TNF-Alpha
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Dr. George Church discusses revolutionary technologies in the field of genetic engineering.
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Dr. George Church discusses revolutionary technologies in the field of genetic engineering.
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Higher omega-6:omega-3 ratios may be associated with progressive increases in TNF-α and interleukin-6 levels as depressive symptoms increase. (2007) www.sciencedaily.com
From the article:
The study, conducted in OSU’s Institute for Behavioral Medicine Research, focused on a group of 43 middle-aged to elderly men and women, nearly half of which were the caregiver spouses of people with Alzheimer’s or other dementias. By including caregivers who typically report greater stress and more depression than similar ad ults who are not caregiving, the researchers could look at how depression and diet might interact to affect inflammation.
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The analysis showed that participants who had much more omega-6 – compared to omega-3 – fatty acids, and who also were reporting more symptoms of depression, had much higher levels of IL-6 and TNF-alpha, two cytokines which enhance inflammation.
“The data suggest that higher depression and a poorer diet in terms of omega-3 can work together to promote inflammation. Other researchers have shown that clinically depressed people – those with more severe depression – often have lower omega-3 levels in their blood, and several studies have shown that supplementing diets with omega-3 improves depression,” Kiecolt-Glaser said, although the reason isn’t clear.
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“This study has shown that even in people who did not take supplements, maybe just a little bit more omega-3, could help reduce their markers for both stress and depression,” Belury said.
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Omega-3 supplementation altered interleukin-6 levels by -12% (vs +36% in placebo group) and TNF-α by -2.3% (vs +12% in placebo group). (2012) www.sciencedaily.com
From the article:
The scientists recruited 138 adults – 45 men and 93 women – who were in good health, but who were either overweight or obese and lived sedentary lives. Their average age was 51 years. Based on body mass index, a measure of weight relative to height, 91 percent of the participants were overweight and 47 percent were obese.
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Participants received either a placebo or one of two different doses of omega-3 fatty acids – either 2.5 grams or 1.25 grams per day. The supplements were calibrated to contain a ratio of the two fish oil fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), of seven to one. Previous research has suggested that EPA has more anti-inflammatory properties than does DHA.
After four months, participants who had taken the omega-3 supplements had significantly lower levels in their blood of two proteins that are markers of inflammation, also called pro-inflammatory cytokines. The low-dose group showed an average 10 percent decrease in the cytokine interleukin-6 (IL-6), and the high-dose group’s overall IL-6 dropped by 12 percent. In comparison, those taking a placebo saw an overall 36 percent increase in IL-6 by the end of the study.
Levels of the cytokine tumor necrosis factor-alpha (TNF-a) also dropped, but in a more modest way, by 0.2 percent and 2.3 percent in the low- and high-dose groups, respectively. The placebo group’s TNF-a increased by an average of 12 percent.
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Social rank and rank uncertainty predicted levels of the pro-inflammatory proteins CRP, IL-6 and TNF-alpha in monkeys. (2016) www.sciencedaily.com
From the article
The team found that social rank and rank uncertainty predicted key risk factors for poor health, specifically pro-inflammatory proteins (C-reactive protein, interleukin-6, and tumor necrosis factor-alpha) which are risk factors for chronic diseases such as cardiovascular disease and diabetes.
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The researchers discovered that high ranking monkeys with low certainty of their social status showed higher markers of inflammation, which can be a sign of a chronic disease state such as diabetes, than those with very certain status. So high-ranking monkeys may experience some health risks, but only when their position is questionable and they are consequently at risk of losing their status.
The opposite pattern was found for low ranking monkeys – high dominance certainty was associated with higher markers of inflammation, whereas low certainty was associated with lower levels of inflammatory proteins. Monkeys that are uncertain in their low rank might have opportunities for upward mobility in the hierarchy, which may be associated with better health outcomes.
