Posts Tagged Neuroprotection

[Abstract] Pharmacological interventions and rehabilitation approach for enhancing brain self-repair and stroke recovery

Abstract

Neuroplasticity is a natural process occurring in the brain for entire life. Stroke is the leading cause of long term disability and huge medical and financial problem throughout the world. Research conducted over the past decade focused mainly on neuroprotection in the acute phase of stroke while very little studies targets chronic stage. Recovery after stroke depends on the ability of our brain to reestablish structural and functional organization of neurovascular networks. Combining adjuvant therapies and drugs may enhance the repair processes and restore impaired brain functions. Currently, there are some drugs and rehabilitative strategies that can facilitate brain repair and improve clinical effect even years after stroke onset. Moreover, some of compounds such as citicoline, fluoxetine, niacin, levodopa etc. are already in clinical use or are being trial in clinical issues. Many studies testing also cell therapies, in our review we will focused on studies where cells have been implemented at the early stage of stroke. Next, we discuss pharmaceutical interventions. In this section selected methods of cognitive, behavioral and physical rehabilitation as well as adjuvant interventions for neuroprotection including non invasive brain stimulation and extremely low frequency electromagnetic field. The modern rehabilitation represents new model of physical interventions with limited therapeutic window up to six months after stroke. However, last studies suggest, that time window for stroke recovery is much longer than previous thought. This review attempts to present the progress in neuroprotective strategies, both pharmacological and non-pharmacological that can stimulate the endogenous neuroplasticity in post stroke patients.

 

via Pharmacological interventions and rehabilitation approach for enhancing brain self-repair and stroke recovery | Bentham Science

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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.

via 9 promising advances in the management of traumatic brain injury | The Neurology Lounge

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[Abstract] Treatment of Traumatic Brain Injury with Vepoloxamer (Purified Poloxamer 188)

ABSTRACT

Vepoloxamer is an amphipathic polymer that has shown potent hemorrheologic, cytoprotective, and anti-inflammatory effects in both pre-clinical and clinical studies. This study was designed to investigate the therapeutic effects of vepoloxamer on sensorimotor and cognitive functional recovery in rats after traumatic brain injury (TBI) induced by controlled cortical impact. Young adult male Wistar rats were randomly divided into the following groups: 1) sham; 2) saline; or 3) vepoloxamer. Vepoloxamer (300 mg/kg) or saline was administered over 60 min via intravenous infusion into tail veins starting at 2 h post-injury. Sensorimotor function and spatial learning were assessed using a modified neurological severity score and foot fault test, and Morris water maze test, respectively. The animals were sacrificed 35 days after injury and their brains were processed for measurement of lesion volume and neuroinflammation. Compared with the saline treatment, vepoloxamer initiated 2 h post-injury significantly improved sensorimotor functional recovery (Days 1–35; p < 0.0001) and spatial learning (Days 32–35; p < 0.0001), reduced cortical lesion volume by 20%, and reduced activation of microglia/macrophages and astrogliosis in many brain regions including injured cortex, corpus callosum, and hippocampus, as well as normalized the bleeding time and reduced brain hemorrhage and microthrombosis formation. In summary, vepoloxamer treatment initiated 2 h post-injury provides neuroprotection and anti-inflammation in rats after TBI and improves functional outcome, indicating that vepoloxamer treatment may have potential value for treatment of TBI. Further investigation of the optimal dose and therapeutic window of vepoloxamer treatment for TBI and the mechanisms underlying beneficial effects are warranted.

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via Treatment of Traumatic Brain Injury with Vepoloxamer (Purified Poloxamer 188) | Abstract

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[REVIEW] Pharmacological Aspects of Neurorehabilitation – Full Text

Abstract

Physicians in neurorehabilitation often deal with pharmacological problems, marshalling antihypertensive, anticonvulsive and anticoagulation treatments. In addition, there is growing interest in positive or negative effects of medication on brain recovery. Of great importance is the concept of so-called “detrimental drugs” known to negatively influence processes of brain reorganization and recovery. To this group belong anti-convulsive agents such as phenytoin and barbiturates as well as benzodiazepines, butyrophynones and the antihypertensives clonidine and prazosine. Whenever possible these drugs should be avoided in the course of brain recovery after a cerebral lesion.

