Exosomes,lipid bilayer-enclosed small cellular vesicles,are actively secreted by various cells and play crucial roles in intercellular communication.These nanosized vesicles transport internalized proteins,mRNA,miRNA,...Exosomes,lipid bilayer-enclosed small cellular vesicles,are actively secreted by various cells and play crucial roles in intercellular communication.These nanosized vesicles transport internalized proteins,mRNA,miRNA,and other bioactive molecules.Recent findings have provided compelling evidence that exosomes derived from stem cells hold great promise as a therapeutic modality for central nervous system disorders.These exosomes exhibit multifaceted properties including antiapoptotic,anti-inflammatory,neurogenic,and vasculogenic effects.Furthermore,exosomes offer several advantages over stem cell therapy,such as high preservation capacity,low immunogenicity,the ability to traverse the blood-brain barrier,and the potential for drug encapsulation.Consequently,researchers have turned their attention to exosomes as a novel therapeutic avenue.Nonetheless,akin to the limitations of stem cell treatment,the limited accumulation of exosomes in the injured brain poses a challenge to their clinical application.To overcome this hurdle,intranasal administration has emerged as a non-invasive and efficacious route for delivering drugs to the central nervous system.By exploiting the olfactory and trigeminal nerve axons,this approach enables the direct transport of therapeutics to the brain while bypassing the blood-brain barrier.Notably,exosomes,owing to their small size,can readily access the nerve pathways using this method.As a result,intranasal administration has gained increasing recognition as an optimal therapeutic strategy for exosomebased treatments.In this comprehensive review,we aim to provide an overview of both basic and clinical research studies investigating the intranasal administration of exosomes for the treatment of central nervous system diseases.Furthermore,we elucidate the underlying therapeutic mechanisms and offer insights into the prospect of this approach.展开更多
OBJECTIVE To evaluate the protective effects of resveratrol nanosuspensions loaded in situ hydrogel on Alzheimer disease model mice after intranasal administration. METHODS Resveratrol nanosuspensions were fabricated ...OBJECTIVE To evaluate the protective effects of resveratrol nanosuspensions loaded in situ hydrogel on Alzheimer disease model mice after intranasal administration. METHODS Resveratrol nanosuspensions were fabricated by antisolvent nano-precipitation method,and then dispersed into0.5% gellan gum to form resveratrol nanosuspenisons loaded ionic sensitive in situ hydrogel. The Alzheimer′s disease models were induced by lateral ventricle injection of Aβ_(25~35)and the protection and treatment effects of resveratrol nanosuspensions loaded in situ hydrogel on study and memory capability were performed after intranasal administration in water maze experiments. The analyses of the changes of cholinergic neurotransmitters in the brain were also determined according to the contents of acetylcholine(ACh),choline acetyltransferase(ChAT) and acetylcholinesterase(AChE). RESULTS Behavior assessment disclosed that in position navigation,escape latency test,each of experimental animals showed a decreased trend with swim training days increase,indicating that in the training process they had the ability of learning and memory in looking for the platform. Compared with the control group,average latency of model group significantly increased. While compared with the model group,treatment group′s average latency was significantly shorter. Space exploration experiment results showed that the times of model group across target quadrant of the platform is less than that of control group. But the crossing times of treatment group with resveratrol increased compared with the model group. As for the changes of cholinergic neurotransmitters,in AD mice brain ACh content decreased; the Ch AT activity decreased,while the activity of ACh E with the ability to hydrolysis acetylcholine increased. The administration of resveratrol can decrease the activity of ACh enzymes but increase Ch AT activity and the levels of acetylcholine. CONCLUSION Resveratrol nanosuspension loaded in situ gel can ameliorate the declining ability of learning and memory of AD model mice after intranasal administration. As a promising approach for the treatment of central nervous system(CNS) disease,intranasal administration route can effectively deliver to the brain and thus enhance the therapeutic effect.展开更多
Iron is the most abundant transition metal in the brain and is essential for brain development and neuronal function;however,its abnormal accumulation is also implicated in various neurological disorders.The olfactory...Iron is the most abundant transition metal in the brain and is essential for brain development and neuronal function;however,its abnormal accumulation is also implicated in various neurological disorders.The olfactory bulb(OB),an early target in neurodegenerative diseases,acts as a gateway for environmental toxins and contains diverse neuronal populations with distinct roles.This study explored the cell-specific vulnerability to iron in the OB using a mouse model of intranasal administration of ferric ammonium citrate(FAC).Olfactory function was assessed through olfactory discrimination tests,while iron levels in OB tissues,cerebrospinal fluid(CSF),and serum were quantified using inductively coupled plasma mass spectrometry(ICP-MS),immunohistochemical staining,and iron assays.Transcriptomic changes and immune responses were assessed using RNA sequencing and immune cell infiltration analysis.Results showed that intranasal FAC administration impaired olfactory function,accompanied by iron deposition in the olfactory mucosa and OB,as well as damage to olfactory sensory neurons.Notably,these effects occurred without elevations in CSF or serum iron levels.OB iron accumulation activated multiple immune cells,including microglia and astrocytes,but did not trigger ferroptosis.Spatial transcriptomic sequencing of healthy adult mouse OBs revealed significant cellular heterogeneity,with an abundance of neuroglia and neurons.Among neurons,GABAergic neurons were the most prevalent,followed by glutamatergic and dopaminergic neurons,while cholinergic and serotonergic neurons were sparsely distributed.Under iron-stressed conditions,oligodendrocytes,dopaminergic neurons,and glutamatergic neurons exhibited significant damage,while GABAergic neurons remained unaffected.These findings highlight the selective vulnerability of neuronal and glial populations to iron-induced stress,offering novel insights into the loss of specific cell types in the OB during iron dysregulation.展开更多
Both geniposide （Ge） and natural borneol （NB） are bioactive substances derived from traditional Chinese herbs. The effect of NB on the pharmacokinetics of Ge in rat via intranasal administration was investigated. ...Both geniposide （Ge） and natural borneol （NB） are bioactive substances derived from traditional Chinese herbs. The effect of NB on the pharmacokinetics of Ge in rat via intranasal administration was investigated. The concentrations of Ge in plasma were determined by reversed-phase high-performance liquid chromatography （HPLC） after intranasal administration of Ge （4 mg/kg） alone and combined with different doses （0.08, 0.8, and 8 mg/kg） of NB. The intravenous administration was given as a reference （4 mg/kg of Ge and 8 mg/kg of NB）. Compared with the intravenous administration, the absolute bioavailability of Ge was 76.14% through intranasal administration combined with NB. Compared with the intranasal administration of Ge alone, Ge could be absorbed rapidly in the nasal cavity combined with NB; the peak time of Ge in the plasma became shorter （3-5 min vs. 40 min）; the peak concentration became higher （1.32-4.25 IJg/ml vs. 0.67 ug/ml）; and, the relative bioavailability of Ge combined with NB was 90.3%-237.8%. The enhancing effect was attenuated as the dose of NB decreased. The results indicated that NB can accelerate the absorption of Ge dose-dependently in the nasal cavity.展开更多