Vandeleest said the results of the study show that status uncertainty alone may be a risk factor for acute diseases. The results also indicate that uncertainty in status over longer periods in relationship to rank are related to chronic disease states as well.
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TNF is associated with reversible depression-like phenotype in hamsters induced by chronic nocturnal dim light exposure. (2012) www.sciencedaily.com
From the article:
While hamsters exposed to light at night for four weeks showed evidence of depressive symptoms, those symptoms essentially disappeared after about two weeks if they returned to normal lighting conditions.
Even changes in the brain that occurred after hamsters lived with chronic light at night reversed themselves after returning to a more normal light cycle.
These findings add to the growing evidence that suggest chronic exposure to artificial light at night may play some role in the rising rates of depression in humans during the past 50 years, said Tracy Bedrosian, lead author of the study and doctoral student in neuroscience at Ohio State University.
“The results we found in hamsters are consistent with what we know about depression in humans,” Bedrosian said.
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Most importantly, hamsters that lived in dim light showed increased expression of the gene that produces tumor necrosis factor.
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They found that blocking effects of that protein, called tumor necrosis factor, prevented the development of depressive-like symptoms in hamsters even when they were exposed to light at night.
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However, hamsters that were returned to a standard light-dark cycle after four weeks of dim light at night saw their TNF levels and even their density of dendritic spines return essentially to normal.
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Mice that were socially isolated before a heart attack had increased TNF-alpha levels and 5 to 8 times more brain neuron damage. (2008) www.sciencedaily.com
From the article:
Results showed that the mice that were socially isolated prior to the heart attack showed five to eight times more damage to their neurons compared to mice that were housed together, said Weil, who is now a post-doctoral researcher at Rockefeller University in New York.
Socially isolated mice also showed evidence of greater inflammation in the hippocampus, when compared to socially housed and control mice.
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Socially isolated mice showed increased activation of microglia, a type of immune cell in the central nervous system that responds to damaged neurons, the study found.
One of the ways microglia respond is by releasing tumor necrosis factor alpha (TNF-a), one of a large family of proteins called cytokines – chemical messengers that are mobilized when the body is injured or has an infection. These cytokines cause inflammation in their effort to repair an injured or infected area of the body.
Levels of TNF-a were elevated in isolated mice, but not in socially housed mice, compared to the control mice.
The higher levels of TNF-a in the socially isolated mice, and the inflammation it caused, was the main reason for the increased neuronal damage in these animals, Nelson said.
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TNF-alpha may upregulate enzyme expression that appears to be important in the conversion of mild cognitive impairment to Alzheimer's disease. (2013) www.sciencedaily.com
From the article:
In the current study, researchers examined autopsied brain tissue from 18 patients with clinically well-characterized AD, 18 patients with MCI, and 18 non-demented patients. They found that BACE1 enzymatic activity was significantly increased in both MCI and AD brains. In 11 of 18 MCI patients, who had undergone a mini-mental state examination (MMSE) before death, the brain cortex BACE1 levels increased during early dementia followed by a precipitous decrease as the decline in cognition progressed. Increased BACE1 activity correlated with plaque numbers and cognition status. Interestingly, they also observed that there was no significant difference in BACE1 activity between MCI and AD.
The researchers also found an increase in tumor necrosis factor alpha (TNFα) in MCI brains. TNFα is an inflammatory cytokine or cell signaling protein required for amyloid protein induced neuronal death. Biochemical examination of the autopsy tissue showed that TNFα rather than other cytokines increases the response to BACE1 protein expression. The increased levels of TNFα in MCI and AD patients were not significantly different from each other.
“There is more and more evidence that BACE1 is intricately involved in the development of AD,” says the study’s lead investigator Yong Shen, PhD, of the Center for Advanced Therapeutic Strategies for Brain Disorders at Roskamp Institute, Sarasota, Florida. “Our previous studies have demonstrated elevated BACE1 enzymatic activity in AD brains and in the cerebrospinal fluid from MCI and AD patients. Our findings here suggest that BACE1 increases early in the course of MCI and is possibly induced by inflammatory molecules like TNFα and that BACE1 enzymatic activity may be important for conversion of MCI to AD. Importantly, we found that the BACE1 activity in tissue from people with MCI was significantly increased by 27%, compared with that from people with no dementia.
