Intranasal Administration of GRP78 Protein (HSPA5) Confers Neuroprotection in a Lactacystin-Induced Rat Model of Parkinson's Disease.

The accumulation of misfolded and aggregated α-synuclein can trigger endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), leading to apoptotic cell death in patients with Parkinson's disease (PD). As the major ER chaperone, glucose-regulated protein 78 (GRP78/BiP/HSPA5) plays a key role in UPR regulation. GRP78 overexpression can modulate the UPR, block apoptosis, and promote the survival of nigral dopamine neurons in a rat model of α-synuclein pathology. Here, we explore the therapeutic potential of intranasal exogenous GRP78 for preventing or slowing PD-like neurodegeneration in a lactacystin-induced rat model. We show that intranasally-administered GRP78 rapidly enters the substantia nigra pars compacta (SNpc) and other afflicted brain regions. It is then internalized by neurons and microglia, preventing the development of the neurodegenerative process in the nigrostriatal system. Lactacystin-induced disturbances, such as the abnormal accumulation of phosphorylated pS129-α-synuclein and activation of the pro-apoptotic GRP78/PERK/eIF2α/CHOP/caspase-3,9 signaling pathway of the UPR, are substantially reversed upon GRP78 administration. Moreover, exogenous GRP78 inhibits both microglia activation and the production of proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), via the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway in model animals. The neuroprotective and anti-inflammatory potential of exogenous GRP78 may inform the development of effective therapeutic agents for PD and other synucleinopathies.

Intranasal Resveratrol Nanoparticles Enhance Neuroprotection in a Model of Multiple Sclerosis.

PURPOSE: Resveratrol is a natural polyphenol which has a very low bioavailability but whose antioxidant, anti-inflammatory and anti-apoptotic properties may have therapeutic potential for the treatment of neurodegenerative diseases such as multiple sclerosis (MS). Previously, we reported the oral administration of resveratrol nanoparticles (RNs) elicited a neuroprotective effect in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS, at significantly lower doses than unconjugated resveratrol (RSV) due to enhanced bioavailability. Furthermore, we demonstrated that the intranasal administration of a cell-derived secretome-based therapy at low concentrations leads to the selective neuroprotection of the optic nerve in EAE mice. The current study sought to assess the potential selective efficacy of lower concentrations of intranasal RNs for attenuating optic nerve damage in EAE mice. METHODS: EAE mice received either a daily intranasal vehicle, RNs or unconjugated resveratrol (RSV) for a period of thirty days beginning on the day of EAE induction. Mice were assessed daily for limb paralysis and weekly for visual function using the optokinetic response (OKR) by observers masked to treatment regimes. After sacrifice at day 30, spinal cords and optic nerves were stained to assess inflammation and demyelination, and retinas were immunostained to quantify retinal ganglion cell (RGC) survival. RESULTS: Intranasal RNs significantly increased RGC survival at half the dose previously shown to be required when given orally, reducing the risk of systemic side effects associated with prolonged use. Both intranasal RSV and RN therapies enhanced RGC survival trends, however, only the effects of intranasal RNs were significant. RGC loss was prevented even in the presence of inflammatory and demyelinating changes induced by EAE in optic nerves. CONCLUSIONS: The intranasal administration of RNs is able to reduce RGC loss independent of the inflammatory and demyelinating effects on the optic nerve and the spinal cord. The concentration of RNs needed to achieve neuroprotection is lower than previously demonstrated with oral administration, suggesting intranasal drug delivery combined with nanoparticle conjugation warrants further exploration as a potential neuroprotective strategy for the treatment of optic neuritis, alone as well as in combination with glucocorticoids.

Long-term enhancements in antidepressant efficacy and neurogenesis: Effects of intranasal co-administration of neuropeptide Y 1 receptor (NPY1R) and galanin receptor 2 (GALR2) agonists in the ventral hippocampus.