The continuously emerging SARS-CoV-2 variants pose a great challenge to the efficacy of current drugs,this necessitates the development of broad-spectrum antiviral drugs.In the previous study,we designed a recombinant...The continuously emerging SARS-CoV-2 variants pose a great challenge to the efficacy of current drugs,this necessitates the development of broad-spectrum antiviral drugs.In the previous study,we designed a recombinant protein,heptad repeat(HR)121,as a variant-proof vaccine.Here,we found it can act as a fusion inhibitor and demonstrated broadly neutralizing activities against SARS-CoV-2 and its main variants.Structure analysis suggested that HR121 targets the HR2 domain in SARS-CoV-2 spike(S)2 subunit to block virus-cell fusion.Functional experiments demonstrated that HR121 can bind HR2 at serological-pH and endosomal-pH,highlighting its inhibition capacity when SARS-CoV-2 enters via either cellular membrane fusion or endosomal route.Importantly,HR121 can effectively inhibit SARS-CoV-2 and Omicron variant pseudoviruses entering the cells,as well as block authentic SARSCoV-2 and Omicron BA.2 replications in human pulmonary alveolar epithelial cells.After intranasal administration to Syrian golden hamsters,it can protect hamsters from SARS-CoV-2 and Omicron BA.2 infection.Together,our results suggest that HR121 is a potent drug candidate with broadly neutralizing activities against SARS-CoV-2 and its variants.展开更多
Tetrabromobisphenol A（TBBPA） and its derivatives are now being highly concerned due to their emerging environmental occurrence and deleterious effects on non-target organisms.Considering the potential neurotoxicity ...Tetrabromobisphenol A（TBBPA） and its derivatives are now being highly concerned due to their emerging environmental occurrence and deleterious effects on non-target organisms.Considering the potential neurotoxicity of TBBPA derivatives which has been demonstrated in vitro, what could happen in vivo is worthy of being studied. Tetrabromobisphenol A bis（2-hydroxyethyl ether）（TBBPA-BHEE）, a representative TBBPA derivative, was selected for a21-day exposure experiment on neonatal Sprague Dawley（SD） rats through intranasal administration. The neurobehavioral, histopathological changes, and differentially expressed genes based on RNA microarray were investigated to evaluate the neurological effects of this chemical. The results indicated that TBBPA-BHEE exposure significantly compromised the motor co-ordination performance and the locomotor activities（p 〈 0.05）. The neurobehavioral phenotype could be attributed to the obvious histopathological changes in both cerebrum and cerebellum, such as neural cell swelling, microglial activation and proliferation. A total of 911 genes were up-regulated, whereas 433 genes were down-regulated. Gene set enrichment analysis showed multiple signaling pathways, including ubiquitin-mediated proteolysis and wingless-int（Wnt） signaling pathway etc. were involved due to TBBPA-BHEE exposure. The gene ontology enrichment analysis showed the basic cellular function and the neurological processes like synaptic transmission were influenced. The toxicological effects of TBBPA-BHEE observed in this study suggested the potential neuronal threaten from unintended exposure,which would be of great value in the biosafety evaluation of TBBPA derivatives.展开更多
Objective To study the pharmacokinetic behavior of tetramethylpyrazine hydrochloride（TMPH） in plasma of rabbits after intranasal administration and the relationship between absorption and dosage, furthermore, to ill...Objective To study the pharmacokinetic behavior of tetramethylpyrazine hydrochloride（TMPH） in plasma of rabbits after intranasal administration and the relationship between absorption and dosage, furthermore, to illustrate the effects of borneol and musk used in combination with TMPH on the plasma concentration profile of TMPH in rabbits. Methods The concentration of TMPH was determined by RP-HPLC method. Coumarin was used as an internal standard. Sample preparation was carried out by extraction and precipitation with methanol. The pharmacokinetic parameters were computed by software program DAS.3.1.4. Results Blood pharmacokinetics of TMPH fitted best to a non-compartment model. After intranasal administration with single dose at 10, 20, and 40 mg/kg of TMPH, the average values of Cmax were 8.075, 16.537, and 33.115 μg/mL, and the average values of AUC0-t were 228.93, 399.273,and 728.917 mg/（L·min）, respectively. Cmax of TMPH in plasma was increased by 31.136% and 38.786% compared with those without borneol and musk, and intranasal bioavailability were increased by 21.587% and 40.633% after intranasal administration of TMPH in combination with borneol, or with borneol and musk. Conclusion Borneol and musk could enhance the intranasal absorption of TMPH and increase the concentration of TMPH in blood of rabbits, especially in the early period. This work also shows the rational compatibility between borneol and musk.展开更多
The existence of the blood-brain barrier(BBB)restricts the entry of drugs from the circulation into the central nervous system(CNS),which severely affects the treatment of neurological diseases,including glioblastoma,...The existence of the blood-brain barrier(BBB)restricts the entry of drugs from the circulation into the central nervous system(CNS),which severely affects the treatment of neurological diseases,including glioblastoma,Parkinson’s disease(PD),and Alzheimer’s disease(AD).With the advantage of bypassing the BBB and avoiding systemic distribution,intranasal administration has emerged as an alternative method of delivering drugs to the brain.Drug delivery directly to the brain using intranasal nanosystems represents a new paradigm for neurological disease treatment because of its advantages in improving drug solubility and stability in vivo,enabling targeted drug delivery and controlled release,and reducing non-specific toxicity.And it has shown efficacy in animal models and clinical applications.Herein,this review describes the mechanisms of intranasal delivery of brain-targeted drugs,the properties of nanosystems for intranasal administration(e.g.,liposomes,nanoemulsions,and micelles),and strategies for intranasal drug delivery to enhance brain-targeted drug delivery.Recent applications of nanosystems in intranasal drug delivery and disease treatment have been comprehensively reviewed.Although encouraging results have been reported,significant challenges still need to be overcome to translate these nanosystems into clinics.Therefore,the future prospects of intranasal drug delivery nanosystems are discussed in depth,expecting to provide useful insights and guidance for effective neurological disease treatment.展开更多
Background Alzheimer’s disease(AD)is the most common neurodegenerative disorder in the elderly,resulting in gradual destruction of cognitive abilities.Research on the development of various AD treatments is underway;...Background Alzheimer’s disease(AD)is the most common neurodegenerative disorder in the elderly,resulting in gradual destruction of cognitive abilities.Research on the development of various AD treatments is underway;however,no definitive treatment has been developed yet.Herein,we present induced pluripotent stem cell(iPSC)-derived cortical neural stem cell secretome(CNSC-SE)as a new treatment candidate for AD and explore its efficacy.Methods We first assessed the effects of CNSC-SE treatment on neural maturation and electromagnetic signal during cortical nerve cell differentiation.Then to confirm the efficacy in vivo,CNSC-SE was administered to the 5×FAD mouse model through the nasal cavity(5μg/g,once a week,4 weeks).The cell-mediated effects on nerve recovery,amyloid beta(Aβ)plaque aggregation,microglial and astrocyte detection in the brain,and neuroinflammatory responses were investigated.Metabolomics analysis of iPSC-derived CNSC-SE revealed that it contained components that could exert neuro-protective effects or amplify cognitive restorative effects.Results Human iPSC-derived CNSC-SE increased neuronal proliferation and dendritic structure formation in vitro.Furthermore,CNSC-SE-treated iPSC-derived cortical neurons acquired electrical network activity and action potential bursts.The 5×FAD mice treated with CNSC-SE showed memory restoration and reduced Aβplaque accumulation.Conclusions Our findings suggest that the iPSC-derived CNSC-SE may serve as a potential,non-invasive therapeutic option for AD in reducing amyloid infiltration and restoring memory.展开更多
