|Bridging larger gaps in peripheral nerves using neural prosthetics and physical therapeutic agents|
Muhammad Sana Ullah Sahar, Matthew Barton, Geoffrey Douglas Tansley
Neural Regeneration Research 2019 14(7):1109-1115
Peripheral nerve injuries are relatively common and can be caused by a variety of traumatic events such as motor vehicle accidents. They can lead to long-term disability, pain, and financial burden, and contribute to poor quality of life. In this review, we systematically analyze the contemporary literature on peripheral nerve gap management using nerve prostheses in conjunction with physical therapeutic agents. The use of nerve prostheses to assist nerve regeneration across large gaps (> 30 mm) has revolutionized neural surgery. The materials used for nerve prostheses have been greatly refined, making them suitable for repairing large nerve gaps. However, research on peripheral nerve gap management using nerve prostheses reports inconsistent functional outcomes, especially when prostheses are integrated with physical therapeutic agents, and thus warrants careful investigation. This review explores the effectiveness of nerve prostheses for bridging large nerve gaps and then addresses their use in combination with physical therapeutic agents.
|Magnesium: Pathophysiological mechanisms and potential therapeutic roles in intracerebral hemorrhage|
Jason J Chang, Rocco Armonda, Nitin Goyal, Adam S Arthur
Neural Regeneration Research 2019 14(7):1116-1121
Intracerebral hemorrhage (ICH) remains the second-most common form of stroke with high morbidity and mortality. ICH can be divided into two pathophysiological stages: an acute primary phase, including hematoma volume expansion, and a subacute secondary phase consisting of blood-brain barrier disruption and perihematomal edema expansion. To date, all major trials for ICH have targeted the primary phase with therapies designed to reduce hematoma expansion through blood pressure control, surgical evacuation, and hemostasis. However, none of these trials has resulted in improved clinical outcomes. Magnesium is a ubiquitous element that also plays roles in vasodilation, hemostasis, and blood-brain barrier preservation. Animal models have highlighted potential therapeutic roles for magnesium in neurological diseases specifically targeting these pathophysiological mechanisms. Retrospective studies have also demonstrated inverse associations between admission magnesium levels and hematoma volume, hematoma expansion, and clinical outcome in patients with ICH. These associations, coupled with the multifactorial role of magnesium that targets both primary and secondary phases of ICH, suggest that magnesium may be a viable target of study in future ICH studies.
|Network-centric medicine for peripheral nerve injury: Treating the whole to boost endogenous mechanisms of neuroprotection and regeneration|
David Romeo-Guitart, Caty Casas
Neural Regeneration Research 2019 14(7):1122-1128
Peripheral nerve injuries caused by accidents may lead to paralysis, sensory disturbances, anaesthesia, and lack of autonomic functions. Functional recovery after disconnection of the motoneuronal soma from target tissue with proximal rupture of axons is determined by several factors: motoneuronal soma viability, proper axonal sprouting across inhibitory zones and elongation toward specific muscle, effective synapse contact rebuilding, and prevention of muscle atrophy. Therapies, such as adjuvant drugs with pleiotropic effects, that promote functional recovery after peripheral nerve injury are needed. Toward this aim, we designed a drug discovery workflow based on a network-centric molecular vision using unbiased proteomic data and neural artificial computational tools. Our focus is on boosting intrinsic capabilities of neurons for neuroprotection; this is in contrast to the common approach based on suppression of a pathobiological pathway known to be associated with disease condition. Using our workflow, we discovered neuroheal, a combination of two repurposed drugs that promotes motoneuronal soma neuroprotection, is anti-inflammatory, enhances axonal regeneration after axotomy, and reduces muscle atrophy. This drug discovery workflow has thus yielded a therapy that is close to its clinical application.
|Exogenous neural stem cell transplantation for cerebral ischemia|
Ling-Yi Liao, Benson Wui-Man Lau, Dalinda Isabel Sánchez-Vidaña, Qiang Gao
Neural Regeneration Research 2019 14(7):1129-1137
Cerebral ischemic injury is the main manifestation of stroke, and its incidence in stroke patients is 70–80%. Although ischemic stroke can be treated with tissue-type plasminogen activator, its time window of effectiveness is narrow. Therefore, the incidence of paralysis, hypoesthesia, aphasia, dysphagia, and cognitive impairment caused by cerebral ischemia is high. Nerve tissue regeneration can promote the recovery of the aforementioned dysfunction. Neural stem cells can participate in the reconstruction of the damaged nervous system and promote the recovery of nervous function during self-repair of damaged brain tissue. Neural stem cell transplantation for ischemic stroke has been a hot topic for more than 10 years. This review discusses the treatment of ischemic stroke with neural stem cells, as well as the mechanisms of their involvement in stroke treatment.
