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.

Repetitive traumatic brain injury–induced complement C1–related inflammation impairs long-term hippocampal neurogenesis

Repetitive traumatic brain injury impacts adult neurogenesis in the hippocampal dentate gyrus,leading to long-term cognitive impairment.However,the mechanism underlying this neurogenesis impairment remains unknown.In this study,we established a male mouse model of repetitive traumatic brain injury and performed long-term evaluation of neurogenesis of the hippocampal dentate gyrus after repetitive traumatic brain injury.Our results showed that repetitive traumatic brain injury inhibited neural stem cell proliferation and development,delayed neuronal maturation,and reduced the complexity of neuronal dendrites and spines.Mice with repetitive traumatic brain injuryalso showed deficits in spatial memory retrieval.Moreover,following repetitive traumatic brain injury,neuroinflammation was enhanced in the neurogenesis microenvironment where C1q levels were increased,C1q binding protein levels were decreased,and canonical Wnt/β-catenin signaling was downregulated.An inhibitor of C1 reversed the long-term impairment of neurogenesis induced by repetitive traumatic brain injury and improved neurological function.These findings suggest that repetitive traumatic brain injury–induced C1-related inflammation impairs long-term neurogenesis in the dentate gyrus and contributes to spatial memory retrieval dysfunction.

High-dose dexamethasone regulates microglial polarization via the GR/JAK1/STAT3 signaling pathway after traumatic brain injury

Although microglial polarization and neuroinflammation are crucial cellular responses after traumatic brain injury,the fundamental regulatory and functional mechanisms remain insufficiently understood.As potent anti-inflammato ry agents,the use of glucoco rticoids in traumatic brain injury is still controversial,and their regulatory effects on microglial polarization are not yet known.In the present study,we sought to determine whether exacerbation of traumatic brain injury caused by high-dose dexamethasone is related to its regulatory effects on microglial polarization and its mechanisms of action.In vitro cultured BV2 cells and primary microglia and a controlled cortical impact mouse model were used to investigate the effects of dexamethasone on microglial polarization.Lipopolysaccharide,dexamethasone,RU486(a glucocorticoid receptor antagonist),and ruxolitinib(a Janus kinase 1 antagonist)were administered.RNA-sequencing data obtained from a C57BL/6 mouse model of traumatic brain injury were used to identify potential targets of dexamethasone.The Morris water maze,quantitative reverse transcription-polymerase chain reaction,western blotting,immunofluorescence and confocal microscopy analysis,and TUNEL,Nissl,and Golgi staining were performed to investigate our hypothesis.High-throughput sequencing results showed that arginase 1,a marker of M2 microglia,was significantly downregulated in the dexamethasone group compared with the traumatic brain injury group at3 days post-traumatic brain injury.Thus dexamethasone inhibited M1 and M2 microglia,with a more pronounced inhibitory effect on M2microglia in vitro and in vivo.Glucocorticoid receptor plays an indispensable role in microglial polarization after dexamethasone treatment following traumatic brain injury.Additionally,glucocorticoid receptor activation increased the number of apoptotic cells and neuronal death,and also decreased the density of dendritic spines.A possible downstream receptor signaling mechanism is the GR/JAK1/STAT3 pathway.Overactivation of glucocorticoid receptor by high-dose dexamethasone reduced the expression of M2 microglia,which plays an antiinflammatory role.In contrast,inhibiting the activation of glucocorticoid receptor reduced the number of apoptotic glia and neurons and decreased the loss of dendritic spines after traumatic brain injury.Dexamethasone may exe rt its neurotoxic effects by inhibiting M2 microglia through the GR/JAK1/STAT3 signaling pathway.