The number of people with Alzheimer’s disease(AD)is increasing annually,with the nidus mainly concentrated in the cortex and hippocampus.Despite of numerous efforts,effective treatment of AD is still facing great cha...The number of people with Alzheimer’s disease(AD)is increasing annually,with the nidus mainly concentrated in the cortex and hippocampus.Despite of numerous efforts,effective treatment of AD is still facing great challenges due to the blood brain barrier(BBB)and limited drug distribution in the AD nidus sites.Thus,in this study,using vinpocetine(VIN)as a model drug,the objective is to explore the feasibility of tackling the above bottleneck via intranasal drug delivery in combination with a brain guider,borneol(BOR),using nanoemulsion(NE)as the carrier.First of all,the NE were prepared and characterized.In vivo behavior of the NE after intranasal administration was investigated.Influence of BOR dose,BOR administration route on drug brain targeting behavior was evaluated,and the influence of BOR addition on drug brain subregion distribution was probed.It was demonstrated that all the NE had comparable size and similar retention behavior after intranasal delivery.Compared to intravenous injection,improved brain targeting effect was observed by intranasal route,and drug targeting index(DTI)of the VIN–NE group was 154.1%,with the nose-to-brain direct transport percentage(DTP)35.1%.Especially,remarkably enhanced brain distribution was achieved after BOR addition in the NE,with the extent depending on BOR dose.VIN brain concentration was the highest in the VIN-1-BOR-NE group at BOR dose of 1 mg/kg,with the DTI reaching 596.1%and the DTP increased to 83.1%.BOR could exert better nose to brain delivery when administrated together with the drug via intranasal route.Notably,BOR can remarkably enhance drug distribution in both hippocampus and cortex,the nidus areas of AD.In conclusion,in combination with intranasal delivery and the intrinsic brain guiding effect of BOR,drug distribution not only in the brain but also in the cortex and hippocampus can be enhanced significantly,providing the perquisite for improved therapeutic efficacy of AD.展开更多
BACKGROUND Sedation during endoscopic ultrasonography(EUS)poses many challenges and moderate-to-deep sedation are often required.The conventional method to preform moderate-to-deep sedation is generally intravenous be...BACKGROUND Sedation during endoscopic ultrasonography(EUS)poses many challenges and moderate-to-deep sedation are often required.The conventional method to preform moderate-to-deep sedation is generally intravenous benzodiazepine alone or in combination with opioids.However,this combination has some limitations.Intranasal medication delivery may be an alternative to this sedation regimen.AIM To determine,by continual reassessment method(CRM),the minimal effective dose of intranasal sufentanil(SUF)when combined with intranasal dexmedetomidine(DEX)for moderate sedation of EUS in at least 95%of patients(ED95).METHODS Thirty patients aged 18-65 and scheduled for EUS were recruited in this study.Subjects received intranasal DEX and SUF for sedation.The dose of DEX(1μg/kg)was fixed,while the dose of SUF was assigned sequentially to the subjects using CRM to determine ED95.The sedation status was assessed by modified observer’s assessment of alertness/sedation(MOAA/S)score.The adverse events and the satisfaction scores of patients and endoscopists were recorded.RESULTS The ED95 was intranasal 0.3μg/kg SUF when combined with intranasal 1μg/kg DEX,with an estimated probability of successful moderate sedation for EUS of 94.9%(95%confidence interval:88.1%-98.9%).When combined with intranasal 1μg/kg DEX,probabilities of successful moderate sedation at each dose level of intranasal SUF were as follows:0μg/kg SUF,52.8%;0.1μg/kg SUF,75.4%;0.2μg/kg SUF,89.9%;0.3μg/kg SUF,94.9%;0.4μg/kg SUF,98.0%;0.5μg/kg SUF,99.0%.CONCLUSION The ED95 needed for moderate sedation for EUS is intranasal 0.3μg/kg SUF when combined with intranasal 1μg/kg DEX,based on CRM.展开更多
Over the past century,age-related diseases,such as cancer,type-2 diabetes,obesity,and mental illness,have shown a significant increase,negatively impacting overall quality of life.Studies on aged animal models have un...Over the past century,age-related diseases,such as cancer,type-2 diabetes,obesity,and mental illness,have shown a significant increase,negatively impacting overall quality of life.Studies on aged animal models have unveiled a progressive discoordination at multiple regulatory levels,including transcriptional,translational,and post-translational processes,resulting from cellular stress and circadian derangements.The circadian clock emerges as a key regulator,sustaining physiological homeostasis and promoting healthy aging through timely molecular coordination of pivotal cellular processes,such as stem-cell function,cellular stress responses,and inter-tissue communication,which become disrupted during aging.Given the crucial role of hypothalamic circuits in regulating organismal physiology,metabolic control,sleep homeostasis,and circadian rhythms,and their dependence on these processes,strategies aimed at enhancing hypothalamic and circadian function,including pharmacological and non-pharmacological approaches,offer systemic benefits for healthy aging.Intranasal brain-directed drug administration represents a promising avenue for effectively targeting specific brain regions,like the hypothalamus,while reducing side effects associated with systemic drug delivery,thereby presenting new therapeutic possibilities for diverse age-related conditions.展开更多
Administration of human umbilical cord-derived mesenchymal stem cells(hUC-MSCs)is believed to be an effective method for treating neurodevelopmental disorde rs.In this study,we investigated the possibility of hUC-MSCs...Administration of human umbilical cord-derived mesenchymal stem cells(hUC-MSCs)is believed to be an effective method for treating neurodevelopmental disorde rs.In this study,we investigated the possibility of hUC-MSCs treatment of neonatal hypoxic/ischemic brain injury associated with maternal immune activation and the underlying mechanism.We established neonatal rat models of hypoxic/ischemic brain injury by exposing pregnant rats to lipopolysaccharide on day 16 or 17 of pregnancy.Rat offspring were intranasally administe red hUC-MSCs on postnatal day 14.We found that polypyrimidine tract-binding protein-1(PTBP-1)participated in the regulation of lipopolysaccharide-induced maternal immune activation,which led to neonatal hypoxic/ischemic brain injury.Intranasal delive ry of hUC-MSCs inhibited PTBP-1 expression,alleviated neonatal brain injury-related inflammation,and regulated the number and function of glial fibrillary acidic protein-positive astrocytes,there by promoting plastic regeneration of neurons and im p roving brain function.These findings suggest that hUC-MSCs can effectively promote the repair of neonatal hypoxic/ischemic brain injury related to maternal immune activation through inhibition of PTBP-1 expression and astrocyte activation.展开更多
To study the influence of the nasal mucociliary system on intranasal drug administration and ways of reducing its influence on nasal absorption Methods Rabbit nasopharynx was closed to stop mucociliary function in...To study the influence of the nasal mucociliary system on intranasal drug administration and ways of reducing its influence on nasal absorption Methods Rabbit nasopharynx was closed to stop mucociliary function in one group In the other group, rabbits maintained their mucociliary function Both groups were given a nasal drip of gentamycin and the serum levels were measured from 0 to 180 minutes after drug administration To reduce the undesirable effects of the nasal mucociliary system, acetylcysteine was mixed into the gentamycin drops In addition, nasal nebulization was evaluated in human volunteers as a means of increasing absorption of the drug in the non ciliary area of the nasal cavity Results Nasal mucociliary function reduced intranasal absorption of drug and made the highest absorbing rate and area under the curve (AUC) decrease by 25 1% and 18 2%, respectively Both the nasal drip containing acetylcysteine and the nebulizer could promote drug absorption in the nasal mucosa The former made the highest intranasal absorption and AUC increase by 18 0% and 10 7%, respectively The latter made the absorption increase 1 5-1 6 times Conclusion The mucociliary system can decrease intranasal drug absorption Application of acetylcysteine or the use of nebulizer can increase drug absorption展开更多
Objective:To study the preventive effect of Timosaponin BII(T-BII)-loaded temperature/ion-sensitive nasal in situ hydrogels(ISGs)on Alzheimer's disease(AD),its preparation technology,characteristics and in vivo ef...Objective:To study the preventive effect of Timosaponin BII(T-BII)-loaded temperature/ion-sensitive nasal in situ hydrogels(ISGs)on Alzheimer's disease(AD),its preparation technology,characteristics and in vivo effects were evaluated.Methods:The morphological and rheological properties were evaluated.The preventive effects of T-BII ISG on scopolamine-induced AD in mice were determined with the index of muscarinicreceptor 1(M1)expression and pathological changes.Results:Results revealed that T-BII ISG significantly increased the content of M1 choline receptors in the hippocampus of mice and ameliorated the damage incurred to the hippocampal cornu ammonis 1(CA1)area.Conclusion:T-BII ISGs is a reasonable and convenient method of exerting an obvious preventive effect on mice with AD induced by scopolamine.This,thereby,lays forth a new treatment option for preventing AD.展开更多
