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.

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）.

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.

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.

Brain and spinal cord trauma:what we know about the therapeutic potential of insulin growth factor 1 gene therapy

Although little attention has been paid to cognitive and emotional dysfunctions observed in patients after spinal co rd injury,several reports have described impairments in cognitive abilities.Our group also has contributed significantly to the study of cognitive impairments in a rat model of spinal co rd injury.These findings are very significant because they demonstrate that cognitive and mood deficits are not induced by lifestyle changes,drugs of abuse,and combined medication.They are related to changes in brain structures involved in cognition and emotion,such as the hippocampus.Chronic spinal cord injury decreases neurogenesis,enhances glial reactivity leading to hippocampal neuroinflammation,and trigge rs cognitive deficits.These brain distal abnormalities are recently called te rtiary damage.Given that there is no treatment for Tertiary Damage,insulin growth factor 1 gene therapy emerges as a good candidate.Insulin growth factor 1 gene thera py recove rs neurogenesis and induces the polarization from pro-inflammato ry towards anti-inflammatory microglial phenotypes,which represents a potential strategy to treat the neuroinflammation that supports te rtiary damage.Insulin growth factor 1 gene therapy can be extended to other central nervous system pathologies such as traumatic brain injury where the neuroinflammatory component is crucial.Insulin growth factor 1 gene therapy could emerge as a new therapeutic strategy for treating traumatic brain injury and 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.

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.

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.

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.

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.

Blood–brain barrier and laser technology for drug brain delivery

Here,we discuss an important problem in medicine as development of efctive strategies for brain drug delivery.This problem is related to the blood-brain barrier(BBB),which is a“customs”controlling the entrance of different molecules from blood into the brain protecting the normal function of central nervous system(CNS).We show three interfaces of anatomical side of BBB and two functional types of BBB一physical and transporter barriers.Although this protective mechanism is essential for health of CNS,it also creates a hindrance to the entry of drugs into the brain.The BBB was discovered over 100 years ago but till now,there is no efective methods for brain drug delivery.There ane more than 70 approaches for overcoming BBB incuding physical,chenical and biological techniques but all of these tools have limitation to be widely used in clinical practice due to invasi venes,challenge in performing,very costly or lim-itation of drug concentration.Photodynamic therapy(PDT)is usual clinical method of surgical navigation for the resection of brain tumor and anti-cancer therapy.Nowadays,the application of PDT is considered as a potential promising tool for brain drug delivery via opening of BBB.Here,we show the first sucoessful experimental results in this field discussing the adventures and disadv antages of PDT-related BBB disruption as well as altematives to overcome these limitations and possi ble mechanisms with new pathways for brain clearance via gly mphatic and lymphatic systems.

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.

功能性水凝胶在创伤性脑损伤组织修复中的作用

背景:目前临床上传统的给药途径(口服或静脉注射)面临难以透过血脑屏障问题,对于开放性重度创伤性脑损伤的临床治疗结果往往低于预期。水凝胶是一类极为亲水的三维网络结构凝胶,在水中迅速溶胀并在此溶胀状态可以保持。目前有部分实验应用可注射性功能水凝胶注射植入损伤部位以达到修复受损脑组织的目的,但这一治疗策略尚未应用于临床。目的:分析功能性水凝胶在创伤性脑损伤后组织修复中的作用,讨论水凝胶通过不同作用方式促进创伤性脑损伤后的神经组织再生,以期为创伤性脑损伤的临床治疗和基础研究提出新的思路。方法:以“hydrogels,functional hydrogel,composite hydrogels,traumatic brain injury,tissue repair,neural regeneration”“功能性水凝胶,创伤性脑损伤,组织修复,神经再生”为关键词在PubMed、Web of Science、中国知网和万方数据库检索2000年8月至2024年3月的相关文献。制定纳入和排除标准,通过阅读文献标题、摘要及全文内容进行筛选,最终纳入60篇相关文献进行综述。结果与结论:①基于分子设计的水凝胶可以模拟神经微结构,促进再生修复,模拟神经血管单元促进血管再生。②基于联合药物治疗原则的水凝胶可以递送内源性神经调控因子,包裹药物促进神经再生。③基于搭载干细胞恢复策略的水凝胶可以作为分子支架递送细胞治疗。④未来研究学者们还需进一步探索神经组织修复相关的功能性水凝胶,为创伤性脑损伤患者的治疗功能重建提供有效策略。