|Potential therapeutic molecular targets for blood-brain barrier disruption after subarachnoid hemorrhage|
Hideki Kanamaru, Hidenori Suzuki
Neural Regeneration Research 2019 14(7):1138-1143
Aneurysmal subarachnoid hemorrhage remains serious hemorrhagic stroke with high morbidities and mortalities. Aneurysm rupture causes arterial bleeding-induced mechanical brain tissue injuries and elevated intracranial pressure, followed by global cerebral ischemia. Post-subarachnoid hemorrhage ischemia, tissue injuries as well as extravasated blood components and the breakdown products activate microglia, astrocytes and Toll-like receptor 4, and disrupt blood-brain barrier associated with the induction of many inflammatory and other cascades. Once blood-brain barrier is disrupted, brain tissues are directly exposed to harmful blood contents and immune cells, which aggravate brain injuries furthermore. Blood-brain barrier disruption after subarachnoid hemorrhage may be developed by a variety of mechanisms including endothelial cell apoptosis and disruption of tight junction proteins. Many molecules and pathways have been reported to disrupt the blood-brain barrier after subarachnoid hemorrhage, but the exact mechanisms remain unclear. Multiple independent and/or interconnected signaling pathways may be involved in blood-brain barrier disruption after subarachnoid hemorrhage. This review provides recent understandings of the mechanisms and the potential therapeutic targets of blood-brain barrier disruption after subarachnoid hemorrhage.
|Choroid plexus tumor necrosis factor receptor 1: A new neuroinflammatory piece of the complex Alzheimer's disease puzzle|
Sophie Steeland, Roosmarijn E Vandenbroucke
Neural Regeneration Research 2019 14(7):1144-1147
Due to the aging of the population and despite the enormous scientific effort, Alzheimer’s disease remains one of the biggest medical and pharmaceutical challenges in current medicine. Novel insights highlight the importance of neuroinflammation as an undeniable player in the onset and progression of Alzheimer’s disease. Tumor necrosis factor is a master inflammatory cytokine that signals via tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2, but that also regulates several brain functions in health and disease. However, clinical trials investigating drugs that interfere with the tumor necrosis factor pathway in Alzheimer’s disease led to inconclusive results, partially because not only the pro-inflammatory tumor necrosis factor/tumor necrosis factor receptor 1, but also the beneficial tumor necrosis factor/tumor necrosis factor receptor 2 signaling was antagonized in these trials. We recently found that tumor necrosis factor is the main upregulated cytokine in the choroid plexus of Alzheimer’s disease patients, signaling via tumor necrosis factor receptor 1. In agreement with this, choroidal tumor necrosis factor/tumor necrosis factor receptor 1 signaling was also upregulated in different Alzheimer’s disease mouse models. Interestingly, both genetic and nanobody-based pharmacological blockage of tumor necrosis factor receptor 1 signaling was accompanied by favorable effects on Alzheimer’s disease-associated inflammation, choroidal morphology and cognitive functioning. Here, we briefly summarize the detrimental effects that can be mediated by tumor necrosis factor/tumor necrosis factor receptor 1 signaling in (early) Alzheimer’s disease, and the consequences this might have on the disease progression. As the main hypothesis in Alzheimer’s disease clinical trials is still based on the amyloid beta-cascade, the importance of Alzheimer’s disease-associated neuroinflammation urge the development of novel therapeutic strategies that might be effective in the early stages of Alzheimer’s disease and prevent the irreversible neurodegeneration and resulting memory decline.
|Transcriptional dysregulation in neurodegenerative diseases: Who tipped the balance of Yin Yang 1 in the brain?|
Zhefan Stephen Chen, Ho Yin Edwin Chan
Neural Regeneration Research 2019 14(7):1148-1151
Yin Yang 1 (YY1) is a multi-functional transcription factor that regulates gene expression in a range of cell types, including neurons. It controls neuronal differentiation, as well as neuronal specification and migration during the development of the mammalian nervous system. Besides, YY1 also mediates the transcription of genes that are required for neuronal survival. An impairment of the transcriptional function of YY1 causes neuronal death. This review summarizes recent research findings that unveil the dysfunction of YY1 in multiple neurodegenerative disorders. The expression of disease proteins perturbs the function of YY1 via distinct molecular mechanisms, including recruitment to protein aggregates, protein degradation and aberrant nuclear/cytoplasmic shuttling. Understanding the pathogenic roles of YY1 will further broaden our knowledge of the disease mechanisms in distinct neurodegenerative disorders.