This study evaluates the sustained antidepressant-like effects and neurogenic potential of a 3-day intranasal co-administration regimen of galanin receptor 2 (GALR2) agonist M1145 and neuropeptide Y Y1 receptor (NPY1R) agonist [Leu31, Pro34]NPY in the ventral hippocampus of adult rats, with outcomes analyzed 3 weeks post-treatment. Utilizing the forced swimming test (FST), we found that this co-administration significantly enhances antidepressant-like behaviors, an effect neutralized by the GALR2 antagonist M871, highlighting the synergistic potential of these neuropeptides in modulating mood-related behaviors. In situ proximity ligation assay (PLA) indicated a significant increase in GALR2/NPYY1R heteroreceptor complexes in the ventral hippocampal dentate gyrus, suggesting a molecular basis for the behavioral outcomes observed. Moreover, proliferating cell nuclear antigen (PCNA) immunolabeling revealed increased cell proliferation in the subgranular zone of the dentate gyrus, specifically in neuroblasts as evidenced by co-labeling with doublecortin (DCX), without affecting quiescent neural progenitors or astrocytes. The study also noted a significant uptick in the number of DCX-positive cells and alterations in dendritic morphology in the ventral hippocampus, indicative of enhanced neuronal differentiation and maturation. These morphological changes highlight the potential of these agonists to facilitate the functional integration of new neurons into existing neural circuits. By demonstrating the long-lasting effects of a brief, 3-day intranasal administration of GALR2 and NPY1R agonists, our findings contribute significantly to the understanding of neuropeptide-mediated neuroplasticity and herald novel therapeutic strategies for the treatment of depression and related mood disorders, emphasizing the therapeutic promise of targeting neurogenesis and neuronal maturation processes.

Nose-to-brain delivery of nanotherapeutics: Transport mechanisms and applications.

The blood-brain barrier presents a key limitation to the administration of therapeutic molecules for the treatment of brain disease. While drugs administered orally or intravenously must cross this barrier to reach brain targets, the unique anatomical structure of the olfactory system provides a route to deliver drugs directly to the brain. Entering the brain via receptor, carrier, and adsorption-mediated transcytosis in the nasal olfactory and trigeminal regions has the potential to increase drug delivery. In this review, we introduce the physiological and anatomical structures of the nasal cavity, and summarize the possible modes of transport and the relevant receptors and carriers in the nose-to-brain pathway. Additionally, we provide examples of nanotherapeutics developed for intranasal drug delivery to the brain. Further development of nanoparticles that can be applied to intranasal delivery systems promises to improve drug efficacy and reduce drug resistance and adverse effects by increasing molecular access to the brain. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease.

Intranasal delivery of phenytoin loaded layered double hydroxide nanoparticles improves therapeutic effect on epileptic seizures.

Improving the efficiency of antiseizure medication entering the brain is the key to reducing its peripheral toxicity. A combination of intranasal administration and nanomedicine presents a practical approach for treating epileptic seizures via bypassing the blood-brain barrier. In this study, phenytoin (PHT) loaded layered double hydroxide nanoparticles (BSA-LDHs-PHT) were fabricated via a coprecipitation - hydrothermal method for epileptic seizure control. In this study, we expound on the preparation method and characterization of BSA-LDHs-PHT. In-vitro drug release experiment shows both rapid and continuous drug release from BSA-LDHs-PHT, which is crucial for acute seizure control and chronic epilepsy therapy. In-vivo biodistribution assays after intranasal administration indicate excellent brain targeting ability of BSA-LDHs. Compared to BSA-Cyanine5.5, BSA-LDHs-Cyanine5.5 were associated with a higher brain/peripheral ratio across all tested time points. Following intranasal delivery with small doses of BSA-LDHs-PHT, the latency of seizures in the pentylenetetrazole-induced mouse models was effectively improved. Collectively, the present study successfully designed and applied BSA-LDHs-PHT as a promising strategy for treating epileptic seizures with an enhanced therapeutic effect.

Zolpidem Stimulant Effect and Dependence: A Case Report on Intranasal Use.