Atrophic rhinitis is a disease which manifests itself mainly by anosmia due to dryness and atrophy of the nasal mucosa. There is no specific therapy for the disease at present. In the past few years, 23 cases of atrop...Atrophic rhinitis is a disease which manifests itself mainly by anosmia due to dryness and atrophy of the nasal mucosa. There is no specific therapy for the disease at present. In the past few years, 23 cases of atrophic rhinitis were treated mainly by deep puncture at three points in the nasal region with satisfactory results. In order to find out the functional changes of the nasal mucosa, the mucociliary transport rate (MTR), surface temperature of the conchal mucosa, acid-base scale of nasal secretion, and volume of nasal secretion were determined before and after the treatment.展开更多
The management of the central nervous system(CNS)disorders is challenging,due to the need of drugs to cross the blood-brain barrier(BBB)and reach the brain.Among the various strategies that have been studied to circum...The management of the central nervous system(CNS)disorders is challenging,due to the need of drugs to cross the blood-brain barrier(BBB)and reach the brain.Among the various strategies that have been studied to circumvent this challenge,the use of the intranasal route to transport drugs from the nose directly to the brain has been showing promising results.In addition,the encapsulation of the drugs in lipid-based nanocarriers,such as solid lipid nanoparticles(SLNs),nanostructured lipid carriers(NLCs)or nanoemulsions(NEs),can improve nose-to-brain transport by increasing the bioavailability and site-specifc delivery.This review provides the state-of-the-art of in vivo studies with lipid-based nanocarriers(SLNs,NLCs and NEs)for nose-to-brain delivery.Based on the literature available from the past two years,we present an insight into the different mechanisms that drugs can follow to reach the brain after intranasal administration.The results of pharmacokinetic and pharmacodynamics studies are reported and a critical analysis of the differences between the anatomy of the nasal cavity of the different animal species used in in vivo studies is carried out.Although the exact mechanism of drug transport from the nose to the brain is not fully understood and its effectiveness in humans is unclear,it appears that the intranasal route together with the use of NLCs,SLNs or NEs is advantageous for targeting drugs to the brain.These systems have been shown to be more effective for nose-to-brain delivery than other routes or formulations with non-encapsulated drugs,so they are expected to be approved by regulatory authorities in the coming years.展开更多
Post-traumatic stress disorder(PTSD)is a psychiatric disease that seriously affects brain function.Currently,selective serotonin reuptake inhibitors(SSRIs)are used to treat PTSD clinically but have decreased efficienc...Post-traumatic stress disorder(PTSD)is a psychiatric disease that seriously affects brain function.Currently,selective serotonin reuptake inhibitors(SSRIs)are used to treat PTSD clinically but have decreased efficiency and increased side effects.In this study,nasal cannabidiol inclusion complex temperature-sensitive hydrogels(CBD TSGs)were prepared and evaluated to treat PTSD.Mice model of PTSD was established with conditional fear box.CBD TSGs could significantly improve the spontaneous behavior,exploratory spirit and alleviate tension in open field box,relieve anxiety and tension in elevated plus maze,and reduce the freezing time.Hematoxylin and eosin and c-FOS immunohistochemistry slides showed that the main injured brain areas in PTSD were the prefrontal cortex,amygdala,and hippocampus CA1.CBD TSGs could reduce the level of tumor necrosis factor-a caused by PTSD.Western blot analysis showed that CBD TSGs increased the expression of the 5-HT1 A receptor.Intranasal administration of CBD TSGs was more efficient and had more obvious brain targeting effects than oral administration,as evidenced by the pharmacokinetics and brain tissue distribution of CBD TSGs.Overall,nasal CBD TSGs are safe and effective and have controlled release.There are a novel promising option for the clinical treatment of PTSD.展开更多
COVID-19 has globally spread to burden the medical system.Even with a massive vaccination,a mucosal vaccine offering more comprehensive and convenient protection is imminent.Here,a micro-sized vaccine based on recombi...COVID-19 has globally spread to burden the medical system.Even with a massive vaccination,a mucosal vaccine offering more comprehensive and convenient protection is imminent.Here,a micro-sized vaccine based on recombinant Lactiplantibacillus plantarum(rLP)displaying spike or receptor-binding domain(RBD)was characterized as microparticles,and its safety and protective effects against SARS-CoV-2 were evaluated.We found a 66.7%mortality reduction and 100%protection with rLP against SARS-CoV-2 in a mouse model.The histological analysis showed decreased hemorrhage symptoms and increased leukocyte infiltration in the lung.Especially,rLP:RBD significantly decreased pulmonary viral loads.For the first time,our study provides a L.plantarum-vectored vaccine to prevent COVID-19 progress and transmission via intranasal vaccination.展开更多
OBJECTIVE: To study the influence of intranasal medication on the structure, pathology and reversibility of the nasal mucosa to provide a basis for the feasibility of intranasal route of drug administration. METHODS: ...OBJECTIVE: To study the influence of intranasal medication on the structure, pathology and reversibility of the nasal mucosa to provide a basis for the feasibility of intranasal route of drug administration. METHODS: Nasal drops of gentamicin were placed in the nasal cavity of rabbits for 3, 5, 7, 14 and 28 days. After that, the drops were stopped and drugs protecting the nasomucosa were used for one and three weeks. After being sacrificed over time, the nasomucosa of the rabbit was observed under optical and electron microscopes. RESULTS: Damage to the nasal mucosa appeared to different extents with prolonged use of nasal drops. Within 3 - 7 days of applying the drug, damages to the nasal mucosa gradually appeared, and after two and four weeks, were most serious. After stopping the drug, the nasal mucosa was gradually restored. CONCLUSION: Damages of drugs to the nasal mucosa could be restored. The intranasal route of drug administration would be feasible and clinically applicable.展开更多
基金supported by KAKENHI under grant number 23K08535,22K09274(to MK)。
文摘Exosomes,lipid bilayer-enclosed small cellular vesicles,are actively secreted by various cells and play crucial roles in intercellular communication.These nanosized vesicles transport internalized proteins,mRNA,miRNA,and other bioactive molecules.Recent findings have provided compelling evidence that exosomes derived from stem cells hold great promise as a therapeutic modality for central nervous system disorders.These exosomes exhibit multifaceted properties including antiapoptotic,anti-inflammatory,neurogenic,and vasculogenic effects.Furthermore,exosomes offer several advantages over stem cell therapy,such as high preservation capacity,low immunogenicity,the ability to traverse the blood-brain barrier,and the potential for drug encapsulation.Consequently,researchers have turned their attention to exosomes as a novel therapeutic avenue.Nonetheless,akin to the limitations of stem cell treatment,the limited accumulation of exosomes in the injured brain poses a challenge to their clinical application.To overcome this hurdle,intranasal administration has emerged as a non-invasive and efficacious route for delivering drugs to the central nervous system.By exploiting the olfactory and trigeminal nerve axons,this approach enables the direct transport of therapeutics to the brain while bypassing the blood-brain barrier.Notably,exosomes,owing to their small size,can readily access the nerve pathways using this method.As a result,intranasal administration has gained increasing recognition as an optimal therapeutic strategy for exosomebased treatments.In this comprehensive review,we aim to provide an overview of both basic and clinical research studies investigating the intranasal administration of exosomes for the treatment of central nervous system diseases.Furthermore,we elucidate the underlying therapeutic mechanisms and offer insights into the prospect of this approach.
