Posts Tagged inflammation

[WEB SITE] Traumatic brain injuries could be healed using peptide hydrogels

Traumatic brain injury (TBI) –– defined as a bump, blow or jolt to the head that disrupts normal brain function –– sent 2.5 million people in the U.S. to the emergency room in 2014, according to statistics from the U.S. Centers for Disease Control and Prevention. Today, researchers report a self-assembling peptide hydrogel that, when injected into the brains of rats with TBI, increased blood vessel regrowth and neuronal survival.

The researchers will present their results at the American Chemical Society (ACS) Fall 2019 National Meeting & Exposition. ACS, the world’s largest scientific society, is holding the meeting here through Thursday. It features more than 9,500 presentations on a wide range of science topics.

“When we think about traumatic brain injuries, we think of soldiers and athletes,” says Biplab Sarkar, Ph.D., who is presenting the work at the meeting. “But most TBIs actually happen when people fall or are involved in motor vehicle accidents. As the average age of the country continues to rise, the number of fall-related accidents in particular will also increase.”

TBIs encompass two types of injuries. Primary injury results from the initial mechanical damage to neurons and other cells in the brain, as well as blood vessels. Secondary injuries, which can occur seconds after the TBI and last for years, include oxidative stress, inflammation and disruption of the blood-brain barrier. “The secondary injury creates this neurotoxic environment that can lead to long-term cognitive effects,” Sarkar says. For example, TBI survivors can experience impaired motor control and an increased rate of depression, he says. Currently, there is no effective regenerative treatment for TBIs.

Sarkar and Vivek Kumar, Ph.D., the project’s principal investigator, wanted to develop a therapy that could help treat secondary injuries.

We wanted to be able to regrow new blood vessels in the area to restore oxygen exchange, which is reduced in patients with a TBI. Also, we wanted to create an environment where neurons can be supported and even thrive.”

Biplab Sarkar, Ph.D., New Jersey Institute of Technology

The researchers, both at the New Jersey Institute of Technology, had previously developed peptides that can self-assemble into hydrogels when injected into rodents. By incorporating snippets of particular protein sequences into the peptides, the team can give them different functions. For example, Sarkar and Kumar previously developed angiogenic peptide hydrogels that grow new blood vessels when injected under the skin of mice.

To adapt their technology to the brain, Sarkar and Kumar modified the peptide sequences to make the material properties of the hydrogel more closely resemble those of brain tissue, which is softer than most other tissues of the body. They also attached a sequence from a neuroprotective protein called ependymin. The researchers tested the new peptide hydrogel in a rat model of TBI. When injected at the injury site, the peptides self-assembled into a hydrogel that acted as a neuroprotective niche to which neurons could attach.

A week after injecting the hydrogel, the team examined the rats’ brains. They found that in the presence of the hydrogel, survival of the brain cells dramatically improved, resulting in about twice as many neurons at the injury site in treated rats than in control animals with brain injury. In addition, the researchers saw signs of new blood vessel formation. “We saw some indications that the rats in the treated group were more ambulatory than those in the control group, but we need to do more experiments to actually quantify that,” Sarkar says.

According to Kumar, one of the next steps will be to study the behavior of the treated animals to assess their functional recovery from TBI. The researchers are also interested in treating rats with a combination of their previous angiogenic peptide and their new neurogenic version to see if this could enhance recovery. And finally, they plan to find out if the peptide hydrogels work for more diffuse brain injuries, such as concussions. “We’ve seen that we can inject these materials into a defined injury and get good tissue regeneration, but we’re also collaborating with different groups to find out if it could help with the types of injuries we see in soldiers, veterans and even people working at construction sites who experience blast injuries,” Kumar says.

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[BLOG POST] A Guide to using Omega-3s for Brain Healing

Are Omega-3s Important for Brain Healing?

There are three types of omega-3 fatty acids: ALA, DHA, and EPA.

ALA (alpha-linolenic acid), found in flax seeds, walnuts, and chia seeds, cannot be synthesized in the body and therefore must be consumed in the diet.  DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) are almost exclusively found in fish.

DHA and EPA have been shown to play a crucial role in brain development. They are involved in neurotransmitter synthesis and functioning. DHA is necessary for the functional maturation of the retina and visual cortex [1]. Infants of mothers who supplemented with DHA had higher mental processing scores, hand-eye coordination, and psychomotor development [2].

Omega-3 supplementation has been shown to improve cognitive functioning in the mature brain as well. Studies have correlated accelerated cognitive decline and mild cognitive impairment with low tissue levels of DHA and EPA [3]. Additionally, omega-3 consumption is associated with a decreased risk for dementia and Alzheimer’s disease [4].

To be completely transparent, there isn’t much research on the use of omega-3s to aid brain healing after a TBI or stroke. However, there is evidence testifying to the crucial role of omega-3s in brain development and linking DHA and EPA to improved cognitive performance. To me this evidence makes a strong case for the use of omega-3s in a brain recovery program.

 

Top 5 Reasons to use Omega-3’s for Brain Healing

  1. DHA is proven essential to brain development

DHA is required for the development of the sensory, perceptual, cognitive, and motor neural systems during fetal and childhood brain growth.  Specifically, DHA is vital for the neuronal formation of axons and dendritic extensions and for proper synaptic functioning. EPA’s importance for the brain’s development is unclear, but colostrum and breast milk do contain EPA. Omega-3 deficiencies during development have been linked to deficits in retinal structure, visual acuity development, and cognitive performance [3].