Zolpidem is a widely used hypnotic. Dependence on zolpidem due to the induction of euphoria is a rare condition, while intranasal misuse of zolpidem is a rather new phenomenon. We present the first case of a patient who developed zolpidem dependence, which was associated with the prompt onset of euphoria exclusively following intranasal use. Mr. A was a 51-year-old polydrug abuser with antisocial personality disorder and a physical dependence on zolpidem. Over several years, he consumed 500 mg of the drug daily, usually divided into 30 mg doses, exclusively via the nasal route because unlike the oral administration of the same dose of the drug, intranasal administration induced euphoria. Euphoric effects manifested 3-5 minutes after taking the drug, and pronounced withdrawal symptoms (i.e., profuse sweating, tremors, nausea, vomiting, diarrhea, and inability to drink and eat), present 7-8 hours after the use could disappear within 3-5 minutes upon drug re-administration. The dependence was managed through a slow tapering of the zolpidem use. Clinicians should be aware that intranasal use of zolpidem could be associated with euphoric effects and the development of addiction. The potential for misuse of zolpidem via the nasal route may be of interest for future research.

Intranasal administration of ceramide liposome suppresses allergic rhinitis by targeting CD300f in murine models.

Allergic rhinitis (AR) is caused by type I hypersensitivity reaction in the nasal tissues. The interaction between CD300f and its ligand ceramide suppresses immunoglobulin E (IgE)-mediated mast cell activation. However, whether CD300f inhibits the development of allergic rhinitis (AR) remains elusive. We aimed to investigate the roles of CD300f in the development of AR and the effectiveness of intranasal administration of ceramide liposomes on AR in murine models. We used ragweed pollen-induced AR models in mice. Notably, CD300f deficiency did not significantly influence the ragweed-specific IgE production, but increased the frequency of mast cell-dependent sneezing as well as the numbers of degranulated mast cells and eosinophils in the nasal tissues in our models. Similar results were also obtained for MCPT5-exprssing mast cell-specific loss of CD300f. Importantly, intranasal administration of ceramide liposomes reduced the frequency of sneezing as well as the numbers of degranulated mast cells and eosinophils in the nasal tissues in AR models. Thus, CD300f-ceramide interaction, predominantly in mast cells, alleviates the symptoms and progression of AR. Therefore, intranasal administration of ceramide liposomes may be a promising therapeutic approach against AR by targeting CD300f.

Medicinal plants for allergic rhinitis: A systematic review and meta-analysis.

Herbal medicine is popularly used among patients who suffer from allergic rhinitis. This systematic review and meta-analysis was conducted to evaluate the efficacy and safety of single medicinal plants in the management of allergic rhinitis. We searched MEDLINE, CENTRAL, and Web of Science for randomised controlled trials which evaluated the use of single medicinal plant for allergic rhinitis among adults and children. Twenty-nine randomised controlled trials (n = 1879) were eligible while 27 (n = 1769) contributed data for meta-analyses. Most studies (studies = 20) compared medicinal plants against placebo and Petasites hybridus was most frequently investigated (studies = 5). Very-low-to-low-certainty evidence suggests that compared to placebo, single medicinal plants may improve overall total nasal symptoms (SMD -0.31, 95% CI -0.59 to -0.02; participants = 249; studies = 5; I2 = 21%) especially nasal congestion and sneezing; and rhinoconjunctivitis quality of life (RQLQ) scores (MD -0.46, 95% CI -0.84 to -0.07; participants = 148; studies = 3; I2 = 0%). Moderate-certainty evidence show no clear differences between single medicinal plants and antihistamine in overall symptoms (Total nasal symptoms: SMD -0.14, 95% CI -0.46 to 0.18; participants = 149; studies = 2; I2 = 0%). As adjunctive therapy, moderate-certainty evidence shows that medicinal plants improved SNOT-22 scores when given as intranasal treatment (MD -7.47, 95% CI -10.75 to -4.18; participants = 124; studies = 2; I2 = 21%). Risk of bias domains were low or not clearly reported in most studies while heterogeneity was substantial in most pooled outcomes. Route of administration and age were identified to be plausible source of heterogeneity for certain outcomes. Medicinal plants appear to be well tolerated up to 8 weeks of use. Clear beneficial evidence of medicinal plants for allergic rhinitis is still lacking. There is a need for improved reporting of herbal trials to allow for critical assessment of the effects of each individual medicinal plant preparation in well-designed future clinical studies.

Formulation of Metoclopramide Hydrochloride-Loaded Lipid Carriers by QbD Approach for Combating Nausea: Safety and Bioavailability Evaluation in New Zealand Rabbit.

