Hypidone hydrochloride(YL-0919)ameliorates functional deficits after traumatic brain injury in mice by activating the sigma-1 receptor for antioxidation

Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.

The Citron homology domain of MAP4Ks improves outcomes of traumatic brain injury

The mitogen-activated protein kinase kinase kinase kinases(MAP4Ks)signaling pathway plays a pivotal role in axonal regrowth and neuronal degeneration following insults.Whether targeting this pathway is beneficial to brain injury remains unclear.In this study,we showed that adeno-associated virus-delivery of the Citron homology domain of MAP4Ks effectively reduces traumatic brain injury-induced reactive gliosis,tauopathy,lesion size,and behavioral deficits.Pharmacological inhibition of MAP4Ks replicated the ameliorative effects observed with expression of the Citron homology domain.Mechanistically,the Citron homology domain acted as a dominant-negative mutant,impeding MAP4K-mediated phosphorylation of the dishevelled proteins and thereby controlling the Wnt/β-catenin pathway.These findings implicate a therapeutic potential of targeting MAP4Ks to alleviate the detrimental effects of traumatic brain injury.

Drug-and cell-based therapies for targeting neuroinflammation in traumatic brain injury

TBI pathology： Traumatic brain injury （TBI） is caused by an external force to the head, resulting in trauma to the brain. Approximately 1.7 million Americans suffer from TBI every year. Out of the 1.7 million suffering from TBI, an estimated 52,000 injuries result in death, leaving a mass amount of peo- ple with symptoms that could last a few days, a few years, or their entire life （Faul et al., 2010）. TBI can be classified as mild, moderate and severe. Depending on the classification and the extent of the injury, TBI can cause both physical symptoms and cognitive disorders （Lozano et al., 2015）.

Advances in extracellular vesicle-based combination therapies for spinal cord injury

Spinal cord injury is a severe insult to the central nervous system that causes persisting neurological deficits.The currently available treatments involve surgical,medical,and rehabilitative strategies.However,none of these techniques can markedly reverse neurological deficits.Recently,extracellular vesicles from various cell sources have been applied to different models of spinal cord injury,thereby generating new cell-free therapies for the treatment of spinal cord injury.However,the use of extracellular vesicles alone is still associated with some notable shortcomings,such as their uncertainty in targeting damaged spinal cord tissues and inability to provide structural support to damaged axons.Therefore,this paper reviews the latest combined strategies for the use of extracellular vesicle-based technology for spinal cord injury,including the combination of extracellular vesicles with nanoparticles,exogenous drugs and/or biological scaffold materials,which facilitate the targeting ability of extracellular vesicles and the combinatorial effects with extracellular vesicles.We also highlight issues relating to the clinical transformation of these extracellular vesicle-based combination strategies for the treatment of spinal cord injury.

Is Goshinjo therapy effective in cognitive impairment after severe traumatic brain injury?

We report a case of a 21-year-old man who had severe traumatic brain injury as a result of an accident at the age of 16 years. Two years and 4 months after the trauma, at the age of 19 years, he still had severe right hemiplegia and cognitive dysfunction including aphasia and attention and memory disturbance. Conventional rehabilitation programs cou（d not resolve all of the neuropsychological problems. He started receiving Goshinjo therapy over a period of 22 months. Following the therapy, significant improvements in verbal intelligence quotient （assessed by the Wechsler Adult Intelligence Scale-Third Edition） and attention and concentration function （using the Wechsler Memory Scale-Revised）, and remission of traumatic epilepsy were observed. Goshinjo therapy is suspected to be effective in the treatment of cognitive dysfunction in the chronic stage after severe traumatic brain injury.