Inflammasome links traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease

Traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease are three distinct neurological disorders that share common pathophysiological mechanisms involving neuroinflammation. One sequela of neuroinflammation includes the pathologic hyperphosphorylation of tau protein, an endogenous microtubule-associated protein that protects the integrity of neuronal cytoskeletons. Tau hyperphosphorylation results in protein misfolding and subsequent accumulation of tau tangles forming neurotoxic aggregates. These misfolded proteins are characteristic of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease and can lead to downstream neuroinflammatory processes, including assembly and activation of the inflammasome complex. Inflammasomes refer to a family of multimeric protein units that, upon activation, release a cascade of signaling molecules resulting in caspase-induced cell death and inflammation mediated by the release of interleukin-1β cytokine. One specific inflammasome, the NOD-like receptor protein 3, has been proposed to be a key regulator of tau phosphorylation where it has been shown that prolonged NOD-like receptor protein 3 activation acts as a causal factor in pathological tau accumulation and spreading. This review begins by describing the epidemiology and pathophysiology of traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease. Next, we highlight neuroinflammation as an overriding theme and discuss the role of the NOD-like receptor protein 3 inflammasome in the formation of tau deposits and how such tauopathic entities spread throughout the brain. We then propose a novel framework linking traumatic brain injury, chronic traumatic encephalopathy, and Alzheimer's disease as inflammasomedependent pathologies that exist along a temporal continuum. Finally, we discuss potential therapeutic targets that may intercept this pathway and ultimately minimize long-term neurological decline.

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.

Bidirectional regulation of the brain-gut-microbiota axis following traumatic brain injury

Traumatic brain injury is a prevalent disorder of the central nervous system.In addition to primary brain parenchymal damage,the enduring biological consequences of traumatic brain injury pose long-term risks for patients with traumatic brain injury;however,the underlying pathogenesis remains unclear,and effective intervention methods are lacking.Intestinal dysfunction is a significant consequence of traumatic brain injury.Being the most densely innervated peripheral tissue in the body,the gut possesses multiple pathways for the establishment of a bidirectional“brain-gut axis”with the central nervous system.The gut harbors a vast microbial community,and alterations of the gut niche contribute to the progression of traumatic brain injury and its unfavorable prognosis through neuronal,hormonal,and immune pathways.A comprehensive understanding of microbiota-mediated peripheral neuroimmunomodulation mechanisms is needed to enhance treatment strategies for traumatic brain injury and its associated complications.We comprehensively reviewed alterations in the gut microecological environment following traumatic brain injury,with a specific focus on the complex biological processes of peripheral nerves,immunity,and microbes triggered by traumatic brain injury,encompassing autonomic dysfunction,neuroendocrine disturbances,peripheral immunosuppression,increased intestinal barrier permeability,compromised responses of sensory nerves to microorganisms,and potential effector nuclei in the central nervous system influenced by gut microbiota.Additionally,we reviewed the mechanisms underlying secondary biological injury and the dynamic pathological responses that occur following injury to enhance our current understanding of how peripheral pathways impact the outcome of patients with traumatic brain injury.This review aimed to propose a conceptual model for future risk assessment of central nervous system-related diseases while elucidating novel insights into the bidirectional effects of the“brain-gut-microbiota axis.”

Understanding the link between type 2 diabetes mellitus and Parkinson's disease:role of brain insulin resistance

Type 2 diabetes mellitus and Parkinson's disease are chronic diseases linked to a growing pandemic that affects older adults and causes significant socio-economic burden.Epidemiological data supporting a close relationship between these two aging-related diseases have resulted in the investigation of shared pathophysiological molecular mechanisms.Impaired insulin signaling in the brain has gained increasing attention during the last decade and has been suggested to contribute to the development of Parkinson's disease through the dysregulation of several pathological processes.The contribution of type 2 diabetes mellitus and insulin resistance in neurodegeneration in Parkinson's disease,with emphasis on brain insulin resistance,is extensively discussed in this article and new therapeutic strategies targeting this pathological link are presented and reviewed.

A new horizon for neuroscience:terahertz biotechnology in brain research

Terahertz biotechnology has been increasingly applied in various biomedical fields and has especially shown great potential for application in brain sciences.In this article,we review the development of terahertz biotechnology and its applications in the field of neuropsychiatry.Available evidence indicates promising prospects for the use of terahertz spectroscopy and terahertz imaging techniques in the diagnosis of amyloid disease,cerebrovascular disease,glioma,psychiatric disease,traumatic brain injury,and myelin deficit.In vitro and animal experiments have also demonstrated the potential therapeutic value of terahertz technology in some neuropsychiatric diseases.Although the precise underlying mechanism of the interactions between terahertz electromagnetic waves and the biosystem is not yet fully understood,the research progress in this field shows great potential for biomedical noninvasive diagnostic and therapeutic applications.However,the biosafety of terahertz radiation requires further exploration regarding its two-sided efficacy in practical applications.This review demonstrates that terahertz biotechnology has the potential to be a promising method in the field of neuropsychiatry based on its unique advantages.