The focus of the research was to overcome the limitations of metoclopramide (MTC) when administered intranasally. The aim was to improve its bioavailability, increase patient compliance, and prolong its residence time in the nasal cavity. MTC-loaded liposomes were prepared by applying the film hydration method. A study was conducted to determine how formulation variables affected encapsulation efficiency (EE %), mean particle size (MPS), and zeta potential (ZP). The MTC-liposomes were further loaded into the in situ gel (gellan gum) for longer residence times following intranasal administration. pH, gelling time, and in vitro release tests were conducted on the formulations produced. In vivo performance of the MTC-loaded in situ gels was appraised based on disparate parameters such as plasma peak concentration, plasma peak time, and elimination coefficient compared to intravenous administration. When the optimal liposome formulation contained 1.98% of SPC, 0.081% of cholesterol, 97.84% of chloroform, and 0.1% of MTC, the EE of MTC was 83.21%, PS was 107.3 nm. After 5 h, more than 80% of the drug was released from MTC-loaded liposome incorporated into gellan gum in situ gel formulation (Lip-GG), which exhibited improved absorption and higher bioavailability compared to MTC loaded into gellan gum in situ gel (MTC-GG). Acceptable cell viability was also achieved. It was found out that MTC-loaded liposomal in situ gel formulations administered through the nasal route could be a better choice than other options due to its ease of administration, accurate dosing, and higher bioavailability in comparison with MTC-GG.

The Nucleocapsid Protein of SARS-CoV-2, Combined with ODN-39M, Is a Potential Component for an Intranasal Bivalent Vaccine with Broader Functionality.

Despite the rapid development of vaccines against COVID-19, they have important limitations, such as safety issues, the scope of their efficacy, and the induction of mucosal immunity. The present study proposes a potential component for a new generation of vaccines. The recombinant nucleocapsid (N) protein from the SARS-CoV-2 Delta variant was combined with the ODN-39M, a synthetic 39 mer unmethylated cytosine-phosphate-guanine oligodeoxynucleotide (CpG ODN), used as an adjuvant. The evaluation of its immunogenicity in Balb/C mice revealed that only administration by intranasal route induced a systemic cross-reactive, cell-mediated immunity (CMI). In turn, this combination was able to induce anti-N IgA in the lungs, which, along with the specific IgG in sera and CMI in the spleen, was cross-reactive against the nucleocapsid protein of SARS-CoV-1. Furthermore, the nasal administration of the N + ODN-39M preparation, combined with RBD Delta protein, enhanced the local and systemic immune response against RBD, with a neutralizing capacity. Results make the N + ODN-39M preparation a suitable component for a future intranasal vaccine with broader functionality against Sarbecoviruses.

Nanotechnology-based delivery of therapeutics through the intranasal pathway and the blood-brain barrier for Alzheimer's disease treatment.

Background: drugs for Alzheimer's disease (AD) fail to exhibit efficacy in clinical trials for a number of reasons, a major one being blood-brain barrier (BBB) permeability. Meanwhile, the increasing incidence of this disease emphasizes the need for effective therapeutics. Herein, we discuss novel nanoplatform technologies developed for the effective delivery of AD drugs by traversing the BBB. Main text: the interfacial and surface chemistry of nanomaterials is utilized in several industries, including pharmaceutical, and has drawn considerable attention in the field of nanotechnology. Various reports have suggested the potential of nanotechnology for AD treatment, describing unique drug carriers that improve drug stability and solubility while maintaining therapeutic dosages. These nanotechnologies are harnessed for the transport of drugs across the BBB, with or without surface modifications. We also discuss the transfer of drugs via the nose-to-brain pathway, as intranasal delivery enables direct drug distribution in the brain. In addition, nanomaterial modifications that prolong drug delivery and improve safety following intranasal administration are addressed. Conclusion: although several studies have yielded promising results, limited efforts have been undertaken to translate research findings into clinical contexts. Nevertheless, nanomaterials hold considerable potential for the development of novel effective therapeutic solutions against AD.

Association between the ROX index and mortality in patients with acute hypoxemic respiratory failure: a retrospective cohort study.