“We believe that BACE1 activity precedes the clinical diagnosis of AD and could be an early indicator of neuronal dysfunction or pathology in AD. Moreover, it may be a good therapeutic target for AD, as evidenced by recent promising clinical trials on BACE1 inhibitors,” he concludes.
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Microglial TNF-alpha suppresses cocaine-induced plasticity and behavioral sensitization in a mouse model. (2016) www.sciencedaily.com
From the article:
“What we discovered is that cocaine activates these microglia, which causes the release of an inflammatory signal which then tries to reverse the changes that cocaine is inducing in the neurons,”
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The team found that TNF suppresses specific synaptic changes caused by cocaine-changes that are thought to underlie addiction. But Dr. Stellwagen explains that this beneficial mechanism doesn’t last. “The microglia response fades over time. One of the things that could transition somebody from just casual use into chronic dependency might be the fading of this adaptive signal which then allows the drugs to solidify their change to the neural circuitry.”
So can microglia be enticed to keep going? To find out, the team used a pharmaceutical agent that stimulates microglial production of TNF. Researchers observed that a cocaine-induced behavioral change in mice, the progressive increase in movement induced by cocaine,-was reduced in the animals who received this agent.
This exciting result holds promise for one day developing treatments that could cut down on drug relapse rates, which can run as high as 80 per cent.
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RCT suggests that TNF-alpha antagonism may improve depressive symptoms in patients with high inflammatory biomarkers. (2012) www.sciencedaily.com
From the article:
Prior studies have suggested that depressed people with evidence of high inflammation are less likely to respond to traditional treatments for the disorder, including anti-depressant medications and psychotherapy. This study was designed to see whether blocking inflammation would be a useful treatment for either a wide range of people with difficult-to-treat depression or only those with high levels of inflammation.
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Study participants all had major depression and were moderately resistant to conventional antidepressant treatment. Each participant was assigned either to infliximab or to a non-active placebo treatment.
When investigators looked at the results for the group as a whole, no significant differences were found in the improvement of depression symptoms between the drug and placebo groups. However, when the subjects with high inflammation were examined separately, they exhibited a much better response to infliximab [TNF inhibitor] than to placebo.
Inflammation in this study was measured using a simple blood test that is readily available in most clinics and hospitals and measures C-reactive protein or CRP. The higher the CRP, the higher the inflammation, and the higher the likelihood of responding to the drug.
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Selective inhibition of soluble TNF prevented neuron loss and reduced motor deficits in a rat model of Parkinson's disease. (2014) www.sciencedaily.com
From the article:
Evidence has been piling up that inflammation is an important mechanism driving the progression of Parkinson’s disease. XPro1595 targets tumor necrosis factor (TNF), a critical inflammatory signaling molecule, and is specific to the soluble form of TNF. This specificity would avoid compromising immunity to infections, a known side effect of existing anti-TNF drugs used to treat disorders such as rheumatoid arthritis.
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Postdoctoral fellow Christopher Barnum, PhD and colleagues used a model of Parkinson’s disease in rats in which the neurotoxin 6-hydroxydopamine (6-OHDA) is injected into only one side of the brain. This reproduces some aspects of Parkinson’s disease: neurons that produce dopamine in the injected side of the brain die, leading to impaired movement on the opposite side of the body.
When XPro1595 is given to the animals 3 days after 6-OHDA injection, just 15 percent of the dopamine-producing neurons were lost five weeks later. That compares to controls in which 55 percent of the same neurons were lost. By reducing dopamine neuron loss with XPro1595, the researchers were also able to reduce motor impairment. In fact, the degree of dopamine cell loss was highly correlated both with the degree of motor impairment and immune cell activation.