基金The project supported by the National Training Program of Innovation and Entrepreneurship for Undergraduates(201610439108)
文摘OBJECTIVE To evaluate the protective effects of resveratrol nanosuspensions loaded in situ hydrogel on Alzheimer disease model mice after intranasal administration. METHODS Resveratrol nanosuspensions were fabricated by antisolvent nano-precipitation method,and then dispersed into0.5% gellan gum to form resveratrol nanosuspenisons loaded ionic sensitive in situ hydrogel. The Alzheimer′s disease models were induced by lateral ventricle injection of Aβ_(25~35)and the protection and treatment effects of resveratrol nanosuspensions loaded in situ hydrogel on study and memory capability were performed after intranasal administration in water maze experiments. The analyses of the changes of cholinergic neurotransmitters in the brain were also determined according to the contents of acetylcholine(ACh),choline acetyltransferase(ChAT) and acetylcholinesterase(AChE). RESULTS Behavior assessment disclosed that in position navigation,escape latency test,each of experimental animals showed a decreased trend with swim training days increase,indicating that in the training process they had the ability of learning and memory in looking for the platform. Compared with the control group,average latency of model group significantly increased. While compared with the model group,treatment group′s average latency was significantly shorter. Space exploration experiment results showed that the times of model group across target quadrant of the platform is less than that of control group. But the crossing times of treatment group with resveratrol increased compared with the model group. As for the changes of cholinergic neurotransmitters,in AD mice brain ACh content decreased; the Ch AT activity decreased,while the activity of ACh E with the ability to hydrolysis acetylcholine increased. The administration of resveratrol can decrease the activity of ACh enzymes but increase Ch AT activity and the levels of acetylcholine. CONCLUSION Resveratrol nanosuspension loaded in situ gel can ameliorate the declining ability of learning and memory of AD model mice after intranasal administration. As a promising approach for the treatment of central nervous system(CNS) disease,intranasal administration route can effectively deliver to the brain and thus enhance the therapeutic effect.
基金supported by the National Natural Science Foundation of China (32471188,32170984,82301787)。
文摘Iron is the most abundant transition metal in the brain and is essential for brain development and neuronal function;however,its abnormal accumulation is also implicated in various neurological disorders.The olfactory bulb(OB),an early target in neurodegenerative diseases,acts as a gateway for environmental toxins and contains diverse neuronal populations with distinct roles.This study explored the cell-specific vulnerability to iron in the OB using a mouse model of intranasal administration of ferric ammonium citrate(FAC).Olfactory function was assessed through olfactory discrimination tests,while iron levels in OB tissues,cerebrospinal fluid(CSF),and serum were quantified using inductively coupled plasma mass spectrometry(ICP-MS),immunohistochemical staining,and iron assays.Transcriptomic changes and immune responses were assessed using RNA sequencing and immune cell infiltration analysis.Results showed that intranasal FAC administration impaired olfactory function,accompanied by iron deposition in the olfactory mucosa and OB,as well as damage to olfactory sensory neurons.Notably,these effects occurred without elevations in CSF or serum iron levels.OB iron accumulation activated multiple immune cells,including microglia and astrocytes,but did not trigger ferroptosis.Spatial transcriptomic sequencing of healthy adult mouse OBs revealed significant cellular heterogeneity,with an abundance of neuroglia and neurons.Among neurons,GABAergic neurons were the most prevalent,followed by glutamatergic and dopaminergic neurons,while cholinergic and serotonergic neurons were sparsely distributed.Under iron-stressed conditions,oligodendrocytes,dopaminergic neurons,and glutamatergic neurons exhibited significant damage,while GABAergic neurons remained unaffected.These findings highlight the selective vulnerability of neuronal and glial populations to iron-induced stress,offering novel insights into the loss of specific cell types in the OB during iron dysregulation.
基金supported by the National Natural Science Foundation of China (No. 81073057)the Key New Drug Creation and Development Programme of China (Nos. 2009ZX09502-008 and 2009ZX09308-003)the Doctoral Fund of the Ministry of Education of China(No. 20090013110007)
文摘Both geniposide （Ge） and natural borneol （NB） are bioactive substances derived from traditional Chinese herbs. The effect of NB on the pharmacokinetics of Ge in rat via intranasal administration was investigated. The concentrations of Ge in plasma were determined by reversed-phase high-performance liquid chromatography （HPLC） after intranasal administration of Ge （4 mg/kg） alone and combined with different doses （0.08, 0.8, and 8 mg/kg） of NB. The intravenous administration was given as a reference （4 mg/kg of Ge and 8 mg/kg of NB）. Compared with the intravenous administration, the absolute bioavailability of Ge was 76.14% through intranasal administration combined with NB. Compared with the intranasal administration of Ge alone, Ge could be absorbed rapidly in the nasal cavity combined with NB; the peak time of Ge in the plasma became shorter （3-5 min vs. 40 min）; the peak concentration became higher （1.32-4.25 IJg/ml vs. 0.67 ug/ml）; and, the relative bioavailability of Ge combined with NB was 90.3%-237.8%. The enhancing effect was attenuated as the dose of NB decreased. The results indicated that NB can accelerate the absorption of Ge dose-dependently in the nasal cavity.
