Posts Tagged oxidative stress

[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.

via Traumatic brain injuries could be healed using peptide hydrogels

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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.

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

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[Abstract] Systematic review of traumatic brain injury and the impact of antioxidant therapy on clinical outcomes. – CNS

Systematic review of traumatic brain injury and the impact of antioxidant therapy on clinical outcomes.

Worldviews Evid Based Nurs. 2016 May 31. doi: 10.1111/wvn.12167. [Epub ahead of print]. Shen Q(1), Hiebert JB(2), Hartwell J(3), Thimmesch AR(4), Pierce JD(5).

BACKGROUND: Traumatic brain injury (TBI) is an acquired brain injury that occurs when there is sudden trauma that leads to brain damage. This acute complex event can happen when the head is violently or suddenly struck or an object pierces the skull or brain. The current principal treatment of TBI includes various pharmaceutical agents, hyperbaric oxygen, and hypothermia. There is evidence that secondary injury from a TBI is specifically related to oxidative stress. However,
the clinical management of TBI often does not include antioxidants to reduce oxidative stress and prevent secondary injury.

AIMS: The purpose of this article is to examine current literature regarding the use of antioxidant therapies in treating TBI. This review evaluates the evidence of antioxidant therapy as an adjunctive treatment used to reduce the underlying mechanisms involved in secondary TBI injury.

METHODS: A systematic review of the literature published between January 2005 and September 2015 was conducted. Five databases were searched including CINAHL, PubMed, the Cochrane Library, PsycINFO, and Web of Science.

FINDINGS: Critical evaluation of the six studies that met inclusion criteria
suggests that antioxidant therapies such as amino acids, vitamins C and E, progesterone, N-acetylcysteine, and enzogenol may be safe and effective adjunctive therapies in adult patients with TBI. Although certain limitations were found, the overall trend of using antioxidant therapies to improve the clinical outcomes of TBI was positive.

LINKING EVIDENCE TO ACTION: By incorporating antioxidant therapies into practice, clinicians can help attenuate the oxidative posttraumatic brain damage and optimize patients’ recovery.

Source: Traumatic Brain Injury Resource Guide – Research Reports – Systematic review of traumatic brain injury and the impact of antioxidant therapy on clinical outcomes

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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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