Safety and efficiency of Wharton’s Jelly-derived mesenchymal stem cell administration in patients with traumatic brain injury:First results of a phase I study

BACKGROUND Traumatic brain injury(TBI)is characterized by a disruption in the normal function of the brain due to an injury following a trauma,which can potentially cause severe physical,cognitive,and emotional impairment.Stem cell transplantation has evolved as a novel treatment modality in the management of TBI,as it has the potential to arrest the degeneration and promote regeneration of new cells in the brain.Wharton’s Jelly-derived mesenchymal stem cells(WJ-MSCs)have recently shown beneficial effects in the functional recovery of neurological deficits.AIM To evaluate the safety and efficiency of MSC therapy in TBI.METHODS We present 6 patients,4 male and 2 female aged between 21 and 27 years who suffered a TBI.These 6 patients underwent 6 doses of intrathecal,intramuscular(i.m.)and intravenous transplantation of WJ-MSCs at a target dose of 1×106/kg for each application route.Spasticity was assessed using the Modified Ashworth scale(MAS),motor function according to the Medical Research Council Muscle Strength Scale,quality of life was assessed by the Functional Independence Measure(FIM)scale and Karnofsky Performance Status scale.RESULTS Our patients showed only early,transient complications,such as subfebrile fever,mild headache,and muscle pain due to i.m.injection,which resolved within 24 h.During the one year follow-up,no other safety issues or adverse events were reported.These 6 patients showed improvements in their cognitive abilities,muscle spasticity,muscle strength,performance scores and fine motor skills when compared before and after the intervention.MAS values,which we used to assess spasticity,were observed to statistically significantly decrease for both left and right sides(P<0.001).The FIM scale includes both motor scores(P<0.05)and cognitive scores(P<0.001)and showed a significant increase in pretest posttest analyses.The difference observed in the participants’Karnofsky Performance Scale values pre and post the intervention was statistically significant(P<0.001).CONCLUSION This study showed that cell transplantation has a safe,effective and promising future in the management of TBI.

Efficacy of super-pulsed 905 nm Low Level Laser Therapy (LLLT) in the management of Traumatic Brain Injury (TBI): A case study

Traumatic brain injury is a major health concern worldwide with massive financial and social impact. Conventional treatments primarily focus on the prevention of further damage to the brain parenchyma, while failing to address the already existent symptoms. Previous clinical studies have shown that Low Level Laser Therapy (LLLT) can significantly reduce pain and induce temporary vasodilation in capillaries, which the authors hypothesize can be used to improve the quality of life in TBI patients by treating their current symptoms, which are predominately migraine-like headaches. This case report illustrates the use of LLLT in the treatment of a patient with a TBI and the great clinical success achieved in the reduction of pain, as measured by VAS—achievable within five treatments of 10 minutes in duration.

The endogenous progenitor response following traumatic brain injury:a target for cell therapy paradigms

Although there is ample evidence that central nervous system progenitor pools respond to traumatic brain injury,the reported effects are variable and likely contribute to both recovery as well as pathophysiology.Through a better understanding of the diverse progenitor populations in the adult brain and their niche-specific reactions to traumatic insult,treatments can be tailo red to enhance the benefits and dampen the deleterious effects of this response.This review provides an overview of endogenous precursors,the associated effects on cognitive recovery,and the potential of exogenous cell therapeutics to modulate these endogenous repair mechanisms.Beyond the hippocampal dentate gyrus and subventricular zone of the lateral ventricles,more recently identified sites of adult neurogenesis,the meninges,as well as circumventricular organs,are also discussed as targets for endogenous repair.Importantly,this review highlights that progenitor prolife ration alone is no longer a meaningful outcome and studies must strive to better chara cterize precursor spatial localization,transcriptional profile,morphology,and functional synaptic integration.With improved insight and a more targeted approach,the stimulation of endogenous neurogenesis remains a promising strategy for recovery following traumatic brain injury.

