Nanotherapeutic modulation of excitotoxicity and oxidative stress in acute brain injury.

Traumatic brain injury (TBI) is a major health and socioeconomic problem that affects all societies. Consciousness disorder is a common complication after TBI while there is still no effective treatment currently. The aim of this study was to investigate the protective effect of electro-acupuncture (EA) on cognitive recovery for patients with mild TBI. A total of 83 patients with initial Glasgow coma scale score higher than 12 points were assigned into this study. Then patients were randomly divided into 2 groups: EA group and control group (group C). Patients in group EA received EA treatment at Neiguan and Shuigou for 2 weeks. At 0 minute before EA treatment (T1), 0 minute after EA treatment (T2), and 8 weeks after EA treatment (T3), level of neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), hypoxia inducible factor-1α (HIF-1α), and malondialdehyde were tested by enzyme-linked immunosorbent assay. The score of Montreal Cognitive Function Assessment (MoCA) and mini-mental state examination (MMSE) as well as cerebral oxygen saturation (rSO2) were detected at the same time. Compared with the baseline at T1, the level of NSE, GFAP, HIF-1α, MDA, and rSO2 decreased, and the score of MoCA and MMSE increased in the 2 groups were significantly increased at T2-3 (P < .05). Compared with group C, the level of NSE, GFAP, HIF-1α, MDA, and rSO2 decreased, and the score of MoCA and MMSE increased were significantly increased at T2-3 in group EA; the difference were statistically significant (P < .05). EA treatment could improve the cognitive recovery for patients with mild TBI and the potential mechanism may be related to improving cerebral hypoxia and alleviating brain injury.

XV. Steroids

Abstracts from The 39^th Annual Symposium of the National Neurotrauma Society, including the AANS/CNS Joint Section on Neurotrauma and Critical Care

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

Abstracts from The 35th Annual National Neurotrauma Symposium July 7-12, 2017 Snowbird, Utah.

Management of brain injury can pose enormous challenges to the health team. There are many studies aimed at discovering or developing pharmacotherapeutic agents targeted at improving outcome of head-injured patients. This paper reviews the role of oxidative stress in neuronal loss following traumatic brain injury and presents experimental and clinical evidence of the role of exogenous antioxidants as neuroprotectants. We reviewed published literature on reactive oxygen species and their role in experimental and clinical brain injuries in journals and the Internet using Yahoo and Google search engines. Traumatic brain injury causes massive production of reactive oxygen species with resultant oxidative stress. In experimental brain injury, exogenous antioxidants are useful in limiting oxidative damage. Results with clinical brain injury are however more varied. Oxidative stress due to excessive generation of reactive oxygen species with consequent impairment of endogenous antioxidant defence mechanisms plays a significant role in the secondary events leading to neuronal death. Enhancement of the defence mechanisms through the use of exogenous antioxidants may be neuroprotective, especially if the agents can penetrate cell membranes, are able to cross the blood-brain barrier and if they are administered within the neuroprotective time window.

Treatment of pediatric traumatic brain injury: A broad path to a narrow gate

Abstracts fromThe 33^rd AnnualNational Neurotrauma SymposiumJune 28–July 1, 2015Santa Fe, New Mexico

Melatonin and N-acetylcysteine reduce brain injury in response to lipopolysaccharide-sensitized hypoxia-ischemia

Keeping cool in acute liver failure: Rationale for the use of mild hypothermia

Dear editor We read with great interest the recent study by Lozano et al1 published in the Neuropsychiatric Disease and Treatment. The recovery after traumatic brain injury (TBI) is related to severity of the initial injury (primary injury) and the presence of secondary injury.2 Evidences suggest that inflammation, oxidative stress, excitotoxicity, apoptosis, and neuroendocrine responses play an important role in the development of secondary brain injury.3 Therefore, an important part in the management of patients with TBI is trying to minimize the occurrence of deleterious secondary lesions. Lozano et al’s1 paper focused on the role of neuroinflammation in brain injury. Although some studies have described experimental drugs which may eventually have neuroprotective effects in patients with TBI,2–4 there is currently no approved pharmacological treatment for neuroinflammatory effects of the acute phase of the injury. The dissociation between experimental data with positive results and consecutive clinical trials with negative results leads to a dilemma for the treatment of patients with TBI. And, we agree with Lozano et al1 that further clarification of the neuroinflammatory mechanisms could be the basis for addressing the gap between bench and clinical results to provide better treatment and reduce death and sequelae of TBI. A strong point of the paper1 is the detailed description of signaling pathways of biochemical cascades of secondary injury in TBI, highlighting the metabolic and cellular processes. The discussion about cell death mechanisms is comprehensive and in simple language, which makes it accessible for clinical teams. The description of acute excitatory mechanisms, oxidative stress, and mitochondrial dysfunction is broad and interesting. Another prominent aspect in the review is the section “Neuroinflammation-based therapies”, which allows an analysis of the current status and perspectives for treatment of post-traumatic neuroinflammation. Our group has a particular interest in the role of MMPs, zinc-dependent peptides capable to break down most of the extracellular matrix components such as COL, ELN, and FN, in the mechanisms of enhancement of brain injury. As discussed by Lozano et al many processes in secondary injury depends on the integrity of the blood–brain barrier,5 an anatomical structure formed by tight junctions, basement membrane, podocyte and glial cells that prevents the passive transport of hydrophilic molecules larger than 500 Da between brain structures and blood.5,6 Experimental studies have shown that MMP-9 levels increase after TBI, breaking down basal lamina components and disrupting the blood–brain barrier.7 In animal studies, Wang et al8 demonstrated increased levels of MMP-9 after TBI which persisted for up to 1 week and such an increase also occurred in the contralateral hemisphere, suggesting that after trauma, changes in cerebral state are not restricted to the injured area. Suehiro et al7 found high levels of MMP-9 in TBI patients in the acute phase correlated with high levels of IL-6. They suggested that MMP-9 might play a role in the damage of TBI and be associated with inflammatory events post-TBI. Moreover, during normal development and physiological conditioning of the cell, activated metalloproteinases are required to break down extracellular matrix molecules to allow cell migration.6 In this context, metalloproteinases may also play a role in allowing the interaction of different types of cells during brain injury or repair. Inflammatory process, as reported by the authors, is a double-edged sword, good toward neuroregeneration and bad toward enhancing brain damage. The comprehension of the mechanisms that rule this subtle switch to one side or the other should be the goal of this group and others working in this challenging domain.

