect might be due to an adaptive or compensatory response to drugs rather than the stated pharmacological mechanisms. A number of animal models are provided showing the decrease in total serotonin in regions of the brain was the longer term effect of SSRIs.

A section on melancholia, a type of manic depression with associated bodily complaints and often delusions points to sustained activation of the HPA axis as an indicator of its effects on energy homeostasis. The authors compare melancholia to an adaptive process known as learned helplessness, in both the excitatory neurotransmitter glutamate increased and its inhibitory counterpart gather is decreased. The authors suggested that these states may be adaptations to environmental stress that increases the energetic expenditure of the brain perhaps to increase problem-solving capacity.

Rumination, which is persistent, distraction resistant thinking is associated with melancholia. Large and complex problems are broken down into smaller more manageable problems which are sequentially studied. Inescapable shock models in rodent experiments are the closest model to melancholia in humans.

In problem solving experiments where using cues in the environment are relevant highly stressed animals will outperform control groups and rodent models of stress show increased expression of glycolytic genes, so the brain may in part be altered by stress mediated by serotonin of regulating glycolysis which will produce ATP at a faster rate than oxidative phosphorylation, which itself is the more efficient process. The paper argues that the melancholic state requires so much energy for problem-solving that growth and reproduction down regulated.

In rodent models of shock there is an increase in serotonin, if and when this shock stimulus is escaped by the animal the transmission of serotonin will be interrupted and no depressive symptoms will be observed. However in cases where rodents were subjected to inescapable shock this serotonin transmission is not interrupted and depressive symptoms are generated. There is some debate about what is going on in the case of inescapable shock learned helplessness, while some might interpret it as a solely degenerative or incapacitating effect on the organism, this paper sees it as an adaptive attempt to escape the environmental stress by altering brain metabolism.

The paper makes a number of different arguments for serotonin and energy homeostasis effects on various parts of the brain correlating to symptoms of melancholia in humans and animals. The shrinkage of the part of the brain called the hippocampus during depression could be an example of this energetic modulation, that the resources are allocated to problem-solving and literal brain growth and regeneration is energetically limited. The final point I’ll mention from this article is the statement that antidepressant medications are seen to only reduce symptoms to the degree that they induce a response by the brain which suppresses the allocation of energy devoted to cognition.
I have a lot of data to get through on this topic, but for today and just briefly mentioned two more papers. The first is a prospective cohort study of almost 4000 people aged 60 years older.
Antidepressant Use in the Elderly Is Associated With an Increased Risk of Dementia

So this looked at people with and without dementia, with or without depression, and with or without the use of SSRI drugs. The findings of the paper’s analysis were that SSRI users had a higher risk of dementia when compared to depressed individuals who did not use SSRIs, or non-depressed individuals. This paper can’t say anything about the effects of SSRIs on dementia, it may be that people who are more depressed are more inclined to use SSRIs and that the potential root cause of depression may be the same as the cause of dementia.

And the last paper we will look at is switching back to endotoxin.

Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia
This paper looks at a rodent model of behavioural sickness and anhedonia. They pretreated the rodents in some of these experiments with the antibiotic minocycline before administering endotoxin. The administration of minocycline reduced cytokine production and behavioural symptoms associated with endotoxin, that is social withdrawal and behaviours indicating anhedonia. The antibiotic also mitigated most of the increase in central nervous system cytokine production and toll -like receptor 2. Toll -like receptor two is upregulated in response to endotoxin, it’s similar but not identical in its effects to toll -like receptor four which I’ve spoken about in previous podcasts. One interesting point that they note in the paper is that the effects of minocycline in this context were similar to the effects seen by vitamin E as alpha-tocopherol in previous studies with endotoxin.

That is the end of the podcast back next week with a continuation of this subject. I post some of the studies that do not make it into the shows on the resonantfm facebook page, so if you’re on facebook that’s another place to follow some of this information. If you find this podcast helpful please consider supporting the shown patron and share these shows around. I’d like everyone who is supporting the shown patron for their support. I put out regular content for patreon supporters, I have been putting out podcasts on the patreon feed recently it’s likely in the short term however is that I will be putting out articles on patriarchal rather than podcasts. I’m currently having a flareup of a thyroid condition which is limiting the amount of research and production I’m able to do so one attempt is to get an episode of the bio cast out every week and a patreon article at about the same frequency, so if you’re a patreon supporter and the podcast feed is a little quiet be sure to check out the patriarch page every so often. Thanks for listening.

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