  1. Has been shown to reduce aggression

I was pleasantly surprised by this benefit. The mechanism by which it works is unknown, but several double-blind studies have shown decreased physical aggression and impulsivity after omega-3 supplementation. DHA in particular has been shown to help prevent aggression resulting from mental stress [3].

  1. Linked to improved cognitive performance

Researchers have concluded that DHA and EPA supplementation can improve higher brain functions – sense of wellbeing, reactivity, attention, cognitive performance, and mood. Additionally, omega-3s have been shown to decrease cognitive decline and lower dementia risk [3].

  1. Beneficial for affective disorders

Affective disorders that respond to DHA/EPA include major depressive disorder, manic depression, schizophrenia, and borderline personality disorder. EPA seems to provide the most benefit when it comes to decreasing depression and managing mood [3].

  1. Reduces inflammation

EPA reverses cellular inflammation, including inflammation in the brain. The primary mediators of inflammation in the body are derived from arachidonic acid, an omega-6 fatty acid. When omega-3 consumption is increased, EPA blocks the production of these pro-inflammatory mediators [5].

 

What is the Best Source of Omega-3s?

This article discusses the use of omega-3s for brain healing.

For ALA (alpha-linolenic acid) I would suggest simply adding a daily tablespoon of ground flax seed to your diet.

DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) are almost exclusively found in fish. While DHA and EPA can be synthesized from ALA in the body, the conversion rate is very low – it’s thought to be around 1% of the total intake of ALA.

Seaweed and microalgae are the only plant sources of DHA and EPA. However, they are found in very low concentrations. While a healthy individual may get by on a plant based omega-3 supplement, it would be very difficult consume the high quantities recommended after a brain injury.

For high doses of EPA and DHA, go with a good quality, highly purified fish oil.  For more information on choosing a good quality fish oil see: Choosing the Best Fish Oil Supplement for Brain Health.

But isn’t Fish Oil a Blood Thinner?

I think Dr. Lewis addresses this concern best,

There is a theoretical risk that high dose omega3s may cause bleeding or stroke. Biochemical pathways tell us this is a valid concern. However, not a single study in the scientific literature has shown this to be of any clinical significance.” [6]

I personally believe that the benefits of fish oil outweigh the risks. I would however recommend that you discuss it with your doctor before using high doses of fish oil, especially if you are on a prescription blood thinner. Do your own research first so that you are prepared to discuss the pros and cons with them (even doctors don’t know everything).

A Guide to using Omega-3s for Brain Healing - How To Brain

How much Fish Oil should You Take?

Currently there is not a set recommendation for daily intake of DHA/EPA for brain function. For healthy individuals, I have seen recommendations ranging from 0.5 grams up to 5 grams. In individuals with brain injury, most of the existing literature suggests much higher doses are needed. Here is the information that I have found relating to dosage:

Dr. Lewis Protocol

Week 1 – Take 3 g of EPA + DHA 3 times a day for a total of 9 g per day.

Week 2 – Take 3 g of EPA + DHA 2 times a day for a total of 6 g per day.

Maintenance dose – Take 3 g of EPA + DHA once a day.

Dr. Lewis suggests starting at an even higher dose and maintaining it for longer if the brain injury is severe. If you explore his website a bit, you will find that he has lots of good information regarding fish oil and brain injury. I particularly liked this article: High Dose Omega-3s in Severe Brain Injury.

Dr. Sears

Dr. Sears doesn’t lay out an exact protocol, but he does recommend using 10 – 15 grams of EPA + DHA per day.

How soon should You see Results?

While I have read testimonies of people seeing almost immediate results, this seems to be the exception not the rule. You should begin to see results within 2 months, but it could take up to 3 months.

It took around 3 months for us to really start seeing improvements with my dad.

Which Supplement should You use?

Since you will be taking high doses, it is vital that you take a high quality supplement.

I have found both Nordic Naturals* and NutriGold* to be very good brands. There are many other brands available though, just make sure the one you choose is third party tested. For more information on choosing a brand read: Choosing the Best Fish Oil Supplement for Brain Health.

Links denoted with an * are affiliate links. I will receive a small commission (at no cost to you) if you purchase something through the one of these links. For my full disclosure click here. Thank you for your support!

A Guide to Using Omega-3s for Brain Healing - How To Brain

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[BLOG POST] 9 promising advances in the management of traumatic brain injury – The Neurology Lounge

 

Traumatic brain injury (TBI) is simply disheartening. It is particularly devastating because it usually affects young people in their prime, with the consequent personal, social, and economic consequences. This blog has previously touched a little on TBI with the post titled Will Smith and chronic traumatic encephalopathy? This was a light-hearted take on concussion in sports, but traumatic brain injury is nothing but a serious burden. So what are the big brains in white coats doing to take down this colossus? Quite a lot it seems. Here, for a taster, are 9 promising advances in the management of traumatic brain injury.