For only two substances (the SSRI fluoxetine and cerebrolysin, a mixture of pleotropic neuropeptides and amino acids) large randomized controlled trials showed a positive influence on facilitating motor recovery after the stroke. Both substances probably work through pleotropic multiple molecular mechanisms and not as a one-to-one agonist on the receptor. In general the use of antidepressive agents especially SSRI after the stroke can also be recommended for non-depressed stroke patients.

Also dopaminergic drugs have been shown in smaller studies to positively influence functional recovery. Considering their low side-effect profile, the tentative use of 100 mg of L-Dopa per day in the subacute phase of the stroke can be recommended. In MS patients the use of antidepressive agents is also recommend to improve life quality.

In patients with diminished states of consciousness amantadine is the only substance which a randomized controlled study proved to have at least some transient effect. The use of amantadine can be recommended for the improvement of the level of consciousness in these patients.

Introduction

Physicians engaged in neurological rehabilitation constantly have to deal with aspects of primary pharmacological treatment of patients, including control of high blood pressure, anticonvulsive therapies and suitable anticoagulation treatment to reduce risk factors and secondary problems. Furthermore, neurological rehabilitation must also take into account pharmacological issues relating to restoration of brain function. This concerns the avoidance of pharmaceuticals that may interfere with brain recovery as well as the use of drugs that may have a positive affect on brain function. This overview aims to provide a critical summary of the options available to the clinician in the pharmacological treatment of patients after acute neurological events as part of the process of the rehabilitation of brain organization and restoration of brain function, as well as discuss the avoidance of potentially negative effects of pharmacological interventions. […]

Continue —>  Thieme E-Journals – Neurology International Open / Full Text

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[ARTICLE] Stroke research at the crossroads – where are we heading? – Full Text HTML

Summary

Stroke causes 5.7 million deaths annually. This ranks stroke as the second most common cause of death and, additionally, it is a major cause of disability. Because of an ageing population, stroke incidence and costs will greatly increase in the future. This makes stroke an ongoing social and economic burden, in contrast to the only very limited therapeutic options.

In the last decade vast sums were spent on translational research focused on neuroprotective strategies in the acute phase of ischaemic stroke. A plethora of candidate agents were tested in experimental models and preclinical studies, but none was proven effective in clinical trials. This gave rise to discussions about the possible reasons for this failure, ending up mainly with criticism of methodological aspects of the preclinical and clinical studies, or of the relevance of animal studies in drug development. Indeed, the question could rather be whether neuroprotection is the right target for successful stroke treatment. In this context, a paradigm change can currently be observed: the focus of experimental and translational stroke research is shifting from early neuroprotection to delayed mechanisms such as stroke-associated comorbidities, regeneration and plasticity.

In this review we highlight a few recently emerging fields in translational stroke research. One such topic is the crosstalk between immunity and the injured brain as key pathomechanism in stroke. On one hand, innate and adaptive immune cells play an important role in the fate of injured brain tissue after stroke; on the other, peripheral immune alterations are critically involved in post-stroke comorbidities.

Another emerging research area is the analysis of mechanisms involved in regeneration and neuronal plasticity after stroke. Here, we discuss the current understanding of basic mechanisms involved after brain injury, clinical imaging approaches and therapeutic strategies to promote regeneration in stroke patients.

Continue —> SMW – Swiss Medical Weekly – Stroke research at the crossroads – where are we heading?

Figure 1 Multiphasic brain interactions after stroke and opportunities for treatment. Previous neuroprotective strategies targeted pathological mechanisms in a very narrow window of opportunity in the (hyper-) acute phase after stroke (orange). Recently, the focus of translational stroke research has shifted towards understanding pathological processes in the subacute and chronic phase such as neuroinflammation and neuroregeneration (green). These targets have the potential for novel therapeutic approaches which are suitable for a larger population of stroke patients then neuroprotective agents or thrombolysis.

 

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[ARTICLE] Neurorestoration after stroke – JNS – Full Text

Abstract

Recent advancements in stem cell biology and neuromodulation have ushered in a battery of new neurorestorative therapies for ischemic stroke. While the understanding of stroke pathophysiology has matured, the ability to restore patients’ quality of life remains inadequate. New therapeutic approaches, including cell transplantation and neurostimulation, focus on reestablishing the circuits disrupted by ischemia through multidimensional mechanisms to improve neuroplasticity and remodeling. The authors provide a broad overview of stroke pathophysiology and existing therapies to highlight the scientific and clinical implications of neurorestorative therapies for stroke.

Continue —> JNS – Neurosurgical Focus –

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