Reperfusion after hypoxia-ischemia exacerbates brain injury with compensatory activation of the antiferroptosis system:based on a novel rat model

Hypoxic-ischemic encephalopathy,which predisposes to neonatal death and neurological sequelae,has a high morbidity,but there is still a lack of effective prevention and treatment in clinical practice.To better understand the pathophysiological mechanism underlying hypoxic-ischemic encephalopathy,in this study we compared hypoxic-ischemic reperfusion brain injury and simple hypoxic-ischemic brain injury in neonatal rats.First,based on the conventional RiceVannucci model of hypoxic-ischemic encephalopathy,we established a rat model of hypoxic-ischemic reperfusion brain injury by creating a common carotid artery muscle bridge.Then we performed tandem mass tag-based proteomic analysis to identify differentially expressed proteins between the hypoxic-ischemic reperfusion brain injury model and the conventional Rice-Vannucci model and found that the majority were mitochondrial proteins.We also performed transmission electron microscopy and found typical characteristics of ferroptosis,including mitochondrial shrinkage,ruptured mitochondrial membranes,and reduced or absent mitochondrial cristae.Further,both rat models showed high levels of glial fibrillary acidic protein and low levels of myelin basic protein,which are biological indicators of hypoxic-ischemic brain injury and indicate similar degrees of damage.Finally,we found that ferroptosis-related Ferritin(Fth1)and glutathione peroxidase 4 were expressed at higher levels in the brain tissue of rats with hypoxic-ischemic reperfusion brain injury than in rats with simple hypoxic-ischemic brain injury.Based on these results,it appears that the rat model of hypoxic-ischemic reperfusion brain injury is more closely related to the pathophysiology of clinical reperfusion.Reperfusion not only aggravates hypoxic-ischemic brain injury but also activates the anti-ferroptosis system.

Unraveling brain aging through the lens of oral microbiota

The oral cavity is a complex physiological community encompassing a wide range of microorganisms.Dysbiosis of oral microbiota can lead to various oral infectious diseases,such as periodontitis and tooth decay,and even affect systemic health,including brain aging and neurodegenerative diseases.Recent studies have highlighted how oral microbes might be involved in brain aging and neurodegeneration,indicating potential avenues for intervention strategies.In this review,we summarize clinical evidence demonstrating a link between oral microbes/oral infectious diseases and brain aging/neurodegenerative diseases,and dissect potential mechanisms by which oral microbes contribute to brain aging and neurodegeneration.We also highlight advances in therapeutic development grounded in the realm of oral microbes,with the goal of advancing brain health and promoting healthy aging.

Resting-state brain network remodeling after different nerve reconstruction surgeries:a functional magnetic resonance imaging study in brachial plexus injury rats

Distinct brain remodeling has been found after different nerve reconstruction strategies,including motor representation of the affected limb.However,differences among reconstruction strategies at the brain network level have not been elucidated.This study aimed to explore intranetwork changes related to altered peripheral neural pathways after different nerve reconstruction surgeries,including nerve repair,endto-end nerve transfer,and end-to-side nerve transfer.Sprague–Dawley rats underwent complete left brachial plexus transection and were divided into four equal groups of eight:no nerve repair,grafted nerve repair,phrenic nerve end-to-end transfer,and end-to-side transfer with a graft sutured to the anterior upper trunk.Resting-state brain functional magnetic resonance imaging was obtained 7 months after surgery.The independent component analysis algorithm was utilized to identify group-level network components of interest and extract resting-state functional connectivity values of each voxel within the component.Alterations in intra-network resting-state functional connectivity were compared among the groups.Target muscle reinnervation was assessed by behavioral observation(elbow flexion)and electromyography.The results showed that alterations in the sensorimotor and interoception networks were mostly related to changes in the peripheral neural pathway.Nerve repair was related to enhanced connectivity within the sensorimotor network,while end-to-side nerve transfer might be more beneficial for restoring control over the affected limb by the original motor representation.The thalamic-cortical pathway was enhanced within the interoception network after nerve repair and end-to-end nerve transfer.Brain areas related to cognition and emotion were enhanced after end-to-side nerve transfer.Our study revealed important brain networks related to different nerve reconstructions.These networks may be potential targets for enhancing motor recovery.