Modified constraint-induced movement therapy enhances cortical plasticity in a rat model of traumatic brain injury:a resting-state functional MRI study

Modified constraint-induced movement therapy(mCIMT)has shown beneficial effects on motor function improvement after brain injury,but the exact mechanism remains unclear.In this study,amplitude of low frequency fluctuation(ALFF)metrics measured by resting-state functional magnetic resonance imaging was obtained to investigate the efficacy and mechanism of mCIMT in a control co rtical impact(CCI)rat model simulating traumatic brain injury.At 3 days after control co rtical impact model establishment,we found that the mean ALFF(mALFF)signals were decreased in the left motor cortex,somatosensory co rtex,insula cortex and the right motor co rtex,and were increased in the right corpus callosum.After 3 weeks of an 8-hour daily mClMT treatment,the mALFF values were significantly increased in the bilateral hemispheres compared with those at 3 days postoperatively.The mALFF signal valu es of left corpus callosum,left somatosensory cortex,right medial prefro ntal cortex,right motor co rtex,left postero dorsal hippocampus,left motor cortex,right corpus callosum,and right somatosensory cortex were increased in the mCIMT group compared with the control cortical impact group.Finally,we identified brain regions with significantly decreased mALFF valu es at 3 days postoperatively.Pearson correlation coefficients with the right forelimb sliding score indicated that the improvement in motor function of the affected upper limb was associated with an increase in mALFF values in these brain regions.Our findings suggest that functional co rtical plasticity changes after brain injury,and that mCIMT is an effective method to improve affected upper limb motor function by promoting bilateral hemispheric co rtical remodeling.mALFF values correlate with behavio ral changes and can potentially be used as biomarkers to assess dynamic cortical plasticity after traumatic brain injury.

Multi-watt near-infrared light therapy as a neuroregenerative treatment for traumatic brain injury

Infrared light represents a broad spectrum of light with wavelengths from 700 nm to 1 million nm（1,000 microns）.At its shortest wavelengths（referred to as near-infrared）,it merges with the red spectrum of visible light.At the longest end（referred to as far-infrared）,it blends into the range of microwaves.

Acute liver failure following levetiracetam therapy for seizure prophylaxis in traumatic brain injury

This case report investigates an uncommon occurrence of drug induced acute liver injury directly associated with the administration of levetiracetam in a patient following traumatic brain injury.

Magnetic resonance imaging and cell-based neurorestorative therapy after brain injury

Restorative cell-based therapies for experimental brain injury, such as stroke and traumatic brain injury,substantially improve functional outcome. We discuss and review state of the art magnetic resonance imaging methodologies and their applications related to cell-based treatment after brain injury. We focus on the potential of magnetic resonance imaging technique and its associated challenges to obtain useful new information related to cell migration, distribution, and quantitation, as well as vascular and neuronal remodeling in response to cell-based therapy after brain injury. The noninvasive nature of imaging might more readily help with translation of cell-based therapy from the laboratory to the clinic.

Liposomes as versatile agents for the management of traumatic and nontraumatic central nervous system disorders:drug stability,targeting efficiency,and safety

Various nanoparticle-based drug delivery systems for the treatment of neurological disorders have been widely studied.However,their inability to cross the blood–brain barrier hampers the clinical translation of these therapeutic strategies.Liposomes are nanoparticles composed of lipid bilayers,which can effectively encapsulate drugs and improve drug delivery across the blood–brain barrier and into brain tissue through their targeting and permeability.Therefore,they can potentially treat traumatic and nontraumatic central nervous system diseases.In this review,we outlined the common properties and preparation methods of liposomes,including thin-film hydration,reverse-phase evaporation,solvent injection techniques,detergent removal methods,and microfluidics techniques.Afterwards,we comprehensively discussed the current applications of liposomes in central nervous system diseases,such as Alzheimer's disease,Parkinson's disease,Huntington's disease,amyotrophic lateral sclerosis,traumatic brain injury,spinal cord injury,and brain tumors.Most studies related to liposomes are still in the laboratory stage and have not yet entered clinical trials.Additionally,their application as drug delivery systems in clinical practice faces challenges such as drug stability,targeting efficiency,and safety.Therefore,we proposed development strategies related to liposomes to further promote their development in neurological disease research.