基金supported in part by grants from the National Natural Science Foundation of China(82151218,81971548)National Key Research and Development Program of China(2021YFC2301703,2021YFC2301303,2022YFC2303700)+1 种基金Yunnan Key Research and Development Program(202103AC100005,202103AQ100001,202102AA310055,China)CAS“Light of West China”。
文摘The continuously emerging SARS-CoV-2 variants pose a great challenge to the efficacy of current drugs,this necessitates the development of broad-spectrum antiviral drugs.In the previous study,we designed a recombinant protein,heptad repeat(HR)121,as a variant-proof vaccine.Here,we found it can act as a fusion inhibitor and demonstrated broadly neutralizing activities against SARS-CoV-2 and its main variants.Structure analysis suggested that HR121 targets the HR2 domain in SARS-CoV-2 spike(S)2 subunit to block virus-cell fusion.Functional experiments demonstrated that HR121 can bind HR2 at serological-pH and endosomal-pH,highlighting its inhibition capacity when SARS-CoV-2 enters via either cellular membrane fusion or endosomal route.Importantly,HR121 can effectively inhibit SARS-CoV-2 and Omicron variant pseudoviruses entering the cells,as well as block authentic SARSCoV-2 and Omicron BA.2 replications in human pulmonary alveolar epithelial cells.After intranasal administration to Syrian golden hamsters,it can protect hamsters from SARS-CoV-2 and Omicron BA.2 infection.Together,our results suggest that HR121 is a potent drug candidate with broadly neutralizing activities against SARS-CoV-2 and its variants.
基金supported by the Major International (Regional) Joint Project (No. 21461142001)the National Basic Research Program of China (No. 2015CB453102)+2 种基金the National Natural Science Foundation of China (Nos. 21621064, 21477153)the Strategic Priority Research Program of the Chinese Academy of Science (No. 14040302)the Chinese Academy of Sciences (No. QYZDJ-SSW-DQC017)
文摘Tetrabromobisphenol A（TBBPA） and its derivatives are now being highly concerned due to their emerging environmental occurrence and deleterious effects on non-target organisms.Considering the potential neurotoxicity of TBBPA derivatives which has been demonstrated in vitro, what could happen in vivo is worthy of being studied. Tetrabromobisphenol A bis（2-hydroxyethyl ether）（TBBPA-BHEE）, a representative TBBPA derivative, was selected for a21-day exposure experiment on neonatal Sprague Dawley（SD） rats through intranasal administration. The neurobehavioral, histopathological changes, and differentially expressed genes based on RNA microarray were investigated to evaluate the neurological effects of this chemical. The results indicated that TBBPA-BHEE exposure significantly compromised the motor co-ordination performance and the locomotor activities（p 〈 0.05）. The neurobehavioral phenotype could be attributed to the obvious histopathological changes in both cerebrum and cerebellum, such as neural cell swelling, microglial activation and proliferation. A total of 911 genes were up-regulated, whereas 433 genes were down-regulated. Gene set enrichment analysis showed multiple signaling pathways, including ubiquitin-mediated proteolysis and wingless-int（Wnt） signaling pathway etc. were involved due to TBBPA-BHEE exposure. The gene ontology enrichment analysis showed the basic cellular function and the neurological processes like synaptic transmission were influenced. The toxicological effects of TBBPA-BHEE observed in this study suggested the potential neuronal threaten from unintended exposure,which would be of great value in the biosafety evaluation of TBBPA derivatives.
基金National Science and Technology Major Project(No.2011ZX09102-003-05,China)
文摘Objective To study the pharmacokinetic behavior of tetramethylpyrazine hydrochloride（TMPH） in plasma of rabbits after intranasal administration and the relationship between absorption and dosage, furthermore, to illustrate the effects of borneol and musk used in combination with TMPH on the plasma concentration profile of TMPH in rabbits. Methods The concentration of TMPH was determined by RP-HPLC method. Coumarin was used as an internal standard. Sample preparation was carried out by extraction and precipitation with methanol. The pharmacokinetic parameters were computed by software program DAS.3.1.4. Results Blood pharmacokinetics of TMPH fitted best to a non-compartment model. After intranasal administration with single dose at 10, 20, and 40 mg/kg of TMPH, the average values of Cmax were 8.075, 16.537, and 33.115 μg/mL, and the average values of AUC0-t were 228.93, 399.273,and 728.917 mg/（L·min）, respectively. Cmax of TMPH in plasma was increased by 31.136% and 38.786% compared with those without borneol and musk, and intranasal bioavailability were increased by 21.587% and 40.633% after intranasal administration of TMPH in combination with borneol, or with borneol and musk. Conclusion Borneol and musk could enhance the intranasal absorption of TMPH and increase the concentration of TMPH in blood of rabbits, especially in the early period. This work also shows the rational compatibility between borneol and musk.
基金supported by the STI 2030-Major Projects(No.2021ZD0201602).
文摘The existence of the blood-brain barrier(BBB)restricts the entry of drugs from the circulation into the central nervous system(CNS),which severely affects the treatment of neurological diseases,including glioblastoma,Parkinson’s disease(PD),and Alzheimer’s disease(AD).With the advantage of bypassing the BBB and avoiding systemic distribution,intranasal administration has emerged as an alternative method of delivering drugs to the brain.Drug delivery directly to the brain using intranasal nanosystems represents a new paradigm for neurological disease treatment because of its advantages in improving drug solubility and stability in vivo,enabling targeted drug delivery and controlled release,and reducing non-specific toxicity.And it has shown efficacy in animal models and clinical applications.Herein,this review describes the mechanisms of intranasal delivery of brain-targeted drugs,the properties of nanosystems for intranasal administration(e.g.,liposomes,nanoemulsions,and micelles),and strategies for intranasal drug delivery to enhance brain-targeted drug delivery.Recent applications of nanosystems in intranasal drug delivery and disease treatment have been comprehensively reviewed.Although encouraging results have been reported,significant challenges still need to be overcome to translate these nanosystems into clinics.Therefore,the future prospects of intranasal drug delivery nanosystems are discussed in depth,expecting to provide useful insights and guidance for effective neurological disease treatment.
基金supported by a grant from the Basic Science Research Program through the National Research Foundation of Korea(NRF),which was funded by the Ministry of Science,ICT(MSIT)of the Korean government(Grant No.NRF-2020R1A2C3004123,NRF-2019R1A5A2027588,and NFR-2021R1C1C2004688)supported by a grant from Catholic Institute of Cell Therapy in 2023(CRC)and by the Basic Medical Science Facilitation Program funded by the Catholic Education Foundation through the Catholic Medical Center of the Catholic University of Korea.
文摘Background Alzheimer’s disease(AD)is the most common neurodegenerative disorder in the elderly,resulting in gradual destruction of cognitive abilities.Research on the development of various AD treatments is underway;however,no definitive treatment has been developed yet.Herein,we present induced pluripotent stem cell(iPSC)-derived cortical neural stem cell secretome(CNSC-SE)as a new treatment candidate for AD and explore its efficacy.Methods We first assessed the effects of CNSC-SE treatment on neural maturation and electromagnetic signal during cortical nerve cell differentiation.Then to confirm the efficacy in vivo,CNSC-SE was administered to the 5×FAD mouse model through the nasal cavity(5μg/g,once a week,4 weeks).The cell-mediated effects on nerve recovery,amyloid beta(Aβ)plaque aggregation,microglial and astrocyte detection in the brain,and neuroinflammatory responses were investigated.Metabolomics analysis of iPSC-derived CNSC-SE revealed that it contained components that could exert neuro-protective effects or amplify cognitive restorative effects.Results Human iPSC-derived CNSC-SE increased neuronal proliferation and dendritic structure formation in vitro.Furthermore,CNSC-SE-treated iPSC-derived cortical neurons acquired electrical network activity and action potential bursts.The 5×FAD mice treated with CNSC-SE showed memory restoration and reduced Aβplaque accumulation.Conclusions Our findings suggest that the iPSC-derived CNSC-SE may serve as a potential,non-invasive therapeutic option for AD in reducing amyloid infiltration and restoring memory.