Non-coding RNAs in acute ischemic stroke:from brain to periphery

Acute ischemic stroke is a clinical emergency and a condition with high morbidity,mortality,and disability.Accurate predictive,diagnostic,and prognostic biomarkers and effective therapeutic targets for acute ischemic stroke remain undetermined.With innovations in high-throughput gene sequencing analysis,many aberrantly expressed non-coding RNAs(ncRNAs)in the brain and peripheral blood after acute ischemic stroke have been found in clinical samples and experimental models.Differentially expressed ncRNAs in the post-stroke brain were demonstrated to play vital roles in pathological processes,leading to neuroprotection or deterioration,thus ncRNAs can serve as therapeutic targets in acute ischemic stroke.Moreover,distinctly expressed ncRNAs in the peripheral blood can be used as biomarkers for acute ischemic stroke prediction,diagnosis,and prognosis.In particular,ncRNAs in peripheral immune cells were recently shown to be involved in the peripheral and brain immune response after acute ischemic stroke.In this review,we consolidate the latest progress of research into the roles of ncRNAs(microRNAs,long ncRNAs,and circular RNAs)in the pathological processes of acute ischemic stroke–induced brain damage,as well as the potential of these ncRNAs to act as biomarkers for acute ischemic stroke prediction,diagnosis,and prognosis.Findings from this review will provide novel ideas for the clinical application of ncRNAs in acute ischemic stroke.

Treadmill exercise in combination with acousto-optic and olfactory stimulation improves cognitive function in APP/PS1 mice through the brain-derived neurotrophic factor-and Cygb-associated signaling pathways

A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer's disease.Consequently,enhancing adult neurogenesis represents a promising therapeutic approach for mitigating disease symptoms and progression.Nonetheless,nonpharmacological interventions aimed at inducing adult neurogenesis are currently limited.Although individual non-pharmacological interventions,such as aerobic exercise,acousto-optic stimulation,and olfactory stimulation,have shown limited capacity to improve neurogenesis and cognitive function in patients with Alzheimer's disease,the therapeutic effect of a strategy that combines these interventions has not been fully explored.In this study,we observed an age-dependent decrease in adult neurogenesis and a concurrent increase in amyloid-beta accumulation in the hippocampus of amyloid precursor protein/presenilin 1 mice aged 2-8 months.Amyloid deposition became evident at 4 months,while neurogenesis declined by 6 months,further deteriorating as the disease progressed.However,following a 4-week multifactor stimulation protocol,which encompassed treadmill running(46 min/d,10 m/min,6 days per week),40 Hz acousto-optic stimulation(1 hour/day,6 days/week),and olfactory stimulation(1 hour/day,6 days/week),we found a significant increase in the number of newborn cells(5'-bromo-2'-deoxyuridine-positive cells),immature neurons(doublecortin-positive cells),newborn immature neurons(5'-bromo-2'-deoxyuridine-positive/doublecortin-positive cells),and newborn astrocytes(5'-bromo-2'-deoxyuridine-positive/glial fibrillary acidic protein-positive cells).Additionally,the amyloid-beta load in the hippocampus decreased.These findings suggest that multifactor stimulation can enhance adult hippocampal neurogenesis and mitigate amyloid-beta neuropathology in amyloid precursor protein/presenilin 1 mice.Furthermore,cognitive abilities were improved,and depressive symptoms were alleviated in amyloid precursor protein/presenilin 1 mice following multifactor stimulation,as evidenced by Morris water maze,novel object recognition,forced swimming test,and tail suspension test results.Notably,the efficacy of multifactor stimulation in consolidating immature neurons persisted for at least 2weeks after treatment cessation.At the molecular level,multifactor stimulation upregulated the expression of neuron-related proteins(NeuN,doublecortin,postsynaptic density protein-95,and synaptophysin),anti-apoptosis-related proteins(Bcl-2 and PARP),and an autophagyassociated protein(LC3B),while decreasing the expression of apoptosis-related proteins(BAX and caspase-9),in the hippocampus of amyloid precursor protein/presenilin 1 mice.These observations might be attributable to both the brain-derived neurotrophic factor-mediated signaling pathway and antioxidant pathways.Furthermore,serum metabolomics analysis indicated that multifactor stimulation regulated differentially expressed metabolites associated with cell apoptosis,oxidative damage,and cognition.Collectively,these findings suggest that multifactor stimulation is a novel non-invasive approach for the prevention and treatment of Alzheimer's disease.