When XPro1595 is given two weeks after injection, 44 percent of the vulnerable neurons are still lost, suggesting that there is a limited window of opportunity to intervene.
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TNF-alpha blocker administration clinically improved patients with chronic neurological dysfunction following stroke and traumatic brain injury (2012) www.sciencedaily.com
From the article:
The observational study¹ of 629 patients, conducted over the course of nearly two years, documents a diverse range of positive effects, including statistically significant rapid clinical improvement in motor impairment, spasticity, cognition, etc. in the stroke group, with a similar pattern of improvement seen in the traumatic brain injury (TBI) group. The study involved 617 patients treated an average of 42 months after stroke and 12 patients treated an average of 115 months after TBI, long after further spontaneous meaningful recovery would be expected.
The study was conducted at the Institute of Neurological Recovery (INR) in the USA.
The drug utilized was etanercept [a TNF blocker], a therapeutic that selectively binds and neutralizes an inflammatory immune molecule that may remain elevated for years following stroke. Etanercept was administered utilizing a novel delivery method, invented by Edward Tobinick M.D., lead author of the study.
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Systemic inflammation accompanied by an increase in serum TNF-alpha is associated with an increase in cognitive decline in Alzheimer's disease. (2009) www.sciencedaily.com
From the article:
The study found that people who had respiratory, gastrointestinal or other infections or even bumps and bruises from a fall were more likely to have high blood levels of tumor necrosis factor-α, a protein involved in the inflammatory process, and were also more likely to experience memory loss or other types of cognitive decline than people who did not have infections and who had low levels of the protein.
The blood levels and cognitive abilities of 222 people with Alzheimer’s disease with an average age of 83 were measured at the beginning of the study and three more times over six months. Caregivers were interviewed to determine whether the participants had experienced any infections or accidental injury that could lead to inflammation.
A total of 110 people experienced an infection or injury that led to inflammation during the study. Those people experienced memory loss that was at twice the rate of those who did not have infections or injuries.
People who had high levels of the protein in their blood at the beginning of the study, which may indicate chronic inflammation, had memory loss at four times the rate of those with low levels of the protein at the start of the study. Those who had high levels of the protein at the start of the study who also experienced acute infections during the study had memory loss at 10 times the rate of those who started with low levels and had no infections over the six-month period.
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TNF-alpha can bring digestion to a halt by stimulating the corresponding control area of the brain, animal study suggests. (2000) www.sciencedaily.com
From the article:
Cells in the NST [nucleus of the solitary tract] are a critical part of the neural circuitry that regulates digestive functions, including vomiting.
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The researchers conducted a study in rats to determine how these brainstem neurons responded to TNF. Rats were injected with levels of TNF comparable to concentrations present during a chronic infection. This TNF concentration activated NST neurons and caused digestion to stop - a condition called stasis. This leads to nausea, loss of appetite, and vomiting.
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In this research, many NST neurons exposed to TNF did not return to a normal level of function during the course of the study. Furthermore, these neurons became overly sensitive to normal gastrointestinal events for a prolonged time.
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Hypoxic brain injury in preemies may be treatable well after birth by administration of TNF-alpha blocker, animal study suggests. (2022) www.sciencedaily.com
From the article
Over a third of cases of cerebral palsy are still linked to being born extremely prematurely. Clinical studies have shown that severe injury can appear many weeks after birth. “The current thinking is that this form of brain injury is so severe that there is no point trying to understand it, let alone treat it,” says senior research fellow Dr Christopher Lear, lead author on the new study. “Just the concept that it might be treatable is revolutionary.”
Critically, giving the well-established anti-inflammatory drug, Etanercept (also known as ‘Enbrel’) [a TNF blocker] three days after a period of oxygen deprivation was able to almost completely prevent severe injury from developing after three weeks' recovery. The article has just been published in a leading journal, Brain. “Virtually all proposed treatments so far need to be started within the first six hours of life,” says Professor Laura Bennet. “This is often not realistic when families are overwhelmed by events around birth.”