Acupuncture-induced oxygen therapy inhibits oxyradical injury and improves microcirculation following brain injury

BACKGROUND： Acupuncture-induced oxygen therapy combines acupoint theory in traditional Chinese medicine and modern oxygen therapy. Clinical studies have shown that acupuncture-induced oxygen therapy results in favorable outcomes for brain injury. However, the mechanisms of action remain poorly understood. OBJECTIVE： To determine pathological changes and malondialdehyde （MDA） content, superoxide dismutase （SOD） and nitric oxide synthase （NOS） activity, as well as hemorheological brain alterations following acupuncture-induced oxygen therapy, and to explore possible mechanisms of acupuncture-induced oxygen therapy on brain injury. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Animal Experimental Center of Xi＇an Medical University from January 2006 to April 2009. MATERIALS： An oxygen delivery device, through the use of acupuncture （oxygen delivery machine ＋ silver hollowed needle, 0.5 mm inner diameter）, was purchased from Research Center ol Machine, Shaanxi University of Science and Technology in China. METHODS： A total of 180 Sprague Dawley rats were randomly assigned to six groups （n = 30）： normal, sham-surgery （dura mater exposure）, model （brain injury induced by free-falling of heavy object to head）, Xiantaimixture （0.417 mL/100 g following brain injury）, electroacupuncture [acupuncture at Baihui （DU 20）, Housanfi （ST 36）, Yanglingquan （GB 34）, and Sanyinjiao （SP 6） following brain injury], and acupuncture-induced oxygen therapy （oxygen delivery through hollowed needle to Baihui （DU 20）, Housanfi （ST 36）, Yanglingquan （GB 34）, and Sanyinjiao （SP 6） following brain injury, 0.01 mL/minute）. Group intervention was performed once a day for 14 consecutive days. MAIN OUTCOME MEASURES： Pathological changes, MDA content, SOD and NOS activity, and hemorheological alterations in the brain. RESULTS： Obvious pathological changes were observed, such as hemorrhage, edema, and cell necrosis, following brain injury. These alterations were significantly improved following 14 days of treatment with Xiantai mixture, electroacupuncture, and acupuncture-induced oxygen therapy. In particular, acupuncture-induced oxygen therapy resulted in recovery to normal conditions. In the Xiantai mixture, electroacupuncture, and acupuncture-induced oxygen therapy groups, MDA content was significantly reduced （P 〈 0.01）, SOD activity was significantly increased （P 〈 0.01）, NOS activity was significantly decreased （P 〈 0.01）, and hemorheological indices were reduced, compared with the model group, in particular, acupunture-induced oxygen therapy resulted in the most obvious changes （P 〈 0.01）. CONCLUSION： Acupuncture-induced oxygen therapy improved pathological changes following brain injury by possibly improving blood supply, ameliorating ischemia/hypoxia, and inhibiting peroxidation and free radicals.

The Use of Antiepileptic Drugs in Acute Neuropsychiatric Conditions: Focus on Traumatic Brain Injury, Pain, and Alcohol Withdrawal

Antiepileptic drugs (AEDs), have demonstrated efficacy treating a number of acute conditions, encompassing a broad range of symptoms and syndromes, in addition to being first-line treatment for epilepsy. Clinically, since their inception, AEDs have been used off-label for acute and chronic medical conditions, both as primary and as adjuvant therapies. In this review, we describe the observed clinical effectiveness of AEDs across a set of commonly encountered acute conditions in the general hospital: traumatic brain injury, pain, alcohol withdrawal. In describing the individual benefits and usages of specific agents, the applicability of these agents to other common neuropsychiatric conditions may be further explored.

Experimental study on ex vivo retrovirus-mediated aFGF gene transfer therapy in traumatic brain injury