Structural and functional connectivity of the whole brain and subnetworks in individuals with mild traumatic brain injury:predictors of patient prognosis

Patients with mild traumatic brain injury have a diverse clinical presentation,and the underlying pathophysiology remains poorly understood.Magnetic resonance imaging is a non-invasive technique that has been widely utilized to investigate neuro biological markers after mild traumatic brain injury.This approach has emerged as a promising tool for investigating the pathogenesis of mild traumatic brain injury.G raph theory is a quantitative method of analyzing complex networks that has been widely used to study changes in brain structure and function.However,most previous mild traumatic brain injury studies using graph theory have focused on specific populations,with limited exploration of simultaneous abnormalities in structural and functional connectivity.Given that mild traumatic brain injury is the most common type of traumatic brain injury encounte red in clinical practice,further investigation of the patient characteristics and evolution of structural and functional connectivity is critical.In the present study,we explored whether abnormal structural and functional connectivity in the acute phase could serve as indicators of longitudinal changes in imaging data and cognitive function in patients with mild traumatic brain injury.In this longitudinal study,we enrolled 46 patients with mild traumatic brain injury who were assessed within 2 wee ks of injury,as well as 36 healthy controls.Resting-state functional magnetic resonance imaging and diffusion-weighted imaging data were acquired for graph theoretical network analysis.In the acute phase,patients with mild traumatic brain injury demonstrated reduced structural connectivity in the dorsal attention network.More than 3 months of followup data revealed signs of recovery in structural and functional connectivity,as well as cognitive function,in 22 out of the 46 patients.Furthermore,better cognitive function was associated with more efficient networks.Finally,our data indicated that small-worldness in the acute stage could serve as a predictor of longitudinal changes in connectivity in patients with mild traumatic brain injury.These findings highlight the importance of integrating structural and functional connectivity in unde rstanding the occurrence and evolution of mild traumatic brain injury.Additionally,exploratory analysis based on subnetworks could serve a predictive function in the prognosis of patients with mild traumatic brain injury.

Epileptic brain network mechanisms and neuroimaging techniques for the brain network

Epilepsy can be defined as a dysfunction of the brain network,and each type of epilepsy involves different brain-network changes that are implicated diffe rently in the control and propagation of interictal or ictal discharges.Gaining more detailed information on brain network alterations can help us to further understand the mechanisms of epilepsy and pave the way for brain network-based precise therapeutic approaches in clinical practice.An increasing number of advanced neuroimaging techniques and electrophysiological techniques such as diffusion tensor imaging-based fiber tra ctography,diffusion kurtosis imaging-based fiber tractography,fiber ball imagingbased tra ctography,electroencephalography,functional magnetic resonance imaging,magnetoencephalography,positron emission tomography,molecular imaging,and functional ultrasound imaging have been extensively used to delineate epileptic networks.In this review,we summarize the relevant neuroimaging and neuroelectrophysiological techniques for assessing structural and functional brain networks in patients with epilepsy,and extensively analyze the imaging mechanisms,advantages,limitations,and clinical application ranges of each technique.A greater focus on emerging advanced technologies,new data analysis software,a combination of multiple techniques,and the construction of personalized virtual epilepsy models can provide a theoretical basis to better understand the brain network mechanisms of epilepsy and make surgical decisions.