BACKGROUND: Although ROX index is frequently used to assess the efficacy of high-flow nasal cannula treatment in acute hypoxemic respiratory failure (AHRF) patients, the relationship between the ROX index and the mortality remains unclear. Therefore, a retrospective cohort study was conducted to evaluate the ability of the ROX index to predict mortality risk in patients with AHRF. METHOD: Patients diagnosed with AHRF were extracted from the MIMIC-IV database and divided into four groups based on the ROX index quartiles. The primary outcome was 28-day mortality, while in-hospital mortality and follow-up mortality were secondary outcomes. To investigate the association between ROX index and mortality in AHRF patients, restricted cubic spline curve and COX proportional risk regression were utilized. RESULT: A non-linear association (L-shaped) has been observed between the ROX index and mortality rate. When the ROX index is below 8.28, there is a notable decline in the 28-day mortality risk of patients as the ROX index increases (HR per SD, 0.858 [95%CI 0.794-0.928] P < 0.001). When the ROX index is above 8.28, no significant association was found between the ROX index and 28-day mortality. In contrast to the Q1 group, the mortality rates in the Q2, Q3, and Q4 groups had a substantial reduction (Q1 vs. Q2: HR, 0.749 [0.590-0.950] P = 0.017; Q3: HR, 0.711 [0.558-0.906] P = 0.006; Q4: HR, 0.641 [0.495-0.830] P < 0.001). CONCLUSION: The ROX index serves as a valuable predictor of mortality risk in adult patients with AHRF, and that a lower ROX index is substantially associated with an increase in mortality.

Allergic Rhinitis: A Review.

Importance: Allergic rhinitis affects an estimated 15% of the US population (approximately 50 million individuals) and is associated with the presence of asthma, eczema, chronic or recurrent sinusitis, cough, and both tension and migraine headaches. Observations: Allergic rhinitis occurs when disruption of the epithelial barrier allows allergens to penetrate the mucosal epithelium of nasal passages, inducing a T-helper type 2 inflammatory response and production of allergen-specific IgE. Allergic rhinitis typically presents with symptoms of nasal congestion, rhinorrhea, postnasal drainage, sneezing, and itching of the eyes, nose, and throat. In an international study, the most common symptoms of allergic rhinitis were rhinorrhea (90.38%) and nasal congestion (94.23%). Patients with nonallergic rhinitis present primarily with nasal congestion and postnasal drainage frequently associated with sinus pressure, ear plugging, muffled sounds and pain, and eustachian tube dysfunction that is less responsive to nasal corticosteroids. Patients with seasonal allergic rhinitis typically have physical examination findings of edematous and pale turbinates. Patients with perennial allergic rhinitis typically have erythematous and inflamed turbinates with serous secretions that appear similar to other forms of chronic rhinitis at physical examination. Patients with nonallergic rhinitis have negative test results for specific IgE aeroallergens. Intermittent allergic rhinitis is defined as symptoms occurring less than 4 consecutive days/week or less than 4 consecutive weeks/year. Persistent allergic rhinitis is defined as symptoms occurring more often than 4 consecutive days/week and for more than 4 consecutive weeks/year. Patients with allergic rhinitis should avoid inciting allergens. In addition, first-line treatment for mild intermittent or mild persistent allergic rhinitis may include a second-generation H1 antihistamine (eg, cetirizine, fexofenadine, desloratadine, loratadine) or an intranasal antihistamine (eg, azelastine, olopatadine), whereas patients with persistent moderate to severe allergic rhinitis should be treated initially with an intranasal corticosteroid (eg, fluticasone, triamcinolone, budesonide, mometasone) either alone or in combination with an intranasal antihistamine. In contrast, first-line therapy for patients with nonallergic rhinitis consists of an intranasal antihistamine as monotherapy or in combination with an intranasal corticosteroid. Conclusions and Relevance: Allergic rhinitis is associated with symptoms of nasal congestion, sneezing, and itching of the eyes, nose, and throat. Patients with allergic rhinitis should be instructed to avoid inciting allergens. Therapies include second-generation H1 antihistamines (eg, cetirizine, fexofenadine, desloratadine, loratadine), intranasal antihistamines (eg, azelastine, olopatadine), and intranasal corticosteroids (eg, fluticasone, triamcinolone, budesonide, mometasone) and should be selected based on the severity and frequency of symptoms and patient preference.

The Optimization Design of Macrophage Membrane Camouflaging Liposomes for Alleviating Ischemic Stroke Injury through Intranasal Delivery.