“A therapeutic window of at least three days is exceptionally long. Much more research is needed before this approach can be tested in humans, but this remarkably wide window for treatment gives us real hope that these findings will one day lead to a new treatment in humans to prevent cerebral palsy,” says Professor Bennet.
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TNF-alpha may be a major contributor to impaired memory formation in Alzheimer's disease, rat study suggests. (2019) www.sciencedaily.com
From the article:
Professor Cliff Abraham and Dr Anurag Singh from the Department of Psychology have identified that a protein in the brain – tumor necrosis factor-alpha (TNFα) – normally associated with inflammation, becomes abnormally active in the Alzheimer’s brain, impairing the memory mechanism.
The overproduction of this protein (TNFα) may be one of the reasons behind the disease-related impairments of memory formation in the brain.
“While TNFα has been linked previously with Alzheimer’s and memory studies, it has not been understood that neural overactivity can drive the production of this protein to inhibit memory mechanisms in the brain,” Professor Abraham, a Principal Investigator with the University’s Brain Health Research Centre, explains.
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Blocking soluble TNF signaling attenuates loss of dopaminergic neurons in rat models of Parkinson's disease. (2006) TNF-alpha plays a central role in nerve and brain self-repair in a mouse model of demyelination. (2001)
From the article:
In addition to its beneficial role, TNF has been a suspected player in Parkinson’s because elevated levels of it are found in post-mortem brains and cerebrospinal fluid of people with the disease. A previous study by other researchers found that non-steroidal anti-inflammatory drugs that block production of TNF and related molecules can reduce the risk of developing Parkinson’s by 46 percent.
In the current study, UT Southwestern researchers injected two different substances into the rats' brains to cause cell death in the substantia nigra —low-dose infusion of LPS, a toxin from bacteria often used to mimic chronic inflammation of the central nervous system, and 6-hydroxydopamine, which kills cells by creating an overwhelming amount of reactive oxygen and nitrogen molecules. Cell death was measured by counting neurons in stained brain slices.
When an experimental TNF inhibitor called XENP345, designed specifically to block soluble TNF, was also introduced into the brain, dopamine neuron death was reduced by about half.
The same effect was found on cultured dopamine neurons exposed to either toxin.
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TNF-alpha plays a central role in nerve and brain self-repair in a mouse model of demyelination. (2001) www.sciencedaily.com
From the article:
The UNC scientists treated those mice and others whose genes were functional with a toxin called cuprizone that slowly stripped away the myelin coating on nerves in their brains and then observed myelin regeneration indicative of nerve repair. Normal mice recovered completely, but those lacking the functioning tumor necrosis factor-alpha gene did not, which indicated how critical the protein was to the repair process.
“We’ve found that these tumor necrosis factor molecules are very important for the white matter in the brain to repair itself,” Ting said. “White matter is part of the brain that allows motor skills, and if you don’t have it, you can’t move.”
“We further found that the repair process acts through a particular pathway that appears to induce the production of nerve precursor cells,” Arnett added. “Those cells will eventually differentiate into oligodendrocytes – cells that make myelin and surround nerve axons.”
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Recent clinical trials of several drugs designed to block the alpha form of TNF, which was considered to be a problem, actually made patients’ conditions worse, Arnett said. In part, the UNC experiments were designed to find out why.
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Administration of an anti-TNF therapeutic to Alzheimer's patients led to cognitive improvement within minutes. (2008) www.sciencedaily.com
From the article:
This new study highlights the importance of certain soluble proteins, called cytokines, in Alzheimer’s disease. The study focuses on one of these cytokines, tumor necrosis factor-alpha(TNF), a critical component of the brain’s immune system. Normally, TNF finely regulates the transmission of neural impulses in the brain. The authors hypothesized that elevated levels of TNF in Alzheimer’s disease interfere with this regulation. To reduce elevated TNF, the authors gave patients an injection of an anti-TNF therapeutic called etanercept. Excess TNF-alpha has been documented in the cerebrospinal fluid of patients with Alzheimer’s.