Neuroprotective effects of autophagy inhibition on hippocampal glutamate receptor subunits after hypoxia-ischemia-induced brain damage in newborn rats

Autophagy has been suggested to participate in the pathology of hypoxic-ischemic brain damage（HIBD）.However,its regulatory role in HIBD remains unclear and was thus examined here using a rat model.To induce HIBD,the left common carotid artery was ligated in neonatal rats,and the rats were subjected to hypoxia for 2 hours.Some of these rats were intraperitoneally pretreated with the autophagy inhibitor 3-methyladenine（10 m M in 10 μL） or the autophagy stimulator rapamycin（1 g/kg） 1 hour before artery ligation.Our findings demonstrated that hypoxia-ischemia-induced hippocampal injury in neonatal rats was accompanied by increased expression levels of the autophagy-related proteins light chain 3 and Beclin-1 as well as of the AMPA receptor subunit GluR 1,but by reduced expression of GluR 2.Pretreatment with the autophagy inhibitor 3-methyladenine blocked hypoxia-ischemia-induced hippocampal injury,whereas pretreatment with the autophagy stimulator rapamycin significantly augmented hippocampal injury.Additionally,3-methyladenine pretreatment blocked the hypoxia-ischemia-induced upregulation of Glu R1 and downregulation of GluR2 in the hippocampus.By contrast,rapamycin further elevated hippocampal Glu R1 levels and exacerbated decreased GluR2 expression levels in neonates with HIBD.Our results indicate that autophagy inhibition favors the prevention of HIBD in neonatal rats,at least in part,through normalizing Glu R1 and GluR2 expression.

Advantages of nanocarriers for basic research in the field of traumatic brain injury

A major challenge for the efficient treatment of traumatic brain injury is the need for therapeutic molecules to cross the blood-brain barrier to enter and accumulate in brain tissue.To overcome this problem,researchers have begun to focus on nanocarriers and other brain-targeting drug delivery systems.In this review,we summarize the epidemiology,basic pathophysiology,current clinical treatment,the establishment of models,and the evaluation indicators that are commonly used for traumatic brain injury.We also report the current status of traumatic brain injury when treated with nanocarriers such as liposomes and vesicles.Nanocarriers can overcome a variety of key biological barriers,improve drug bioavailability,increase intracellular penetration and retention time,achieve drug enrichment,control drug release,and achieve brain-targeting drug delivery.However,the application of nanocarriers remains in the basic research stage and has yet to be fully translated to the clinic.

Effects of exogenous ganglioside-1 on learning and memory in a neonatal rat model of hypoxia-ischemia brain injury

BACKGROUND： Exogenous ganglioside-1 （GM1） can cross the blood-brain barrier and play a protective role against hypoxia-ischemia-induced brain damage. OBJECTIVE： To examine the possible mechanisms of exogenous GM1 protection in hypoxia-ischemia-induced brain damage in a neonatal rat model by measuring changes in brain mass, pathological morphology, growth-associated protein-43 expression, and neurobehavioral manifestations. DESIGN, TIME AND SETTING： A randomized block-design study was performed at the Immunohistochemistry Laboratory of the Pediatric Research Institute, Children＇s Hospital of Chongqing Medical University from August 2005 to August 2006. MATERIALS： A total of 36 neonatal, 7-day-old, Sprague Dawley rats were used in this experiment. The hypoxia-ischemia-induced brain damage model was established by permanently occluding the right carotid artery, followed by oxygen inhalation at a low concentration （8% O2, 92% N2） for 2 hours, METHODS： All rats were randomly divided into the following groups： GMI, model, and sham operation, with 12 rats each group. Rats in the GM 1 and model groups received hypoxic/ischemic-induced brain damage. Rats in the GM1 group received injections of GM1 （i.p., 20 mg/kg） at 0, 24, 48, 72, 96, 120, and 144 hours following models established, and rats in the model group were administered （i.p.） the same amount of saline. The right carotid artery was separated, but not ligated, in the sham operation group rats. MAIN OUTCOME MEASURES： At 1 week after surgery, expression of growth-associated protein-43, a marker of neural development and plasticity, was detected in the hippocampal CA3 region by immunohistochemistry. Brain mass was measured, and the pathological morphology was observed. At 4 weeks after surgery, behavioral changes in the remaining rats were tested by Morris water maze, and growth-associated protein-43 expression was measured. RESULTS： （1） In the GMI and sham operation groups, growth-associated protein-43 expression was greater in the hippocampal CA3 region compared to the model group 1 week after surgery （P 〈 0.05）. In all three groups, brain weight of the right hemisphere was significantly less than the left hemisphere, in particular in the model group （P 〈 0.05）. In the GMI group, the weight difference between two hemispheres, as well as the extent of damage in the right hemisphere, was less than the model group （P 〈 0.01 ）. In the sham operation Uoup, brain tissue consisted of integrated structures and ordered cells. In the model group, the cerebral cortex layers of the right hemisphere were not defined, neurons were damaged, and neurons were disarranged in the hippocampal area. In the GM1 group, neurons were dense in the right cerebral cortex and hippocampal area, with no significant change in glial proliferation. （2） The average time of escape latency in the GM1 group was shortened 4 weeks alter surgery, and significantly less than the model group （P 〈 0.05）. In addition, the frequency platform passing in the GMI group was significantly greater than the model group （P 〈 0.01）. CONCLUSION： Exogenous GM1 may reduce brain injury and improve learning and memory in hypoxia-ischemia-induced brain damage rats. This protection may be associated with increased growth-associated protein-43 expression, which is involved in neuronal remodeling processes.