|Effects of Ginkgo biloba extract EGb761 on neural differentiation of stem cells offer new hope for neurological disease treatment|
Chao Ren, Yong-Qiang Ji, Hong Liu, Zhe Wang, Jia-Hui Wang, Cai-Yi Zhang, Li-Na Guan, Pei-Yuan Yin
Neural Regeneration Research 2019 14(7):1152-1157
Stem cell transplantation has brought new hope for the treatment of neurological diseases. The key to stem cell therapy lies in inducing the specific differentiation of stem cells into nerve cells. Because the differentiation of stem cells in vitro and in vivo is affected by multiple factors, the final differentiation outcome is strongly associated with the microenvironment in which the stem cells are located. Accordingly, the optimal microenvironment for inducing stem cell differentiation is a hot topic. EGb761 is extracted from the leaves of the Ginkgo biloba tree. It is used worldwide and is becoming one of the focuses of stem cell research. Studies have shown that EGb761 can antagonize oxygen free radicals, stabilize cell membranes, promote neurogenesis and synaptogenesis, increase the level of brain-derived neurotrophic factors, and replicate the environment required during the differentiation of stem cells into nerve cells. This offers the possibility of using EGb761 to induce the differentiation of stem cells, facilitating stem cell transplantation. To provide a comprehensive reference for the future application of EGb761 in stem cell therapy, we reviewed studies investigating the influence of EGb761 on stem cells. These started with the composition and neuropharmacology of EGb761, and eventually led to the finding that EGb761 and some of its important components play important roles in the differentiation of stem cells and the protection of a beneficial microenvironment for stem cell transplantation.
|Amelioration of Alzheimer's disease pathology and cognitive deficits by immunomodulatory agents in animal models of Alzheimer's disease|
Bridget Martinez, Philip V Peplow
Neural Regeneration Research 2019 14(7):1158-1176
The most common age-related neurodegenerative disease is Alzheimer’s disease (AD) characterized by aggregated amyloid-β (Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles, together with loss of cholinergic neurons, synaptic alterations, and chronic inflammation within the brain. These lead to progressive impairment of cognitive function. There is evidence of innate immune activation in AD with microgliosis. Classically-activated microglia (M1 state) secrete inflammatory and neurotoxic mediators, and peripheral immune cells are recruited to inflammation sites in the brain. The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects. Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials. Treatment with immunomodulatory/anti-inflammatory agents early in the disease process, while not preventive, is able to inhibit the inflammatory consequences of both Aβ and tau aggregation. The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD. The majority of the animal studies reviewed had used transgenic models of early-onset AD. More effort needs to be given to creat models of late-onset AD. The effects of a combinational therapy involving two or more of the tested pharmaceutical agents, or one of these agents given in conjunction with one of the cell-based therapies, in an aged animal model of AD would warrant investigation.