The new study documents a dramatic and unprecedented therapeutic effect in an Alzheimer’s patient: improvement within minutes following delivery of perispinal etanercept, which is etanercept given by injection in the spine. Etanercept (trade name Enbrel) binds and inactivates excess TNF. Etanercept is FDA approved to treat a number of immune-mediated disorders and is used off label in the study.
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While the article discusses one patient, many other patients with mild to severe Alzheimer’s received the treatment and all have shown sustained and marked improvement.
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Evidence in mice suggests that TNF-alpha release in response to viral infection causes learning problems. (2017) www.sciencedaily.com
From the article:
Evidence in mice suggests that the entry of a virus anywhere in the bloodstream turns on “first responder” immune cells called CX3CR1highLY6Clow monocytes, which then release the inflammatory signaling protein TNF-α. According to the authors of the study, TNF-α then travels to the brain where it blocks the formation of nerve cell connections needed to turn sensory information into memories.
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Researchers also measured the levels of pro-inflammatory signaling proteins (cytokines) in mice at several time points after the injection of poly(I:C), and found a larger, longer-lasting increase in levels of TNF-α than in other cytokines. Given their findings, the team guessed that the impact of systemic immune response on brain cell connections was executed through TNF-α signaling. Indeed, mice engineered to lack TNF-α signals in white blood cells saw neither a drop in dendritic spine formation nor in motor learning ability when exposed to the viral mimetic.
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Blocking soluble TNF signaling attenuates loss of dopaminergic neurons in models of Parkinson’s disease. (2006) www.sciencedaily.com
Blocking the action of TNF-alpha may slow the progression of Parkinson’s disease.
Parkinson’s disease is a progressive neurodegenerative disorder that affects the central nervous system. It is caused by the destruction of nerve cells in the part of the brain called the substantia nigra. Approximately 1 percent of all adults over the age of 60 years lives with Parkinson’s disease. Findings from a 2006 study suggest that blocking the action of tumor necrosis factor-alpha slows the progression of Parkinson’s disease.
Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine that is produced by a wide range of cells, including macrophages, lymphocytes, glial cells, and others. TNF-alpha signaling inhibits tumorigenesis, prevents viral replication, and induces fever and apoptosis. Dysregulation of the TNF-alpha signaling pathway has been implicated in a variety of disorders, including cancer, autoimmune diseases, Alzheimer’s disease, and depression.
The investigators injected the brains of mice with either lipopolysaccharide (LPS, an endotoxin that promotes acute inflammation) or 6-hydroxydopamine (a neurotoxin) and assessed the animals' brains for evidence of substantia nigra cell death. They injected a compound called XENP345 (a TNF-alpha inhibitor) into the brains of some of the mice. They also applied LPS and 6-hydroxydopamine to cultured neuronal cells and assessed the effects of XENP345 on cell death.
They found that both LPS and 6-hydroxydopamine caused marked cell death in the substantia nigra region of the animals' brains. They also found that inhibiting TNF-alpha via XENP345 in the brains and in cultured cells reduced cell death by roughly half.
These findings suggest that inhibiting the activity of the pro-inflammatory cytokine TNF-alpha reduces cell death in an animal model of Parkinson’s disease. Robust evidence indicates that exercise, which also reduces inflammation, slows the progression of Parkinson’s disease. Learn more about the effects of exercise on Parkinson’s disease in this episode featuring Dr. Giselle Petzinger.
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Probiotics may improve inflammation-associated behavioral changes in mice by lowering TNF-alpha blood levels. (2015) www.sciencedaily.com
Probiotics attenuate inflammation-associated sickness behaviors.