Alzheimer's disease: cerebrolysin and nanotechnology as a therapeutic strategy.

Workshop on animal models of traumatic brain injury.

The blood-brain barrier (BBB), as a crucial gate of brain-blood molecular exchange, is involved in the pathogenesis of multiple neurological diseases. Oxidative stress is caused by an imbalance between the production of reactive oxygen species (ROS) and the scavenger system. Since oxidative stress plays a significant role in the production and maintenance of the BBB, the cerebrovascular system is especially vulnerable to it. The pathways that initiate BBB dysfunction include, but are not limited to, mitochondrial dysfunction, excitotoxicity, iron metabolism, cytokines, pyroptosis, and necroptosis, all converging on the generation of ROS. Interestingly, ROS also provide common triggers that directly regulate BBB damage, parameters including tight junction (TJ) modifications, transporters, matrix metalloproteinase (MMP) activation, inflammatory responses, and autophagy. We will discuss the role of oxidative stress-mediated BBB disruption in neurological diseases, such as hemorrhagic stroke, ischemic stroke (IS), Alzheimer’s disease (AD), Parkinson’s disease (PD), traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), and cerebral small vessel disease (CSVD). This review will also discuss the latest clinical evidence of potential biomarkers and antioxidant drugs towards oxidative stress in neurological diseases. A deeper understanding of how oxidative stress damages BBB may open up more therapeutic options for the treatment of neurological diseases.

Objective To investigate the effects of basic fibroblast growth factor (bFGF) on pericytes in the blood brain barrier at acute stage after traumatic brain injury (TBI) in mice. Methods A total of 90 mice with a C57BL/6 background were randomly divided into sham group, TBI group, and TBI+ bFGF group, with 30 rats per group. The models of moderate TBl were established using the controlled cortical impactor. After 24 hours, the changes of nerve function were evaluated by Garcia neurological score. Each mouse received an intraperitoneal injection of Evans blue dye for measuring the permeability of blood brain barrier. Western blot was used to test the related indices of pericytes after the cerebral cortex was quickly dissected: platelet-derived growth factor receptor beta (PDGFR-β), aminopeptidase N(CD13), desmin, neurogliocyte 2 (NG2), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Paraffin sections were prepared for HE staining and morphological changes were observed. Immunofluorescence assay was used to test the related indices of pericytes: PDGFR-β, CD13, and cell surface glycoprotein MUC18 (CD146). Results Garcia neurological score revealed that the score in TBI group was significantly decreased compared with that in sham group (P<0.01), but the score of TBI+ bFGF group was significantly increased compared with that of TBI group (P<0.05). Permeability of blood brain barrier in TBI group was significantly increased compared with that in sham group (P<0.01), but in TBI+ bFGF group this parameter significantly reduced compared with that in TBI group (P<0.01). Western blot analysis revealed that the expressions of PDGFR-β, CD13, desmin, NG2 proteins in TBI group were significantly decreased compared with those in sham group (P<0.05), while the expressions of PDGFR-β, CD13, desmin, NG2 proteins in TBI+ bFGF group were significantly increased compared with those in TBI group (P<0.05). HE staining revealed injury of brain parenchyma in TBI group was the severest compared with both sham group and TBI+ bFGF group. Immunofluorescence staining results revealed that the proteins expressions of PDGFR-β, CD13, and CD146 in TBI group were significantly decreased compared with those in sham group (all P<0.01), and those in TBI+ bFGF group were significantly increased compared with those in TBI group (all P<0.05). Conclusions bFGF can prevent pericyte death via protecting its proteins to conserve blood-brain barrier. bFGF can also significantly ameliorate the injury of brain parenchyma. Key words: Brain injuries; Fibroblast growth factor 2; Pericyte