Better understanding of pathology

An amyloid PET imaging study by Gregory Scott and colleagues, published in the journal Neurology, reported a rather surprising link between the pathology seen in long-term survivors of traumatic brain injury, with the pathology seen in Alzheimers disease (AD). In both conditions, there is an increased burden of β-amyloid () in the brain, produced by damage to the nerve axons. The paper, titled Amyloid pathology and axonal injury after brain trauma, however notes that the pattern of  deposition in TBI can be distinguished from the one seen in AD. The big question this finding raises is, does TBI eventually result in AD? The answer remains unclear, and this is discussed in the accompanying editorial titled Amyloid plaques in TBI.

Blood tests to detect concussion

The ideal biomarker for any disorder is one which is easy to detect, such as a simple blood test. A headline that screams Blood test may offer new way to detect concussions is therefore bound to attract attention. The benefits of such a test would be legion, especially if the test can reduce the requirement for CT scans which carry the risks of radiation exposure. This is where glial fibrillary acidic protein (GFAP) may be promising. The research is published in the journal, Academic Research Medicine, with a rather convoluted title, Performance of Glial Fibrillary Acidic Protein in Detecting Traumatic Intracranial Lesions on Computed Tomography in Children and Youth With Mild Head Trauma. The premise of the paper is the fact that GFAP is released into the blood stream from the glial cells of the brain soon after brain injury. What the authors therefore did was to take blood samples within 6 hours of TBI in children. And they demonstrated that GFAP levels are significantly higher following head injury, compared to injuries elsewhere in the body. This sounds exciting, but we have to wait and see where it takes us.

Advanced imaging

Brain Scars Detected in Concussions is the attention-grabbing headline for this one, published in MIT Technology Review. Follow the trail and it leads to the actual scientific paper in the journal Radiology, with a fairly straight-forward title, Findings from Structural MR Imaging in Military Traumatic Brain Injury The authors studied >800 subjects in what is the largest trial of traumatic brain injury in the military. Using high resolution 3T brain magnetic resonance imaging (MRI), they demonstrated that even what is reported as mild brain injury leaves its marks on the brain, usually in the form of white matter hyperintense lesions and pituitary abnormalities. It simply goes to show that nothing is mild when it comes to the brain, the most complex entity in the universe.

Implanted monitoring sensors

Current technologies which monitor patients with traumatic brain injury are, to say the least, cumbersome and very invasive. Imagine if all the tubes and wires could be replaced with microsensors, smaller than grains of rice, implanted in the brain. These would enable close monitoring of critical indices such as temperature and intracranial pressure. And imagine that these tiny sensors just dissolve away when they have done their job, leaving no damage. Now imagine that all this is reality. I came across this one from a CBS News piece titled Tiny implanted sensors monitor brain injuries, then dissolve away. Don’t scoff yet, it is grounded in a scientific paper published in the prestigious journal, Nature, under the title Bioresorbable silicon electronic sensors for the brain. But don’t get too exited yet, this is currently only being trialled in mice.

Drugs to reduce brain inflammation

What if the inflammation that is set off following traumatic brain injury could be stopped in its tracks? Then a lot of the damage from brain injury could be avoided. Is there a drug that could do this? Well, it seems there is, and it is the humble blood pressure drug Telmisartan. This one came to my attention in Medical News Today, in a piece titled Hypertension drug reduces inflammation from traumatic brain injury. Telmisartan seemingly blocks the production of a pro-inflammatory protein in the liver. By doing this, Telmisartan may effectively mitigate brain damage, but only if it is administered very early after traumatic brain injury. The original paper is published in the prestigious journal, Brain, and it is titled Neurorestoration after traumatic brain injury through angiotensin II receptor blockage. Again, don’t get too warm and fuzzy about this yet; so far, only mice have seen the benefits.

Treatment of fatigue

Fatigue is a major long-term consequence of traumatic brain injury, impairing the quality of life of affected subjects in a very frustrating way. It therefore goes without saying, (even if it actually has to be said), that any intervention that alleviates the lethargy of TBI will be energising news. And an intervention seems to be looming in the horizon! Researchers writing in the journal, Acta Neurologica Scandinavica, have reported that Methylphenidate significantly improved fatigue in the 20 subjects they studied. Published under the title Long-term treatment with methylphenidate for fatigue after traumatic brain injury, the study is rather small, not enough to make us start dancing the jig yet. The authors have rightly called for larger randomized trials to corroborate their findings, and we are all waiting with bated breaths.

Treatment of behavioural abnormalities

Many survivors of traumatic brain injury are left with behavioural disturbances which are baffling to the victim, and challenging to their families. Unfortunately, many of the drugs used to treat these behaviours are not effective. This is where some brilliant minds come in, with the idea of stimulating blood stem cell production to enhance behavioural recovery. I am not clear what inspired this idea, but the idea has inspired the paper titled Granulocyte colony-stimulating factor promotes behavioral recovery in a mouse model of traumatic brain injury. The authors report that the administration of G‐CSF for 3 days after mild TBI improved the performance of mice in a water maze…within 2 weeks. As the water maze is a test of learning and memory, and not of behaviour, I can only imagine the authors thought-surely only well-behaved mice will bother to take the test. It is however fascinating that G‐CSF treatment actually seems to fix brain damage in TBI, and it does so by stimulating astrocytosis and microgliosis, increasing the expression of neurotrophic factors, and generating new neurons in the hippocampus“. The promise, if translated to humans, should therefore go way beyond water mazes, but we have to wait and see.