Objective:To exploretheeffectsof ex vivo retrovirus-mediatedgenetransfertherapywithacidicfibroblast growthfactor(aFGF)in themanagementof traumaticbraininjury.Methods:PLXSN-SPaFGF,a recombinantretroviral vectorexpressingbiologicallyactiveaFGFwas constructedandtransfectedintoculturedembryonicastroglialcellswhich wereinjectedintothesurroundingareasof thecontusionin theratleftparietalcortex.From3d to1monthaftertheim-plantation,thesurvivalof andaFGFgeneexpressionintheimplantedastroglialcellswereexamined,andneuronalapopto-sisandratmotorfunctionimpairmentevaluated.Re sults:TheimplantedaFGF-transducedastroglialcellssurvivedandex-pressedaFGFmRNAandproteinevidentlyat3d aftergrafting.Thenumberof andaFGFgeneexpressionintheastroglial cellsincreasedremarkebly7d anddecreasedto someextent1monthaftertheimplantation.ThereweresignificantaFGF mRNA andproteinexpressionin theneuronssurroundingthecontusionat7d thatdecreasedto relativelylow levels1monthaftertheimplantationof aFGF-transduedastrocytes.Diminishedneuronalapoptosis(P<0.05)andsignificantlyim-provedinthepreviouslyimpairedmotorfunction(P<0.05)of theratswereobservedfrom7d to1monthaftertheimplan-tation.Con clu sion:Thisexperimentsuccessfullyconductedex vivo aFGFgenetransfertherapyin traumaticbraininjury whichprovedto be effectiveinrescuinginjurednervecellfromdeathandenhancingrecoveryof neurologicaldeficiency.

Effect of rehabilitation training combined with neurotrophic therapy on the nerve cytokine secretion and oxidative stress in rehabilitation period of patients with traumatic brain injury

Objective:To study the effect of rehabilitation training combined with neurotrophic therapy on the nerve cytokine secretion and oxidative stress in rehabilitation period of patients with traumatic brain injury.Methods:A total of 98 patients in rehabilitation period of traumatic brain injury who were treated in our hospital between July 2013 and September 2016 were collected and divided into control group and observation group according to the random number table method, and 49 cases in each group. Control group received regular neurotrophic therapy, and observation group received rehabilitation training combined with neurotrophic therapy. The differences in the contents of nerve cytokines and oxidative stress indexes were compared between the two groups before and after intervention.Results:Before intervention, differences in serum levels of nerve injury indexes, neurotrophy indexes, amino acid neurotransmitters and oxidative stress indexes were not statistically significant between the two groups of patients. After intervention, serum nerve injury indexes MBP, NGB, NSE and S-100B levels as well as excitatory amino acids Glu and Asp levels of observation group were lower than those of control group;neurotrophy indexes BDNF and GDNF levels as well as inhibitory amino acids GABA and Gly levels were higher than those of control group;serum oxidative stress indexes SOD and CAT levels were higher than those of control group;MDA level was lower than that of control group.Conclusions:Rehabilitation training combined with neurotrophic therapy can effectively optimize the nerve function and reduce the systemic oxidative stress state of patients in rehabilitation period of traumatic brain injury.

Decreased numbers of circulating endothelial progenitor cells are associated with hyperglycemia in patients with traumatic brain injury

Hyperglycemia reduces the number of circulating endothelial progenitor cells, accelerates their senescence and impairs their function.However, the relationship between blood glucose levels and endothelial progenitor cells in peripheral blood of patients with traumatic brain injury is unclear. In this study, 101 traumatic brain injury patients admitted to the Department of Neurosurgery, Tianjin Medical University General Hospital or the Department of Neurosurgery, Tianjin Huanhu Hospital, China, were enrolled from April 2005 to March 2007. The number of circulating endothelial progenitor cells and blood glucose levels were measured at 1, 4, 7, 14 and 21 days after traumatic brain injury by flow cytometry and automatic biochemical analysis, respectively. The number of circulating endothelial progenitor cells and blood sugar levels in 37 healthy control subjects were also examined. Compared with controls, the number of circulating endothelial progenitor cells in traumatic brain injury patients was decreased at 1 day after injury, and then increased at 4 days after injury,and reached a peak at 7 days after injury. Compared with controls, blood glucose levels in traumatic brain injury patients peaked at 1 day and then decreased until 7 days and then remained stable. At 1, 4, and 7 days after injury, the number of circulating endothelial progenitor cells was negatively correlated with blood sugar levels(r =-0.147, P < 0.05). Our results verify that hyperglycemia in patients with traumatic brain injury is associated with decreased numbers of circulating endothelial progenitor cells. This study was approved by the Ethical Committee of Tianjin Medical University General Hospital, China(approval No. 200501) in January 2015.

