Posts tagged neuroinflammation
Articles and news from the latest research reports.
Brain inflammation dramatically disrupts memory retrieval networks
Brain inflammation can rapidly disrupt our ability to retrieve complex memories of similar but distinct experiences, according to UC Irvine neuroscientists Jennifer Czerniawski and John Guzowski.
Their study – which appears today in The Journal of Neuroscience – specifically identifies how immune system signaling molecules, called cytokines, impair communication among neurons in the hippocampus, an area of the brain critical for discrimination memory. The findings offer insight into why cognitive deficits occurs in people undergoing chemotherapy and those with autoimmune or neurodegenerative diseases.
Moreover, since cytokines are elevated in the brain in each of these conditions, the work suggests potential therapeutic targets to alleviate memory problems in these patients.
“Our research provides the first link among immune system activation, altered neural circuit function and impaired discrimination memory,” said Guzowski, the James L. McGaugh Chair in the Neurobiology of Learning & Memory. “The implications may be beneficial for those who have chronic diseases, such as multiple sclerosis, in which memory loss occurs and even for cancer patients.”
What he found interesting is that increased cytokine levels in the hippocampus only affected complex discrimination memory, the type that lets us differentiate among generally similar experiences – what we did at work or ate at dinner, for example. A simpler form of memory processed by the hippocampus – which would be akin to remembering where you work – was not altered by brain inflammation.
In the study, Czerniawski, a UCI postdoctoral scholar, exposed rats to two similar but discernable environments over several days. They received a mild foot shock daily in one, making them apprehensive about entering that specific site. Once the rodents showed that they had learned the difference between the two environments, some were given a low dose of a bacterial agent to induce a neuroinflammatory response, leading to cytokine release in the brain. Those animals were then no longer able to distinguish between the two environments.
Afterward, the researchers explored the activity patterns of neurons – the primary cell type for information processing – in the rats’ hippocampi using a gene-based cellular imaging method developed in the Guzowski lab. In the rodents that received the bacterial agent (and exhibited memory deterioration), the networks of neurons activated in the two environments were very similar, unlike those in the animals not given the agent (whose memories remained strong). This finding suggests that cytokines impaired recall by disrupting the function of these specific neuron circuits in the hippocampus.
“The cytokines caused the neural network to react as if no learning had taken place,” said Guzowski, associate professor of neurobiology & behavior. “The neural circuit activity was back to the pattern seen before learning.”
The work may also shed light on a chemotherapy-related mental phenomenon known as “chemo brain,” in which cancer patients find it difficult to efficiently process information. UCI neuro-oncologists have found that chemotherapeutic agents destroy stem cells in the brain that would have become neurons for creating and storing memories.
Dr. Daniela Bota, who co-authored that study, is currently collaborating with Guzowski’s research group to see if brain inflammation may be another of the underlying causes of “chemo brain” symptoms.
She said they’re looking for a simple intervention, such as an anti-inflammatory or steroid drug, that could lessen post-chemo inflammation. Bota will test this approach on patients, pending the outcome of animal studies.
“It will be interesting to see if limiting neuroinflammation will give cancer patients fewer or no problems,” she said. “It’s a wonderful idea, and it presents a new method to limit brain cell damage, improving quality of life. This is a great example of basic science and clinical ideas coming together to benefit patients.”
Toward a clearer diagnosis of chronic fatigue syndrome
Chronic fatigue syndrome, which is also known as myalgic encephalomyelitis, is a debilitating condition characterized by chronic, profound, and disabling fatigue. Unfortunately, the causes are not well understood.
Neuroinflammation—the inflammation of nerve cells—has been hypothesized to be a cause of the condition, but no clear evidence has been put forth to support this idea. Now, in this clinically important study, published in the Journal of Nuclear Medicine, the researchers found that indeed the levels of neuroinflammation markers are elevated in CFS/ME patients compared to the healthy controls.
The researchers performed PET scanning on nine people diagnosed with CFS/ME and ten healthy people, and asked them to complete a questionnaire describing their levels of fatigue, cognitive impairment, pain, and depression. For the PET scan they used a protein that is expressed by microglia and astrocyte cells, which are known to be active in neuroinflammation.