Drugs to accelerate recovery

The idea behind using Etanercept to promote recovery from brain injury sound logical. A paper published in the journal, Clinical Drug Investigation, explains that brain injury sets off a chronic lingering inflammation which is driven by tumour necrosis factor (TNF). A TNF inhibitor will therefore be aptly placed to stop the inflammation. What better TNF inhibitor than Eternacept to try out, and what better way to deliver it than directly into the nervous system. And this is what the authors of the paper, titled Immediate neurological recovery following perispinal etanercept years after brain injury, did. And based on their findings, they made some very powerful claims: “a single dose of perispinal etanercept produced an immediate, profound, and sustained improvementin expressive aphasia, speech apraxia, and left hemiparesis in a patient with chronic, intractable, debilitating neurological dysfunction present for more than 3 years after acute brain injury”. A single patient, mind you. Not that I am sceptical by nature, but a larger study confirming this will be very reassuring.

Neuroprotection

And finally, that elusive holy grail of neurological therapeutics, neuroprotection. Well, does it exist? A review of the subject published in the journal, International Journal of Molecular Sciences, paints a rather gloomy picture of the current state of play. Titled Neuroprotective Strategies After Traumatic Brain Injury, it said “despite strong experimental data, more than 30 clinical trials of neuroprotection in TBI patients have failed“. But all is not lost. The authors promise that “recent changes in experimental approach and advances in clinical trial methodologyhave raised the potential for successful clinical translation”. Another review article, this time in the journal Critical Care, doesn’t offer any more cheery news about the current state of affairs when it says that the “use of these potential interventions in human randomized controlled studies has generally given disappointing results”. But the review, titled Neuroprotection in acute brain injury: an up-to-date review, goes through promising new strategies for neuroprotection following brain injury: these include hyperbaric oxygensex hormones, volatile anaesthetic agents, and mesenchymal stromal cells. The authors conclude on a positive note: “despite all the disappointments, there are many new therapeutic possibilities still to be explored and tested”.

What an optimistic way to end! We are not quite there yet, but these are encouraging steps.

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[WEB PAGE] Plantar fasciitis stretches: 6 exercises and other home remedies – Videos

Best exercises and remedies for plantar fasciitis

Last reviewed
Foot stretches and exercises can help plantar fasciitis by relieving pain, improving muscle strength, and promoting flexibility in the foot muscles and ligaments.

Overuse, strain, and inflammation on the plantar fascia ligament that connects the heel to the toes cause the foot injury that doctors refer to as plantar fasciitis. The tissue that the condition affects is under the arch of the foot but can cause a stabbing pain in the heel.

Plantar fasciitis usually resolves within 6 to 18 months without treatment. With 6 months of consistent, nonoperative treatment, people with plantar fasciitis will recover 97 percent of the time.

In this article, we look at stretches and exercises for plantar fasciitis relief and recovery and other home remedies that could help.

Plantar fasciitis stretches

Plantar fasciitis may often be an overuse injury. Often, it occurs in runners or people who are overweight or obese. It may also cause tension in surrounding muscles, leading to pain beyond the heel.

A few simple stretches can reduce tension in the foot and calf. This offers both rapid pain relief and a steady improvement of symptoms over time.

People can perform these exercises two or three times every day. They should not be painful.

1. Stretching the calf

Man doing calf muscle and foot stretch against wall

Muscle tightness in the feet and calves can make the pain of plantar fasciitis worse. Loosening the calf muscles can relieve the pain. Try the following stretch:

  • lean your hands against a wall
  • straighten the knee of the affected leg and bend the other knee in front
  • keep both feet flat on the ground
  • there should be a stretching sensation in the heel and calf of the extended leg
  • hold for 10 seconds
  • repeat two to three times

2. Rolling stretch

Placing a round object under the foot and rolling back and forth can help loosen up the foot muscles. People can use a rolling pin, golf ball, or specialized foam roller for this. Sports stores and online stores sell foam foot rollers.

Use the following steps to stretch the foot:

  • sit tall on a chair
  • roll a round object under the arch of the foot
  • roll for 2 minutes

3. Stretching the plantar fascia

To relieve muscle tightness in the plantar fascia, try the following:

  • sitting on a chair, cross the injured heel over the other leg
  • hold the foot in your opposite hand
  • pull the toes toward the shin to create tension in the arch of the foot
  • place the other hand on the bottom of the foot to feel for tension in the plantar fascia
  • use a towel to grasp and stretch the foot if it is difficult to hold otherwise
  • hold for 10 seconds
  • repeat two to three times

4. Foot flexes

Pregnant woman stretching foot and leg with towel or exercise band

Flexing the foot increases blood flow to the area and relieves tension in the calves, which can help with pain. This exercise uses an elastic stretch band, which people can buy from sports stores or online.