基金supported by the Distinguished Professor Project of Liaoning Province.
文摘The number of people with Alzheimer’s disease(AD)is increasing annually,with the nidus mainly concentrated in the cortex and hippocampus.Despite of numerous efforts,effective treatment of AD is still facing great challenges due to the blood brain barrier(BBB)and limited drug distribution in the AD nidus sites.Thus,in this study,using vinpocetine(VIN)as a model drug,the objective is to explore the feasibility of tackling the above bottleneck via intranasal drug delivery in combination with a brain guider,borneol(BOR),using nanoemulsion(NE)as the carrier.First of all,the NE were prepared and characterized.In vivo behavior of the NE after intranasal administration was investigated.Influence of BOR dose,BOR administration route on drug brain targeting behavior was evaluated,and the influence of BOR addition on drug brain subregion distribution was probed.It was demonstrated that all the NE had comparable size and similar retention behavior after intranasal delivery.Compared to intravenous injection,improved brain targeting effect was observed by intranasal route,and drug targeting index(DTI)of the VIN–NE group was 154.1%,with the nose-to-brain direct transport percentage(DTP)35.1%.Especially,remarkably enhanced brain distribution was achieved after BOR addition in the NE,with the extent depending on BOR dose.VIN brain concentration was the highest in the VIN-1-BOR-NE group at BOR dose of 1 mg/kg,with the DTI reaching 596.1%and the DTP increased to 83.1%.BOR could exert better nose to brain delivery when administrated together with the drug via intranasal route.Notably,BOR can remarkably enhance drug distribution in both hippocampus and cortex,the nidus areas of AD.In conclusion,in combination with intranasal delivery and the intrinsic brain guiding effect of BOR,drug distribution not only in the brain but also in the cortex and hippocampus can be enhanced significantly,providing the perquisite for improved therapeutic efficacy of AD.
基金Supported by the Research Foundation of Beijing Friendship Hospital,Capital Medical University,No. yyqdkt2018-16the Beijing Municipal Administration of Hospitals’ Youth Program,No. QML20190101the Scientific Research Common Program of Beijing Municipal Commission of Education,No. KM202010025021
文摘BACKGROUND Sedation during endoscopic ultrasonography(EUS)poses many challenges and moderate-to-deep sedation are often required.The conventional method to preform moderate-to-deep sedation is generally intravenous benzodiazepine alone or in combination with opioids.However,this combination has some limitations.Intranasal medication delivery may be an alternative to this sedation regimen.AIM To determine,by continual reassessment method(CRM),the minimal effective dose of intranasal sufentanil(SUF)when combined with intranasal dexmedetomidine(DEX)for moderate sedation of EUS in at least 95%of patients(ED95).METHODS Thirty patients aged 18-65 and scheduled for EUS were recruited in this study.Subjects received intranasal DEX and SUF for sedation.The dose of DEX(1μg/kg)was fixed,while the dose of SUF was assigned sequentially to the subjects using CRM to determine ED95.The sedation status was assessed by modified observer’s assessment of alertness/sedation(MOAA/S)score.The adverse events and the satisfaction scores of patients and endoscopists were recorded.RESULTS The ED95 was intranasal 0.3μg/kg SUF when combined with intranasal 1μg/kg DEX,with an estimated probability of successful moderate sedation for EUS of 94.9%(95%confidence interval:88.1%-98.9%).When combined with intranasal 1μg/kg DEX,probabilities of successful moderate sedation at each dose level of intranasal SUF were as follows:0μg/kg SUF,52.8%;0.1μg/kg SUF,75.4%;0.2μg/kg SUF,89.9%;0.3μg/kg SUF,94.9%;0.4μg/kg SUF,98.0%;0.5μg/kg SUF,99.0%.CONCLUSION The ED95 needed for moderate sedation for EUS is intranasal 0.3μg/kg SUF when combined with intranasal 1μg/kg DEX,based on CRM.
基金supported by National Council of Science and Technology(CONACYT)(grants FC 2016/2672 and FOSISS 272757),INMEGEN(09/2017/I)the Ministry of Education,Science,Technology and Innovation of Mexico City(SECTEI)(grant 228/2021).
文摘Over the past century,age-related diseases,such as cancer,type-2 diabetes,obesity,and mental illness,have shown a significant increase,negatively impacting overall quality of life.Studies on aged animal models have unveiled a progressive discoordination at multiple regulatory levels,including transcriptional,translational,and post-translational processes,resulting from cellular stress and circadian derangements.The circadian clock emerges as a key regulator,sustaining physiological homeostasis and promoting healthy aging through timely molecular coordination of pivotal cellular processes,such as stem-cell function,cellular stress responses,and inter-tissue communication,which become disrupted during aging.Given the crucial role of hypothalamic circuits in regulating organismal physiology,metabolic control,sleep homeostasis,and circadian rhythms,and their dependence on these processes,strategies aimed at enhancing hypothalamic and circadian function,including pharmacological and non-pharmacological approaches,offer systemic benefits for healthy aging.Intranasal brain-directed drug administration represents a promising avenue for effectively targeting specific brain regions,like the hypothalamus,while reducing side effects associated with systemic drug delivery,thereby presenting new therapeutic possibilities for diverse age-related conditions.
基金the National Natural Science Foundation of China,No.81471308(to JL)Stem cell Clinical Research Registry Program,No.CMR-20161129-1003(to JL)+2 种基金Liaoning Province Excellent Talent Program Project of China,No.XLYC1902031(to JL)Dalian Innovation Fund of China,No.2018J11CY025(to JL)National Defense Science and Technology New Special Zone Contract,No.19-163-00-kx-003-001-01(to JL)。
文摘Administration of human umbilical cord-derived mesenchymal stem cells(hUC-MSCs)is believed to be an effective method for treating neurodevelopmental disorde rs.In this study,we investigated the possibility of hUC-MSCs treatment of neonatal hypoxic/ischemic brain injury associated with maternal immune activation and the underlying mechanism.We established neonatal rat models of hypoxic/ischemic brain injury by exposing pregnant rats to lipopolysaccharide on day 16 or 17 of pregnancy.Rat offspring were intranasally administe red hUC-MSCs on postnatal day 14.We found that polypyrimidine tract-binding protein-1(PTBP-1)participated in the regulation of lipopolysaccharide-induced maternal immune activation,which led to neonatal hypoxic/ischemic brain injury.Intranasal delive ry of hUC-MSCs inhibited PTBP-1 expression,alleviated neonatal brain injury-related inflammation,and regulated the number and function of glial fibrillary acidic protein-positive astrocytes,there by promoting plastic regeneration of neurons and im p roving brain function.These findings suggest that hUC-MSCs can effectively promote the repair of neonatal hypoxic/ischemic brain injury related to maternal immune activation through inhibition of PTBP-1 expression and astrocyte activation.