The researchers found that neuroinflammation is higher in CFS/ME patients than in healthy people. They also found that inflammation in certain areas of the brain—the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons—was elevated in a way that correlated with the symptoms, so that for instance, patients who reported impaired cognition tended to demonstrate neuroinflammation in the amygdala, which is known to be involved in cognition. This provides clear evidence of the association between neuroinflammation and the symptoms experienced by patients with CFS/ME.
Though the study was a small one, confirmation of the concept that PET scanning could be used as an objective test for CFS/ME could lead to better diagnosis and ultimately to the development of new therapies to provide relief to the many people around the world afflicted by this condition. Dr. Yasuyoshi Watanabe, who led the study at RIKEN, stated, “We plan to continue research following this exciting discovery in order to develop objective tests for CFS/ME and ultimately ways to cure and prevent this debilitating disease.”
How Infections in Newborns are Linked to Later Behavior Problems
In animal study, inflammation stops cells from accessing iron needed for brain development
Researchers exploring the link between newborn infections and later behavior and movement problems have found that inflammation in the brain keeps cells from accessing iron that they need to perform a critical role in brain development.
Specific cells in the brain need iron to produce the white matter that ensures efficient communication among cells in the central nervous system. White matter refers to white-colored bundles of myelin, a protective coating on the axons that project from the main body of a brain cell.
The scientists induced a mild E. coli infection in 3-day-old mice. This caused a transient inflammatory response in their brains that was resolved within 72 hours. This brain inflammation, though fleeting, interfered with storage and release of iron, temporarily resulting in reduced iron availability in the brain. When the iron was needed most, it was unavailable, researchers say.
“What’s important is that the timing of the inflammation during brain development switches the brain’s gears from development to trying to deal with inflammation,” said Jonathan Godbout, associate professor of neuroscience at The Ohio State University and senior author of the study. “The consequence of that is this abnormal iron storage by neurons that limits access of iron to the rest of the brain.”
The research is published in the Oct. 9, 2013, issue of The Journal of Neuroscience.
The cells that need iron during this critical period of development are called oligodendrocytes, which produce myelin and wrap it around axons. In the current study, neonatal infection caused neurons to increase their storage of iron, which deprived iron from oligodendrocytes.
In other mice, the scientists confirmed that neonatal E. coli infection was associated with motor coordination problems and hyperactivity two months later – the equivalent to young adulthood in humans. The brains of these same mice contained lower levels of myelin and fewer oligodendrocytes, suggesting that brief reductions in brain-iron availability during early development have long-lasting effects on brain myelination.
The timing of infection in newborn mice generally coincides with the late stages of the third trimester of pregnancy in humans. The myelination process begins during fetal development and continues after birth.
Though other researchers have observed links between newborn infections and effects on myelin and behavior, scientists had not figured out why those associations exist. Godbout’s group focuses on understanding how immune system activation can trigger unexpected interactions between the central nervous system and other parts of the body.
“We’re not the first to show early inflammatory events can change the brain and behavior, but we’re the first to propose a detailed mechanism connecting neonatal inflammation to physiological changes in the central nervous system,” said Daniel McKim, a lead author on the paper and a student in Ohio State’s Neuroscience Graduate Studies Program.
The neonatal infection caused several changes in brain physiology. For example, infected mice had increased inflammatory markers, altered neuronal iron storage, and reduced oligodendrocytes and myelin in their brains. Importantly, the impairments in brain myelination corresponded with behavioral and motor impairments two months after infection.
Though it’s unknown if these movement problems would last a lifetime, McKim noted that “since these impairments lasted into what would be young adulthood in humans, it seems likely to be relatively permanent.”
The reduced myelination linked to movement and behavior issues in this study has also been associated with schizophrenia and autism spectrum disorders in previous work by other scientists, said Godbout, also an investigator in Ohio State’s Institute for Behavioral Medicine Research (IBMR).
“More research in this area could confirm that human behavioral complications can arise from inflammation changing the myelin pattern. Schizophrenia and autism disorders are part of that,” he said.
This current study did not identify potential interventions to prevent these effects of early-life infection. Godbout and colleagues theorize that maternal nutrition – a diet high in antioxidants, for example – might help lower the inflammation in the brain that follows a neonatal infection.
“The prenatal and neonatal period is such an active time of development,” Godbout said. “That’s really the key – these inflammatory challenges during critical points in development seem to have profound effects. We might just want to think more about that clinically.”