Use the following steps:

  • sit on the floor with legs straight
  • wrap the elastic band around your foot, holding the ends in your hands
  • gently point the toes away from the body
  • slowly return to starting position
  • repeat 10 times

5. Towel curls

Curling a hand towel or facecloth with the toes can stretch the foot and calf muscles. Try doing these stretches before walking or doing any other morning tasks. Use the following steps:

  • sit on a chair with both feet flat and a small towel in front of the feet
  • grasp the center of the towel with your toes
  • curl the towel towards you
  • relax the foot and repeat five times
Marble feet exercise

6. Marble pickups

Picking up a marble with the toes will flex and stretch the foot muscles. Use the following steps:

  • sit on a chair with knees bent and feet flat on the floor
  • place 20 marbles and a bowl at your feet
  • pick up one marble at a time by curling your toes, and place the marble into the bowl
  • repeat 20 times

Other home remedies

A number of other home remedies can help reduce the inflammation and pain of plantar fasciitis:

The RICE method

When the pain first appears, keeping off the injured foot can help. First aid for a foot injury can include the RICE method:

  • Rest the painful area for a few days.
  • Ice the area for 20 minutes at a time to relieve inflammation.
  • Compress the area with a soft wrap to reduce swelling.
  • Elevate the area by putting the foot on a few pillows.

Elevating the foot with a pillow can be especially helpful when a person is sleeping.

Anti-inflammatory medication

Non-steroidal anti-inflammatory drugs (NSAID), such as ibuprofen, help to reduce both pain and inflammation. People may wish to take this medication as directed on the package or recommended by a doctor.

Some people find that a few weeks of NSAID treatment improves their symptoms.

Shoe inserts

Shoe inserts offer additional support to the arch of the foot. Inserts will limit stress on the plantar fascia and may be especially helpful to people who spend much of the day on their feet. Soft, supportive arch inserts may work as well.

Always speak to a doctor who specializes in foot health, called a podiatrist, for more information.

Massage

Some people find that massage helps with symptoms. Focus on massaging the arch of the foot around the injured area.

If surrounding muscles have become tense because of the pain, massage those too. Some people find relief from massaging the arch of the foot with an ice bottle.

Medical treatments

If stretches, exercises, and home remedies do not help, a doctor may recommend medical treatment. However, surgery is rarely needed.

A doctor may suggest the following:

Risk factors for plantar fasciitis

People who walk or run for exercise may be at risk of plantar fasciitis.

People who walk or run for exercise may be at risk of plantar fasciitis.

A thick mass of tissue called the plantar fascia connects the toes to the heel bone. Inflammation in this tissue, called plantar fasciitis, can cause intense pain in the heel.

The pain may get worse when getting out of bed or when standing after a long period of sitting.

Doctors do not fully understand why some people get this injury and others do not. Some evidence suggests that overuse causes the inflammation.

Risk factors for plantar fasciitis include:

  • spending long periods of time standing
  • walking or running for exercise
  • having tight calf muscles
  • overweight and obesity
  • pes cavus, a condition that causes the arch of the foot to be hollow when standing

Outlook

Plantar fasciitis will usually resolve by itself without treatment. People can speed up recovery and relieve pain with specific foot and calf stretches and exercises.

For some people, plantar fasciitis becomes a chronic condition. Symptoms may improve and then appear again, or the pain may remain consistent for a year or longer. A 2018 study suggests that people who have previously had the injury are more likely to have it again.

Because of the risk of chronic pain, people with plantar fasciitis should see a doctor about their symptoms. There are many different treatment options that may help.

 

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[ARTICLE] The Involvement of Iron in Traumatic Brain Injury and Neurodegenerative Disease – Full Text

Traumatic brain injury (TBI) consists of acute and long-term pathophysiological sequelae that ultimately lead to cognitive and motor function deficits, with age being a critical risk factor for poorer prognosis. TBI has been recently linked to the development of neurodegenerative diseases later in life including Alzheimer’s disease, Parkinson’s disease, chronic traumatic encephalopathy, and multiple sclerosis. The accumulation of iron in the brain has been documented in a number of neurodegenerative diseases, and also in normal aging, and can contribute to neurotoxicity through a variety of mechanisms including the production of free radicals leading to oxidative stress, excitotoxicity and by promoting inflammatory reactions. A growing body of evidence similarly supports a deleterious role of iron in the pathogenesis of TBI. Iron deposition in the injured brain can occur via hemorrhage/microhemorrhages (heme-bound iron) or independently as labile iron (non-heme bound), which is considered to be more damaging to the brain. This review focusses on the role of iron in potentiating neurodegeneration in TBI, with insight into the intersection with neurodegenerative conditions. An important implication of this work is the potential for therapeutic approaches that target iron to attenuate the neuropathology/phenotype related to TBI and to also reduce the associated risk of developing neurodegenerative disease.

Introduction

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, particularly amongst young adults. Ten million individuals are affected by TBI annually, costing a staggering $9–10 billion/year (Gardner et al., 2017). The aged population have a greater risk of sustaining a TBI, with frequent falls being the major cause of injury, and they also have worse outcomes post-injury compared to other age groups (Stocchetti et al., 2012). Aging is also accompanied by a number of co-morbidities which may contribute to poorer outcomes in these individuals following TBI (Stocchetti et al., 2012). Common secondary events that follow the primary impact are neuronal cell death, oxidative stress, brain oedema, blood-brain barrier (BBB) breakdown, and inflammation (Toklu and Tumer, 2015). TBI often results in debilitating long-term cognitive and motor impairments, and there are currently no approved treatments available for TBI patients (Bramlett and Dietrich, 2015). This highlights the need for therapeutic agents that can alleviate brain damage and the deficits caused by the primary injury and more specifically the reversible secondary pathologies that develop after TBI.