文摘To study the influence of the nasal mucociliary system on intranasal drug administration and ways of reducing its influence on nasal absorption Methods Rabbit nasopharynx was closed to stop mucociliary function in one group In the other group, rabbits maintained their mucociliary function Both groups were given a nasal drip of gentamycin and the serum levels were measured from 0 to 180 minutes after drug administration To reduce the undesirable effects of the nasal mucociliary system, acetylcysteine was mixed into the gentamycin drops In addition, nasal nebulization was evaluated in human volunteers as a means of increasing absorption of the drug in the non ciliary area of the nasal cavity Results Nasal mucociliary function reduced intranasal absorption of drug and made the highest absorbing rate and area under the curve (AUC) decrease by 25 1% and 18 2%, respectively Both the nasal drip containing acetylcysteine and the nebulizer could promote drug absorption in the nasal mucosa The former made the highest intranasal absorption and AUC increase by 18 0% and 10 7%, respectively The latter made the absorption increase 1 5-1 6 times Conclusion The mucociliary system can decrease intranasal drug absorption Application of acetylcysteine or the use of nebulizer can increase drug absorption
基金This study was funded by the Beijing Natural Science Foundation(7202147).
文摘Objective:To study the preventive effect of Timosaponin BII(T-BII)-loaded temperature/ion-sensitive nasal in situ hydrogels(ISGs)on Alzheimer's disease(AD),its preparation technology,characteristics and in vivo effects were evaluated.Methods:The morphological and rheological properties were evaluated.The preventive effects of T-BII ISG on scopolamine-induced AD in mice were determined with the index of muscarinicreceptor 1(M1)expression and pathological changes.Results:Results revealed that T-BII ISG significantly increased the content of M1 choline receptors in the hippocampus of mice and ameliorated the damage incurred to the hippocampal cornu ammonis 1(CA1)area.Conclusion:T-BII ISGs is a reasonable and convenient method of exerting an obvious preventive effect on mice with AD induced by scopolamine.This,thereby,lays forth a new treatment option for preventing AD.
文摘Atrophic rhinitis is a disease which manifests itself mainly by anosmia due to dryness and atrophy of the nasal mucosa. There is no specific therapy for the disease at present. In the past few years, 23 cases of atrophic rhinitis were treated mainly by deep puncture at three points in the nasal region with satisfactory results. In order to find out the functional changes of the nasal mucosa, the mucociliary transport rate (MTR), surface temperature of the conchal mucosa, acid-base scale of nasal secretion, and volume of nasal secretion were determined before and after the treatment.
基金supported by Fundacao para a Ciência e a Tecnologia(FCT)(SFRH/136177/2018,Portugal)the Applied Molecular Biosciences Unit-UCIBIO which is fnanced by national funds from FCT(UIDP/04378/2020 and UIDB/04378/2020)。
文摘The management of the central nervous system(CNS)disorders is challenging,due to the need of drugs to cross the blood-brain barrier(BBB)and reach the brain.Among the various strategies that have been studied to circumvent this challenge,the use of the intranasal route to transport drugs from the nose directly to the brain has been showing promising results.In addition,the encapsulation of the drugs in lipid-based nanocarriers,such as solid lipid nanoparticles(SLNs),nanostructured lipid carriers(NLCs)or nanoemulsions(NEs),can improve nose-to-brain transport by increasing the bioavailability and site-specifc delivery.This review provides the state-of-the-art of in vivo studies with lipid-based nanocarriers(SLNs,NLCs and NEs)for nose-to-brain delivery.Based on the literature available from the past two years,we present an insight into the different mechanisms that drugs can follow to reach the brain after intranasal administration.The results of pharmacokinetic and pharmacodynamics studies are reported and a critical analysis of the differences between the anatomy of the nasal cavity of the different animal species used in in vivo studies is carried out.Although the exact mechanism of drug transport from the nose to the brain is not fully understood and its effectiveness in humans is unclear,it appears that the intranasal route together with the use of NLCs,SLNs or NEs is advantageous for targeting drugs to the brain.These systems have been shown to be more effective for nose-to-brain delivery than other routes or formulations with non-encapsulated drugs,so they are expected to be approved by regulatory authorities in the coming years.
基金funded by the Beijing Municipal Natural Science Foundation,China(7202147 and 7172072,China)
文摘Post-traumatic stress disorder(PTSD)is a psychiatric disease that seriously affects brain function.Currently,selective serotonin reuptake inhibitors(SSRIs)are used to treat PTSD clinically but have decreased efficiency and increased side effects.In this study,nasal cannabidiol inclusion complex temperature-sensitive hydrogels(CBD TSGs)were prepared and evaluated to treat PTSD.Mice model of PTSD was established with conditional fear box.CBD TSGs could significantly improve the spontaneous behavior,exploratory spirit and alleviate tension in open field box,relieve anxiety and tension in elevated plus maze,and reduce the freezing time.Hematoxylin and eosin and c-FOS immunohistochemistry slides showed that the main injured brain areas in PTSD were the prefrontal cortex,amygdala,and hippocampus CA1.CBD TSGs could reduce the level of tumor necrosis factor-a caused by PTSD.Western blot analysis showed that CBD TSGs increased the expression of the 5-HT1 A receptor.Intranasal administration of CBD TSGs was more efficient and had more obvious brain targeting effects than oral administration,as evidenced by the pharmacokinetics and brain tissue distribution of CBD TSGs.Overall,nasal CBD TSGs are safe and effective and have controlled release.There are a novel promising option for the clinical treatment of PTSD.
基金funding from the National Key Research and Development Program of China(No.2022YFC2604204)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2020-I2M-5-001)+1 种基金the National Natural Science Foundation of China(No.31972719,31802224)Wenzhou Science and Technology Plan Project(S2020010,X20210072)。
文摘COVID-19 has globally spread to burden the medical system.Even with a massive vaccination,a mucosal vaccine offering more comprehensive and convenient protection is imminent.Here,a micro-sized vaccine based on recombinant Lactiplantibacillus plantarum(rLP)displaying spike or receptor-binding domain(RBD)was characterized as microparticles,and its safety and protective effects against SARS-CoV-2 were evaluated.We found a 66.7%mortality reduction and 100%protection with rLP against SARS-CoV-2 in a mouse model.The histological analysis showed decreased hemorrhage symptoms and increased leukocyte infiltration in the lung.Especially,rLP:RBD significantly decreased pulmonary viral loads.For the first time,our study provides a L.plantarum-vectored vaccine to prevent COVID-19 progress and transmission via intranasal vaccination.
文摘OBJECTIVE: To study the influence of intranasal medication on the structure, pathology and reversibility of the nasal mucosa to provide a basis for the feasibility of intranasal route of drug administration. METHODS: Nasal drops of gentamicin were placed in the nasal cavity of rabbits for 3, 5, 7, 14 and 28 days. After that, the drops were stopped and drugs protecting the nasomucosa were used for one and three weeks. After being sacrificed over time, the nasomucosa of the rabbit was observed under optical and electron microscopes. RESULTS: Damage to the nasal mucosa appeared to different extents with prolonged use of nasal drops. Within 3 - 7 days of applying the drug, damages to the nasal mucosa gradually appeared, and after two and four weeks, were most serious. After stopping the drug, the nasal mucosa was gradually restored. CONCLUSION: Damages of drugs to the nasal mucosa could be restored. The intranasal route of drug administration would be feasible and clinically applicable.