![New research proves the validity of one of the most promising approaches for combating Alzheimer’s disease (AD) with medicines that treat not just some of the symptoms, but actually stop or prevent the disease itself, scientists are reporting. The study, in the journal ACS Medicinal Chemistry Letters, also identifies a potential new oral drug that the scientists say could lead the way.
Wenhui Hu and colleagues point out that existing drugs for AD provide only “minimal” relief of memory loss and other symptoms, creating an urgent need for new medicines that actually combat the underlying destruction of brain cells. Research suggests that inflammation of nerve cells in the brain is a key part of that process. One medicine, Minozac, is in clinical trials. But Hu says Minozac still has more space to improve its efficacy. So the scientists sifted through compounds with a molecular architecture similar to Minozac in an effort to find more active substances.
The report describes success in doing so. They discovered one compound that appeared especially effective in relieving nerve inflammation and in improving learning and memory in lab mice widely used in AD research. “In general, this study not only proves that countering neuroinflammation is indeed a potential therapeutic strategy for Alzheimer’s disease, but also provides a good lead compound with efficacy comparable to donepezil [an existing AD medicine] for further oral anti-AD drug discovery and development,” the report states.](http://33.media.tumblr.com/tumblr_mbd4avIakE1rog5d1o1_500.gif)
New research proves the validity of one of the most promising approaches for combating Alzheimer’s disease (AD) with medicines that treat not just some of the symptoms, but actually stop or prevent the disease itself, scientists are reporting. The study, in the journal ACS Medicinal Chemistry Letters, also identifies a potential new oral drug that the scientists say could lead the way.
Wenhui Hu and colleagues point out that existing drugs for AD provide only “minimal” relief of memory loss and other symptoms, creating an urgent need for new medicines that actually combat the underlying destruction of brain cells. Research suggests that inflammation of nerve cells in the brain is a key part of that process. One medicine, Minozac, is in clinical trials. But Hu says Minozac still has more space to improve its efficacy. So the scientists sifted through compounds with a molecular architecture similar to Minozac in an effort to find more active substances.
The report describes success in doing so. They discovered one compound that appeared especially effective in relieving nerve inflammation and in improving learning and memory in lab mice widely used in AD research. “In general, this study not only proves that countering neuroinflammation is indeed a potential therapeutic strategy for Alzheimer’s disease, but also provides a good lead compound with efficacy comparable to donepezil [an existing AD medicine] for further oral anti-AD drug discovery and development,” the report states.
New drug could treat Alzheimer’s, multiple sclerosis and brain injury
July 24, 2012
A new class of drug developed at Northwestern University Feinberg School of Medicine shows early promise of being a one-size-fits-all therapy for Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and traumatic brain injury by reducing inflammation in the brain.
Northwestern has recently been issued patents to cover this new drug class and has licensed the commercial development to a biotech company that has recently completed the first human Phase 1 clinical trial for the drug.
The drugs in this class target a particular type of brain inflammation, which is a common denominator in these neurological diseases and in traumatic brain injury and stroke. This brain inflammation, also called neuroinflammation, is increasingly believed to play a major role in the progressive damage characteristic of these chronic diseases and brain injuries.
By addressing brain inflammation, the new class of drugs — represented by MW151 and MW189 — offers an entirely different therapeutic approach to Alzheimer’s than current ones being tested to prevent the development of beta amyloid plaques in the brain. The plaques are an indicator of the disease but not a proven cause.
A new preclinical study published today in the Journal of Neuroscience, reports that when one of the new Northwestern drugs is given to a mouse genetically engineered to develop Alzheimer’s, it prevents the development of the full-blown disease. The study, from Northwestern’s Feinberg School and the University of Kentucky, identifies the optimal therapeutic time window for administering the drug, which is taken orally and easily crosses the blood-brain barrier.
"This could become part of a collection of drugs you could use to prevent the development of Alzheimer’s," said D. Martin Watterson, a professor of molecular pharmacology and biological chemistry at the Feinberg School, whose lab developed the drug. He is a coauthor of the study.
In previous animal studies, the same drug reduced the neurological damage caused by closed-head traumatic brain injury and inhibited the development of a multiple sclerosis-like disease. In these diseases as well as in Alzheimer’s, the studies show the therapy time window is critical.