Iron homeostasis appears to be an important process in the pathobiology of TBI. Iron is essential for normal brain functioning where it acts as an essential cofactor for several enzymatic/cellular processes (Ke and Qian, 2007). However, impaired regulation of iron can result in the production of reactive oxygen species (ROS) and the consequent promotion of oxidative stress, which can wreak havoc on an already compromised brain in the context of TBI (Nunez et al., 2012). Interestingly, the accumulation of iron in various tissues and cells in the body and brain is an inevitable consequence of aging (Hagemeier et al., 2012Del et al., 2015). A concomitant increase in the iron storage protein (i.e., ferritin), which can scavenge any excess iron and prevent undesired production of ROS, is also evident with aging (Andersen et al., 2014). However, failed or weakened antioxidant defenses and mitochondrial dysfunction that progresses with aging can disrupt the balance and allow for excessive iron to be released (Venkateshappa et al., 2012a,bAndersen et al., 2014). This can cause pathological iron overload resulting in cellular damage that is considered to be a contributing factor in several degenerative diseases that are more prevalent with age, such as cancer, liver fibrosis, cardiovascular disease, diabetes (type II), and particularly neurological conditions such as Alzheimer’s disease (AD) (Smith et al., 1997Kalinowski and Richardson, 2005Ward et al., 2014Hare et al., 2016). Abnormal brain iron deposition has also been discovered in other neurodegenerative diseases, such as Parkinson’s disease (PD) (Griffiths et al., 1999Zhang et al., 2010Barbosa et al., 2015), multiple sclerosis (MS) (Bergsland et al., 2017), amyotrophic lateral sclerosis (ALS) (Oshiro et al., 2011), Huntington’s disease (Agrawal et al., 2018), and Friedreich’s ataxia (Martelli and Puccio, 2014), and there is now increasing evidence of altered iron levels in TBI patients (Raz et al., 2011Lu et al., 2015). This raises the interesting proposition of an intersection between aging, iron, TBI and neurodegenerative disease. Whilst the role of iron in TBI is not well known, the literature suggests that the levels of iron (and other metals such as zinc) are abnormally regulated following injury, and that the pharmacological targeting (e.g., using chelators or chaperones) of these metals may be beneficial in improving outcomes. Iron chelation therapy has been approved for decades for the treatment of iron overload conditions, and there is a recent heightened interest for their use in neurodegenerative diseases (Kalinowski and Richardson, 2005Dusek et al., 2016). Here, we review the role of iron dyshomeostasis in TBI and gain a deeper understanding of its involvement in neurodegeneration as well as neuroinflammation (Figure 1). We further examine the potential benefit of utilizing iron chelation therapy with the hope of limiting iron-induced neurotoxicity in TBI.

Figure 1. The consequence of iron dyshomeostasis following TBI. TBI results in several secondary events including blood-brain barrier (BBB) breakdown, hemorrhage and iron dyshomeostasis. Together this leads to the accumulation of heme and/or non-heme bound iron in the brain. Iron can participate in Haber-Weiss/Fenton reactions and can promote oxidative stress, neuronal death, inflammation as well as tau phosphorylation/amyloid-β deposition. This contributes to the pathology of TBI, ultimately resulting in neurological decline and an increased risk of developing neurodegenerative disease.

[…]

Continue —>  Frontiers | The Involvement of Iron in Traumatic Brain Injury and Neurodegenerative Disease | Neuroscience

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[WEB SITE] How Ketogenic Diets Curb Inflammation 

Summary: The neurological benefits experienced by those with epilepsy who follow ketogenic diets may be a result of the low carb diet lowering brain inflammation, researchers report.

Source: UCSF.

Ketogenic diets — extreme low-carbohydrate, high-fat regimens that have long been known to benefit epilepsy and other neurological illnesses — may work by lowering inflammation in the brain, according to new research by UC San Francisco scientists. The UCSF team has discovered a molecular key to the diet’s apparent effects, opening the door for new therapies that could reduce harmful brain inflammation following stroke and brain trauma by mimicking the beneficial effects of an extreme low-carb diet

“It’s a key issue in the field — how to suppress inflammation in brain after injury,” said Raymond Swanson, MD, a professor of neurology at UC San Francisco, chief of the neurology service at the San Francisco Veterans Affairs Medical Center, and senior author of the new study.

In the paper, published online September 22, 2017 in the journal Nature Communications, Swanson and his colleagues found the previously undiscovered mechanism by which a low carbohydrate diet reduces inflammation in the brain. Importantly, the team identified a pivotal protein that links the diet to inflammatory genes, which, if blocked, could mirror the anti-inflammatory effects of ketogenic diets.

“The ketogenic diet is very difficult to follow in everyday life, and particularly when the patient is very sick,” Swanson said. “The idea that we can achieve some of the benefits of a ketogenic diet by this approach is the really exciting thing here.”

Low-Carb Benefits

The high-fat, low-carbohydrate regimen of ketogenic diets changes the way the body uses energy. In response to the shortage of carb-derived sugars such as glucose, the body begins breaking down fat into ketones and ketoacids, which it can use as alternative fuels.