Hypoxia-ischemia in the immature rodent brain impairs serotonergic neuronal function in certain dorsal raphé nuclei

Neonatal hypoxia-ischemia(HI) results in losses of serotonergic neurons in specific dorsal raphé nuclei. However, not all serotonergic raphé neurons are lost and it is therefore important to assess the function of remaining neurons in order to understand their potential to contribute to neurological disorders in the HI-affected neonate. The main objective of this study was to determine how serotonergic neurons, remaining in the dorsal raphé nuclei after neonatal HI, respond to an external stimulus(restraint stress). On postnatal day 3(P3), male rat pups were randomly allocated to one of the following groups:(i) control + no restraint(n = 5),(ii) control + restraint(n = 6),(iii) P3 HI + no restraint(n = 5) or(iv) P3 HI + restraint(n = 7). In the two HI groups, rat pups underwent surgery to ligate the common carotid artery and were then exposed to 6% O2 for 30 minutes. Six weeks after P3 HI, on P45, rats were subjected to restraint stress for 30 minutes. Using dual immunolabeling for Fos protein, a marker for neuronal activity, and serotonin(5-hydroxytrypamine; 5-HT), numbers of Fos-positive 5-HT neurons were determined in five dorsal raphé nuclei. We found that restraint stress alone increased numbers of Fos-positive 5-HT neurons in all five dorsal raphé nuclei compared to control animals. However, following P3 HI, the number of stress-induced Fos-positive 5-HT neurons was decreased significantly in the dorsal raphé ventrolateral, interfascicular and ventral nuclei compared with control animals exposed to restraint stress. In contrast, numbers of stress-induced Fos-positive 5-HT neurons in the dorsal raphé dorsal and caudal nuclei were not affected by P3 HI. These data indicate that not only are dorsal raphé serotonergic neurons lost after neonatal HI, but also remaining dorsal raphé serotonergic neurons have reduced differential functional viability in response to an external stimulus. Procedures were approved by the University of Queensland Animal Ethics Committee(UQCCR958/08/NHMRC) on February 27, 2009.

Gut microbial regulation of innate and adaptive immunity after traumatic brain injury

Acute care management of traumatic brain injury is focused on the prevention and reduction of secondary insults such as hypotension,hypoxia,intracranial hypertension,and detrimental inflammation.However,the imperative to balance multiple clinical concerns simultaneously often results in therapeutic strategies targeted to address one clinical concern causing unintended effects in other remote organ systems.Recently the bidirectional communication between the gastrointestinal tract and the brain has been shown to influence both the central nervous system and gastrointestinal tract homeostasis in health and disease.A critical component of this axis is the microorganisms of the gut known as the gut microbiome.Changes in gut microbial populations in the setting of central nervous system disease,including traumatic brain injury,have been reported in both humans and experimental animal models and can be further disrupted by off-target effects of patient care.In this review article,we will explore the important role gut microbial populations play in regulating brain-resident and peripheral immune cell responses after traumatic brain injury.We will discuss the role of bacterial metabolites in gut microbial regulation of neuroinflammation and their potential as an avenue for therapeutic intervention in the setting of traumatic brain injury.