Ischemic stroke is associated with a high mortality rate, and effective treatment strategies are currently lacking. In this study, we aimed to develop a novel nano delivery system to treat ischemic stroke via intranasal administration. A three-factor Box-Behnken experimental design was used to optimize the formulation of liposomes co-loaded with Panax notoginseng saponins (PNSs) and Ginsenoside Rg3 (Rg3) (Lip-Rg3/PNS). Macrophage membranes were coated onto the surface of the optimized liposomes to target the ischemic site of the brain. The double-loaded liposomes disguised by macrophage membranes (MM-Lip-Rg3/PNS) were spherical, in a "shell-core" structure, with encapsulation rates of 81.41% (PNS) and 93.81% (Rg3), and showed good stability. In vitro, MM-Lip-Rg3/PNS was taken up by brain endothelial cells via the clathrin-dependent endocytosis and micropinocytosis pathways. Network pharmacology experiments predicted that MM-Lip-Rg3/PNS could regulate multiple signaling pathways and treat ischemic stroke by reducing apoptosis and inflammatory responses. After 14 days of treatment with MM-Lip-Rg3/PNS, the survival rate, weight, and neurological score of middle cerebral artery occlusion (MCAO) rats significantly improved. The hematoxylin and eosin (H&E) and TUNEL staining results showed that MM-Lip-Rg3/PNS can reduce neuronal apoptosis and inflammatory cell infiltration and protect the ischemic brain. In vivo biological experiments have shown that free Rg3, PNS, and MM-Lip-Rg3/PNS can alleviate inflammation and apoptosis, especially MM-Lip-Rg3/PNS, indicating that biomimetic liposomes can improve the therapeutic effects of drugs. Overall, MM-Lip-Rg3/PNS is a potential biomimetic nano targeted formulation for ischemic stroke therapy.

Intranasal Nose-to-Brain Drug Delivery via the Olfactory Region in Mice: Two In-Depth Protocols for Region-Specific Intranasal Application of Antibodies and for Expression Analysis of Fc Receptors via In Situ Hybridization in the Nasal Mucosa.

A region-specific catheter-based intranasal administration method was successfully developed, established, and validated as reported previously. By using this method, drugs can be applicated specifically to the olfactory region. Thereby, intranasally administered drugs could be delivered via neuronal connections to the central nervous system. Here, we present a detailed protocol with a step-by-step procedure for nose-to-brain delivery via the olfactory mucosa.Fc receptors such as the neonatal Fc receptor (FcRn) and potentially Fcγ receptor IIb (FcγRIIb) are involved in the uptake and transport of antibodies via the olfactory nasal mucosa. To better characterize their expression levels and their role in CNS drug delivery via the nose, an in situ hybridization (ISH) protocol was adapted for nasal mucosa samples and described in abundant details.

Combined sedation in pediatric magnetic resonance imaging: determination of median effective dose of intranasal dexmedetomidine combined with oral midazolam.

BACKGROUND: The exact median effective dose (ED50) of intranasal dexmedetomidine combined with oral midazolam sedation for magnetic resonance imaging (MRI) examination in children remains unknow and the aim of this study was to determine the ED50 of their combination. METHODS: This is a prospective dose-finding study. A total of 53 children aged from 2 months to 6 years scheduled for MRI examination from February 2023 to April 2023 were randomly divided into group D (to determine the ED50 of intranasal dexmedetomidine) and group M (to determine the ED50 of oral midazolam). The dosage of dexmedetomidine and midazolam was adjusted according to the modified Dixon's up-and-down method, and the ED50 was calculated with a probit regression approach. RESULTS: The ED50 of intranasal dexmedetomidine when combined with 0.5 mg∙kg- 1 oral midazolam was 0.39 µg∙kg- 1 [95% confidence interval (CI) 0.30 to 0.46 µg∙kg- 1] while the ED50 of oral midazolam was 0.17 mg∙kg- 1 (95% CI 0.01 to 0.29 mg∙kg- 1) when combined with 1 µg∙kg- 1 intranasal dexmedetomidine. The sedation onset time of children with successful sedation in group D was longer than in group M (30.0[25.0, 38.0]vs 19.5[15.0, 35.0] min, P < 0.05). No other adverse effects were observed in the day and 24 h after medication except one dysphoria. CONCLUSION: This drug combination sedation regimen appears suitable for children scheduled for MRI examinations, offering a more precise approach to guide the clinical use of sedative drugs in children. TRIAL REGISTRATION: Chinese Clinical Trial Registry, identifier: ChiCTR2300068611(24/02/2023).