In rodents, ketogenic diets — and caloric restriction, in general — are known to reduce inflammation, improve outcomes after brain injury, and even extend lifespan. These benefits are less well-established in humans, however, in part because of the difficulty in maintaining a ketogenic state.

In addition, despite evidence that ketogenic diets can modulate the inflammatory response in rodents, it has been difficult to tease out the precise molecular nuts and bolts by which these diets influence the immune system.

Intricate Molecular Waltz

In the new study, the researchers used a small molecule called 2-deoxyglucose, or 2DG, to block glucose metabolism and produce a ketogenic state in rats and controlled laboratory cell lines. The team found that 2DG could bring inflammation levels down to almost control levels.

This image shows hippocampal slices.

Immunostaining for Iba1 and iNOS identify activated microglia in mouse hippocampal slice cultures after 24 h incubation with LPS (10 μg/ml) or LPS + 2DG (1 mM) NeuroscienceNews.com image is credited to Swanson et al./Nature Communications.

“I was most surprised by the magnitude of this effect, because I thought ketogenic diets might help just a little bit,” Swanson said. “But when we got these big effects with 2DG, I thought wow, there’s really something here.”

The team further found that reduced glucose metabolism lowered a key barometer of energy metabolism — the NADH/NAD+ ratio — which in turn activated a protein called CtBP that acts to suppress activity of inflammatory genes.

In a clever experiment, the researchers designed a drug-like peptide molecule that blocks the ability of CtBP to enter its inactive state —essentially forcing the protein to constantly block inflammatory gene activity and mimicking the effect of a ketogenic state.

Peptides, which are small proteins, don’t work well themselves as drugs because they are unstable, expensive, and people make antibodies against them. But other molecules that act the same way as the peptide could provide ketogenic benefits without requiring extreme dietary changes, Swanson said.

The study has applications beyond brain-related inflammation. The presence of excess glucose in people with diabetes, for example, is associated with a pro-inflammatory state that often leads to atherosclerosis, the buildup of fatty plaques that can block key arteries. The new study could provide a way of interfering with the relationship between the extra glucose in patients with diabetes and this inflammatory response.

Source: How Ketogenic Diets Curb Inflammation – Neuroscience News

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[WEB SITE] OCD linked to inflammation in the brain

 

Woman washing hands OCD
A common symptom of OCD is an obsession with cleanliness.
Obsessive-compulsive disorder is an intrusive condition that remains difficult to treat. This is due, in part, to the causes behind the disorder remaining hidden. Recent research, however, points the finger at brain inflammation.

Obsessive-compulsive disorder (OCD) is characterized by uncontrollable obsessions and compulsions. Individuals with OCD may experience intrusive thoughts that produce anxiety or a need to repeat certain actions to relieve pent-up anxiety.

Common obsessions in OCD revolve around cleanliness, sexual taboos, aggressive thoughts, and symmetry.

Affecting an estimated 1 percent of people in the United States, around half of OCD cases are classed as severe.

OCD is generally treated with talking therapies – in particular, a type of cognitive behavior therapy called exposure and response prevention is recommended. There are also some medications available, with selective serotonin reuptake inhibitors being the most commonly prescribed. Currently, however, therapies only work for around 70 percent of OCD-affected individuals.

One of the biggest stumbling blocks to finding good treatments is that the physical causes of OCD are not known.

Inflammation and OCD

Breaking research published this week in JAMA Psychiatry takes a look at the role of brain inflammation in OCD. The senior author of the study is Dr. Jeffrey Meyer, head of the Neuroimaging Program in Mood & Anxiety at the Centre for Addiction and Mental Health in Toronto, Canada.

Inflammation is a natural process; it is a normal component of the immune response and a standard reaction to injury. However, if the level of inflammation is inappropriate or continues for too long, it can have negative consequences. For instance, in a number of diseases including rheumatoid arthritis and atherosclerosis, inflammation is heavily involved.

Growing evidence suggests that certain psychiatric conditions may involve neuroinflammation, some of which include major depressive disorder, schizophrenia, and bipolar.

Dr. Meyer and his team set out to understand whether inflammation in the brain could play a role in the development of OCD. To this end, they recruited 40 participants, comprising 20 with OCD and 20 without. Each was scanned using positron emission tomography that had been adapted to pinpoint and measure inflammation in the brain.

Specifically, the researchers were able to selectively dye microglia, which are cells that act as the nervous system’s most prominent immune defense and which are activated during inflammation. The researchers measured levels of microglia in six brain regions known to be important in OCD, including the orbitofrontal cortex and anterior cingulate cortex.

The results were clear: in the brain regions associated with OCD, individuals with the disorder had 32 percent more inflammation when compared with people without the condition.

This finding represents one of the biggest breakthroughs in understanding the biology of OCD, and may lead to the development of new treatments.”

Dr. Jeffrey Meyer

From inflammation to treatment

Another interesting finding was that individuals who reported the highest levels of stress when trying to stop themselves from acting on compulsions also had the highest levels of inflammation in a particular brain region.

As so many diseases involve inflammation, there are already a range of drugs designed to tackle it. Because these drugs already exist on the market, it may be a fruitful avenue of research in the hunt for more effective treatments for OCD.

“Medications developed to target brain inflammation in other disorders could be useful in treating OCD,” Dr. Meyer says. “Work needs to be done to uncover the specific factors that contribute to brain inflammation, but finding a way to reduce inflammation’s harmful effects and increase its helpful effects could enable us to develop a new treatment much more quickly.”