|Precision medicine in pantothenate kinase-associated neurodegeneration|
Mónica Alvarez-Cordoba, Marina Villanueva-Paz, Irene Villalón-García, Suleva Povea-Cabello, Juan M Suárez-Rivero, Marta Talaverón-Rey, Javier Abril-Jaramillo, Ana Belén Vintimilla-Tosi, José A Sánchez-Alcázar
Neural Regeneration Research 2019 14(7):1177-1185
Neurodegeneration with brain iron accumulation is a broad term that describes a heterogeneous group of progressive and invalidating neurologic disorders in which iron deposits in certain brain areas, mainly the basal ganglia. The predominant clinical symptoms include spasticity, progressive dystonia, Parkinson’s disease-like symptoms, neuropsychiatric alterations, and retinal degeneration. Among the neurodegeneration with brain iron accumulation disorders, the most frequent subtype is pantothenate kinase-associated neurodegeneration (PKAN) caused by defects in the gene encoding the enzyme pantothenate kinase 2 (PANK2) which catalyzed the first reaction of the coenzyme A biosynthesis pathway. Currently there is no effective treatment to prevent the inexorable course of these disorders. The aim of this review is to open up a discussion on the utility of using cellular models derived from patients as a valuable tool for the development of precision medicine in PKAN. Recently, we have described that dermal fibroblasts obtained from PKAN patients can manifest the main pathological changes of the disease such as intracellular iron accumulation accompanied by large amounts of lipofuscin granules, mitochondrial dysfunction and a pronounced increase of markers of oxidative stress. In addition, PKAN fibroblasts showed a morphological senescence-like phenotype. Interestingly, pantothenate supplementation, the substrate of the PANK2 enzyme, corrected all pathophysiological alterations in responder PKAN fibroblasts with low/residual PANK2 enzyme expression. However, pantothenate treatment had no favourable effect on PKAN fibroblasts harbouring mutations associated with the expression of a truncated/incomplete protein. The correction of pathological alterations by pantothenate in individual mutations was also verified in induced neurons obtained by direct reprograming of PKAN fibroblasts. Our observations indicate that pantothenate supplementation can increase/stabilize the expression levels of PANK2 in specific mutations. Fibroblasts and induced neurons derived from patients can provide a useful tool for recognizing PKAN patients who can respond to pantothenate treatment. The presence of low but significant PANK2 expression which can be increased in particular mutations gives valuable information which can support the treatment with high dose of pantothenate. The evaluation of personalized treatments in vitro of fibroblasts and neuronal cells derived from PKAN patients with a wide range of pharmacological options currently available, and monitoring its effect on the pathophysiological changes, can help for a better therapeutic strategy. In addition, these cell models will be also useful for testing the efficacy of new therapeutic options developed in the future.
Δευτέρα, 25 Φεβρουαρίου 2019
Alkaline water is water that's less acidic than regular tap water. This means it is rich in alkalizing compounds, including calcium, silica, potassium, magnesium, and bicarbonate.https://www.precisionnutrition.com/alkaline-water-legit-or-hoax
Seeing little relief with PPIs for patients, study author looked to dietary treatment for LPR
Treatment of laryngopharyngeal reflux (LPR) with alkaline water and the Mediterranean diet may be as effective as treatment with proton-pump inhibitors (PPIs), according to research published online in JAMA Otolaryngology–Head & Neck Surgery in September. Like gastroesophageal reflux disease, a similar condition, LPR occurs when acidic gastric juices in the stomach back up into the esophagus, but in LPR, the gastric juices reach the throat, resulting in symptoms such as hoarseness, sore throat, cough, and excessive mucous.
In the study, researchers conducted a retrospective medical chart review comparing the change in Reflux Symptom Index (RSI) in two groups of patients, those treated between 2010 and 2012 with PPIs and standard reflux precautions and those treated between 2013 and 2015 with a plant-based Mediterranean diet and alkaline water that had a pH of at least 8. The team found that 54.1% of patients in the PPI group achieved a clinically meaningful reduction of at least 6 points, but 62.5% in the dietary group achieved similar results. Furthermore, those in the dietary group achieved a greater reduction in RSI: 39.8% compared with 27.2% in the PPI group.
"It's pretty clear that this data suggests that we, as health care professionals, need to start getting patients educated so they understand how important a role diet plays," said study lead author Craig H. Zalvan, MD, FACS, chief of otolaryngology and medical director at The Institute for Voice and Swallowing Disorders at Phelps Hospital in Sleepy Hollow, NY.
Zalvan said he thought to study dietary treatment for LPR after seeing that a sizable number of patients don't get much relief with PPIs.
"The standard of care for LPR has always been PPIs, and many of my patients got better with them, but a bunch didn't. At most it helps about 50% of patients," Zalvan said. "I looked at chronic diseases like heart disease, diabetes, and stroke, and their successful treatment with a plant-based diet, so I thought there's got to be a better way to treat LPR with diet [as well] and not have people constantly taking pills."
Zalvan added that the idea to incorporate alkaline water into treatment stemmed from prior research conducted by Jaime Koufman, MD, at the Voice Institute of New York in New York City, which suggests that alkaline water may benefit patients with reflux because it deactivates pepsin and acts as an acid buffer.
Zalvan said that as medication experts and readily accessible members of the health care team, pharmacists can help boost the signal about treatment options for LPR.
"Pharmacists can reinforce that PPIs are meant to be short-term medications for an acute problem, and that in order to get off them, diet will play a major part," Zalvan said. "If patients come to me and I say they should try diet, and then they go to the pharmacy and the pharmacist says they should try diet, patients are more likely to try diet."
For the full article, please visit www.pharmacytoday.org for the November 2017 issue of Pharmacy Today.
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