All but Small: miRNAs from Wharton's Jelly-Mesenchymal Stromal Cell Small Extracellular Vesicles Rescue Premature White Matter Injury after Intranasal Administration.

White matter injury (WMI) is a common neurological issue in premature-born neonates, often causing long-term disabilities. We recently demonstrated a key beneficial role of Wharton's jelly mesenchymal stromal cell-derived small extracellular vesicles (WJ-MSC-sEVs) microRNAs (miRNAs) in WMI-related processes in vitro. Here, we studied the functions of WJ-MSC-sEV miRNAs in vivo using a preclinical rat model of premature WMI. Premature WMI was induced in rat pups through inflammation and hypoxia-ischemia. Small EVs were purified from the culture supernatant of human WJ-MSCs. The capacity of WJ-MSC-sEV-derived miRNAs to decrease microglia activation and promote oligodendrocyte maturation was evaluated by knocking down (k.d) DROSHA in WJ-MSCs, releasing sEVs containing significantly less mature miRNAs. Wharton's jelly MSC-sEVs intranasally administrated 24 h upon injury reached the brain within 1 h, remained detectable for at least 24 h, significantly reduced microglial activation, and promoted oligodendrocyte maturation. The DROSHA k.d in WJ-MSCs lowered the therapeutic capabilities of sEVs in experimental premature WMI. Our results strongly indicate the relevance of miRNAs in the therapeutic abilities of WJ-MSC-sEVs in premature WMI in vivo, opening the path to clinical application.

Oxytocin and social learning in socially anxious men and women.

OBJECTIVE: This study extended a classic self-referential learning paradigm by investigating the effects of intranasally-administered oxytocin in high and low socially anxious participants during social learning, as a function of social anxiety levels and sex. METHODS: In a randomized double-blinded design, 160 participants were either given intranasal oxytocin (24 I.U.) or placebo. Subsequently, while lying in an MR scanner, participants were shown neutral faces that were paired with positively, neutrally, or negatively valenced self-referential sentences, during which we measured self-reported arousal and sympathy of the facial stimuli, pupil dilation, and changes in the brain-oxygen-level dependent signal. Four-factor mixed analyses of variance with the between-subjects factors group (high socially anxious vs. low socially anxious), substance (oxytocin vs. placebo), and sex (male vs. female) and the within-subjects factor sentence valence (positive vs. neutral vs. negative) were conducted for each measure, respectively. RESULTS: Administration of intranasal oxytocin yielded an increase in sympathy ratings in high socially anxious compared to low socially anxious individuals and decreased arousal ratings for positively-conditioned faces in low socially anxious participants. As an objective physiological measure of arousal, pupil dilation mirrored the behavioral results. Oxytocin effects on neural activation in the insula interacted with anxiety levels and sex: low socially anxious individuals yielded lower activation under oxytocin than placebo; the converse was observed in high socially anxious individuals. This interaction also differed between sexes, as men yielded higher activation levels than women. These findings were more prominent for positively- and negatively-conditioned faces. Within the amygdala, high socially anxious men yielded higher activation than high socially anxious women in the left hemisphere, and low socially anxious men yielded higher activation than low socially anxious women from positively- and negatively-conditioned faces, though no influence of oxytocin was detected. CONCLUSION: These results suggest oxytocin-induced behavioral, physiological, and neural changes as a function of social learning in socially low and high anxious individuals. These findings challenge the amygdalocentric view of the role of emotions in social learning, instead contributing to the growing body of findings implicating the insula therein, revealing an interaction between oxytocin, sex, and emotional valence. Such discoveries raise an interesting set of questions regarding the computational goals of regions such as the insula in emotional learning and how neural activity can play a diagnostic or prognostic role in social anxiety, potentially leading to new treatment opportunities that may combine oxytocin and neurofeedback differentially for men and women.