Studies are now under way that examine the possibility of designing a blood marker test that could distinguish which patients would benefit most from anti-inflammatory drugs.

Although, as ever, more research is needed, this finding could mark a significant move forward in understanding and treating OCD.

Learn how certain gene mutations can cause OCD-like behaviors.

Source: OCD linked to inflammation in the brain – Medical News Today

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[WEB SITE] Epilepsy drug therapies to be improved by new targeted approach

Published: Wednesday 17 May 2017

New research from the University of Liverpool, in collaboration with the Mario Negri Institute in Milan, published in the Journal of Clinical Investigation, has identified a protein that could help patients with epilepsy respond more positively to drug therapies.

Epilepsy continues to be a serious health problem and is the most common serious neurological disease. Despite 30 years of drug development, approximately 30% of people with epilepsy do not become free of fits (also called seizures) with currently available drugs.

New, more effective drugs are therefore required for these individuals. We do not fully understand why some people develop seizures, why some go onto develop epilepsy (continuing seizures), and most importantly, why some patients cannot be controlled with current drugs.

Inflammation

There is now increasing body of evidence suggesting that local inflammation in the brain may be important in preventing control of seizures. Inflammation refers to the process by which the body reacts to insults such as having a fit. In most cases, the inflammation settles down, but in a small number of patients, the inflammation continues.

The aim of the research, undertaken by Dr Lauren Walker while she was a Medical Research Council (MRC) Clinical Training Fellow, was to address the important question of how can inflammation be detected by using blood samples, and whether this may provide us with new ways of treating patients in the future to reduce the inflammation and therefore improve seizure control.

The research focused on a protein called high mobility group box-1 (HMGB1), which exists in different forms in tissues and bloodstream (called isoforms), as it can provide a marker to gauge the level of inflammation present.

Predicting drug response

The results showed that there was a persistent increase in these isoforms in patients with newly-diagnosed epilepsy who had continuing seizure activity, despite anti-epileptic drug therapy, but not in those where the fits were controlled.

An accompanying drug study also found that HMGB1 isoforms may predict how an epilepsy patient’s seizures will respond to anti-inflammatory drugs.

Dr Lauren Walker, said: “Our data suggest that HMGB1 isoforms represent potential new drug targets, which could also identify which patients will respond to anti-inflammatory therapies. This will require evaluation in larger-scale prospective trials.”

Innovative scheme

Professor Sir Munir Pirmohamed, Director of the MRC Centre for Drug Safety Science and Programme lead for the MRC Clinical Pharmacology scheme, said: “The MRC Clinical Pharmacology scheme is a highly successful scheme to train “high flyers” who are likely to become future leaders in academia and industry.

“Dr Walker’s research is testament to this and shows how this innovative scheme, which was jointly funded by the MRC and Industry, can tackle areas of unmet clinical need, and identify new ways of treating patients with epilepsy using a personalised medicine approach”.

Article: Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy, Lauren Elizabeth Walker et al., Journal of Clinical Investigation, doi: 10.1172/JCI92001, published 15 May 2017.

Source: Epilepsy drug therapies to be improved by new targeted approach – Medical News Today

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[WEB SITE] Chemical Test Quickly Finds Cognitive Damage in Stroke Patients – Scientific American

CT-scan of a brain with a right MCA infarct. Lucien Monfils/Wikimedia Commons, CC BY-SA 3.0

A stroke happens when blood flow to the brain is interrupted and brain cells starve of oxygen. Aftereffects include muscle weakness and altered senses. In many cases, strokes also affect the way a patient thinks or processes information.

Quickly identifying the effects of a stroke helps doctors to tailor rehabilitation programs to the needs of a patient. Currently, structural neuroimaging and neuropsychological tests assess cognitive damage, but these take time and require the patient to be involved and compliant.

Now, a team led by Weizhong Wang and Xiaoying Bi from the Second Military Medical University in Shanghai has analysed metabolic changes following a stroke. The researchers were particularly interested in identifying changes related to post-stroke cognitive impairment. Bi explains that these changes may be ‘caused by inflammation, neurotoxicity or oxidative stress’ because of the stroke.

The team used paired ultra-high performance liquid chromatography and Q-TOF mass spectrometry to study serum samples from a control group, a post-stroke cognitively impaired group and a post-stroke non-cognitively impaired group of patients. Multivariate data analysis of the data set highlighted the different metabolic profiles of the groups and identified a wide range of metabolic changes.

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To create a practical test, the team then used a regression model to pare down the metabolites to three that were simple to check for: glutamine—an amino acid; kynurenine—a metabolite of tryptophan; and lysoPC(18:2)—a lysophospholipid. These biomarkers can rapidly identify post-stroke cognitive impairment without actively involving the patient in the testing.

Peng Song, a specialist in neuro-analytical chemistry, from the Eastman Chemical Company in the US says the research signals the coming age of clinical metabolomics. ‘The finding paves the way for a better understanding of the molecular mechanisms and eventually, more effective treatment,’ he adds.

This article is reproduced with permission from Chemistry World. The article was first published on November 2, 2015.

Source: Chemical Test Quickly Finds Cognitive Damage in Stroke Patients – Scientific American

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