Combination of mild therapeutic hypothermia and adipose-derived stem cells for ischemic brain injury

Mild therapeutic hypothermia has been shown to mitigate cerebral ischemia, reduce cerebral edema, and improve the prognosis of patients with cerebral ischemia. Adipose-derived stem cell-based therapy can decrease neuronal death and infiltration of inflammatory cells, exerting a neuroprotective effect. We hypothesized that the combination of mild therapeutic hypothermia and adipose-derived stem cells would be neuroprotective for treatment of stroke. A rat model of transient middle cerebral artery occlusion was established using the nylon monofilament method. Mild therapeutic hypothermia（33°C） was induced after 2 hours of ischemia. Adipose-derived stem cells were administered through the femoral vein during reperfusion. The severity of neurological dysfunction was measured by a modified Neurological Severity Score Scaling System. The area of the infarct lesion was determined by 2,3,5-triphenyltetrazolium chloride staining. Apoptotic neurons were detected by terminal deoxynucleotidyl transferase-mediated d UTP-biotin nick end labeling（TUNEL） staining. The regeneration of microvessels and changes in the glial scar were detected by immunofluorescence staining. The inflammatory responses after ischemic brain injury were evaluated by in situ staining using markers of inflammatory cells. The expression of inflammatory cytokines was measured by reverse transcription-polymerase chain reaction. Compared with mild therapeutic hypothermia or adipose-derived stem cell treatment alone, their combination substantially improved neurological deficits and decreased infarct size. They synergistically reduced the number of TUNEL-positive cells and glial fibrillary acidic protein expression, increased vascular endothelial growth factor levels, effectively reduced inflammatory cell infiltration and down-regulated the m RNA expression of the proinflammatory cytokines interleukin-1β, tumor necrosis factor-α and interleukin-6. Our findings indicate that combined treatment is a better approach for treating stroke compared with mild therapeutic hypothermia or adipose-derived stem cells alone.

Curative effect of ganglioside sodium for adjuvant therapy on acute severe craniocerebral injury

Objective: To study the effect of adjuvant therapy of ganglioside sodium on intracranial pressure (ICP), partial pressure of brain tissue oxygen (PbtO2), nerve injury molecules, nerve protection molecules and indexes of oxidative stress in patients with acute severe craniocerebral injury. <br> Methods: Forty-seven patients with severe craniocerebral injury treated in the emergency department of our hospital during the period time from December 2012 to October 2015 were selected for retrospective analyses. They were divided into the ganglioside group and the normal treatment group according to the usage of ganglioside sodium in the process of the emergency treatment. At days 1, 3, 5 and 7 before and after treatment, theICP and PbtO2 in patients of the two groups were measured. After 7 days of treatment, the nerve injury molecules, nerve protection molecules and the indexes of oxidative stress in serum of the patients of the two groups were determined. <br> Results: At days 1, 3, 5 and 7 before and after treatment, theICP in patients of the ganglioside group were all significantly lower than those of the normal treatment group, while the PbtO2 were all significantly higher than those of normal treatment group. After 7 days of treatment, the contents of serum methane dicarboxylic aldehyde, advanced oxidation protein products, 8-hydroxy-2'-deoxyguanosine urine, S100β, glial fibrillary acidic portein, neuron specific enolase, myelin basic protein, neuroglobin and ubiquitin carboxyl-terminal hydrolase L1 in patients of the ganglioside group were notably lower than those of the normal treatment group, while the contents of superoxidase dismutase, glutathione peroxidase, catalase, nerve growth factor and brain derived neurotrophic factor were significantly higher than those of the normal treatment group. <br> Conclusions: The adjuvant therapy of ganglioside sodium in patients with severe craniocerebral injury can effectively reduceICP, improve PbtO2 and alleviate the injuries of neurons and glial cells caused by oxidative stress.