The gut-brain axis, a bidirectional signaling pathway between the gastrointestinal tract and the nervous system, plays critical roles in human health. Key elements of this pathway are the tens of trillions of microbes that comprise the intestinal microbiota. Findings from a 2015 study suggest that probiotics attenuate inflammation-associated sickness behaviors.
Probiotics are typically defined as live microorganisms that, when consumed in sufficient amounts, confer a health benefit on the consumer. They contain a variety of microorganisms, but Lactobacillus and Bifidobacterium bacteria are among the most common. Probiotics can be found in yogurt, kefir, kimchi, and other fermented foods and are widely available as dietary supplements.
Sickness behaviors are adaptive behavioral changes that occur during infection or chronic inflammatory disorders and may include lethargy, depressed mood, appetite loss, sleepiness, pain, or confusion. Evidence suggests that tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory cytokine produced by immune cells, activates microglia (the brain’s resident immune cells) and recruits white blood cells to the brain, driving the development of inflammation-associated sickness behaviors.
The investigators used a model of liver inflammation in mice to study the effects of a probiotic on inflammation-associated sickness behavior. Mice with this form of liver inflammation typically have high levels of pro-inflammatory cytokines and exhibit distinct sickness behaviors. They fed the mice either a probiotic or a placebo and then they studied the animals' behavior. They also measured TNF-alpha levels in the animals' blood and the number of activated immune cells in the animals' brains.
They found that although the probiotic did not reduce the severity of liver inflammation in the mice, it did reduce sickness behaviors better than the placebo. Mice that received the probiotics also had lower TNF-alpha levels and fewer activated immune cells in their brains compared to mice that received a placebo.
These findings suggest that probiotics attenuate inflammation-associated sickness behaviors in mice, likely via modulation of the gut-brain axis. Learn about factors to consider when choosing a probiotic supplement in this clip featuring Dr. Jed Fahey.
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TNF-alpha production within the brain may partially explain the behavioral changes in mice with cholestatic liver damage. (2006) www.sciencedaily.com
TNF-alpha in the brain drives sickness behaviors associated with liver disease.
Many liver disorders cause behavioral symptoms, often referred to as sickness behaviors, such as fatigue, loss of appetite, and “brain fog.” Evidence suggests that these symptoms arise from alterations in the central nervous system, but scientists don’t fully understand what drives them. Findings from a 2006 study suggest that sickness behaviors in the setting of cholestasis, a common liver disorder, are caused by the presence of tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory cytokine, in the brain.
Cholestasis is characterized by impaired bile flow and subsequent retention of bile acids, bilirubin, and other substances, including lipopolysaccharide, an endotoxin, in the liver and blood. It is a common disorder of pregnancy but can affect all demographics, including children. Most people with cholestasis report experiencing sickness behaviors, especially fatigue, which occurs in roughly 86 percent of people with the disorder.
TNF-alpha is produced by many types of immune cells. It exists in soluble and transmembrane forms, both of which mediate a variety of opposing physiological and pathological functions, depending on which of its receptors it binds to. For example, binding to TNF receptor 1 promotes apoptosis (programmed cell death) and inflammation; binding to TNF receptor 2 promotes cell survival, resolution of inflammation, immunity, and cellular repair. Elevated TNF-alpha is associated with chronic pain syndromes and anxious behaviors.
The investigators tied off the bile ducts of healthy mice to induce cholestasis. Then they isolated endothelial cells from the blood vessels in the animals' brains to see if the cells were activated and if the cells interacted with immune cells. They also measured TNF-alpha production by monocytes (white blood cells).
They found that endothelial cells were activated in the setting of cholestasis, and these activated cells readily interacted with immune cells that had been recruited to the brain. In turn, the immune cells increased their production of TNF-alpha. In light of the known effects of TNF-alpha on sickness behaviors, these findings suggest that TNF-alpha production in the brain mediates sickness behaviors in mice with liver disease.