Intranasal Treatment Research Articles

Intranasal Carnosine Mitigates α-Synuclein Pathology and Motor Dysfunction in the Thy1-aSyn Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is a debilitating neurodegenerative disorder. Early symptoms include motor dysfunction and impaired olfaction. Toxic aggregation of α-synuclein (aSyn) in the olfactory bulb (OB) and substantia nigra pars compacta (SNpc) is a hallmark of PD neuropathology. Intranasal (IN) carnosine (2 mg/d for 8 weeks) was previously demonstrated to improve motor behavior and mitochondrial function in Thy1-aSyn mice, a model of PD. The present studies evaluated the efficacy of IN carnosine at a higher dose in slowing progression of motor deficits and aSyn accumulation in Thy1-aSyn mice. After baseline neurobehavioral assessments, IN carnosine was administered (0.0, 2.0, or 4.0 mg/day) to wild-type and Thy1-aSyn mice for 8 weeks. Olfactory and motor behavioral measurements were repeated prior to end point tissue collection. Brain sections were immunostained for aSyn and tyrosine hydroxylase (TH). Immunopositive cells were counted using design-based stereology in the SNpc and OB mitral cell layer (MCL). Behavioral assessments revealed a dose-dependent improvement in motor function with increasing carnosine dose. Thy1-aSyn mice treated with 2.0 or 4.0 mg/d IN carnosine exhibited fewer aSyn-positive (aSyn(+)) cell bodies in the SNpc compared to vehicle-treated mice. Moreover, the number of aSyn(+) cell bodies in carnosine-treated Thy1-aSyn mice was reduced to vehicle-treated wild-type levels in the SNpc. Carnosine treatment did not affect the number of aSyn(+) cell bodies in the OB-MCL or the number of TH(+) cells in the SNpc. In summary, intranasal carnosine treatment decreased aSyn accumulation in the SNpc, which may underlie its mitigation of motor deficits in the Thy1-aSyn mice.

Intranasal insulin ameliorates neurological impairment after intracerebral hemorrhage in mice.

In Alzheimer's disease and ischemic stroke, intranasal insulin can act as a neuroprotective agent. However, whether intranasal insulin has a neuroprotective effect in intracerebral hemorrhage and its potential mechanisms remain poorly understood. In this study, a mouse model of autologous blood-induced intracerebral hemorrhage was treated with 0.5, 1, or 2 IU insulin via intranasal delivery, twice per day, until 24 or 72 hours after surgery. Compared with saline treatment, 1 IU intranasal insulin treatment significantly reduced hematoma volume and brain edema after cerebral hemorrhage, decreased blood-brain barrier permeability and neuronal degeneration damage, reduced neurobehavioral deficits, and improved the survival rate of mice. Expression levels of p-AKT and p-GSK3β were significantly increased in the perihematoma tissues after intranasal insulin therapy. Our findings suggest that intranasal insulin therapy can protect the neurological function of mice after intracerebral hemorrhage through the AKT/GSK3β signaling pathway. The study was approved by the Ethics Committee of the North Sichuan Medical College of China (approval No. NSMC(A)2019(01)) on January 7, 2019.

Astragalus membranaceus polysaccharides potentiate the growth-inhibitory activity of immune checkpoint inhibitors against pulmonary metastatic melanoma in mice

Astragalus membranaceus (A. membranaceus) is commonly used in various herbal formulations to treat several human and animal diseases. Polysaccharides, which are the major bioactive components in the A. membranaceus, exhibit various bioactive properties. However, the ability of A. membranaceus polysaccharides (APS) to activate the mucosal immune response has not been examined. We examined the effect of intranasal administration of APS on mucosal immune cell activation and the growth-inhibitory activity against pulmonary metastatic melanoma in mice by combination treatment with immune checkpoint blockade. The intranasal treatment of APS increased the number of lineage−CD11c+ dendritic cell (DCs) in the mesenteric lymph nodes (mLN) through the upregulation of CC-chemokine receptor 7 expression. Moreover, intranasal treatment of APS activated DCs, which further stimulated natural killer (NK) and T cells in the mLN. The APS/anti-PD-L1 antibody combination inhibited the pulmonary infiltration of B16 melanoma cells. The depletion of NK cells and CD8 T cells in mice mitigated the anti-cancer effect of this combination, thereby highlighting the critical role of NK cells and CD8 T cells in mediating anti-cancer immunity. These findings demonstrated that APS could be used as a topical mucosal adjuvant to enhance the immune check point inhibitor anti-cancer effect.

Effect of intranasal corticosteroid treatment on allergen-induced changes in group 2 innate lymphoid cells in allergic rhinitis with mild asthma.

Allergic rhinitis is characterized by rhinorrhea, nasal congestion, sneezing and nasal pruritus. Group 2 innate lymphoid cells (ILC2s), CD4+ T cells and eosinophils in nasal mucosa are increased significantly after nasal allergen challenge (NAC). Effects of intranasal corticosteroids (INCS) on ILC2s remain to be investigated. Subjects (n=10) with allergic rhinitis and mild asthma were enrolled in a single-blind, placebo-controlled, sequential treatment study and treated twice daily with intranasal triamcinolone acetonide (220µg) or placebo for 14days, separated by a 7-day washout period. Following treatment, subjects underwent NAC and upper airway function was assessed. Cells from the nasal mucosa and blood, sampled 24h post-NAC, underwent flow cytometric enumeration for ILC2s, CD4+ T and eosinophil progenitor (EoPs) levels. Cell differentials and cytokine levels were assessed in nasal lavage. Treatment with INCS significantly attenuated ILC2s, IL-5+ /IL-13+ ILC2s, HLA-DR+ ILC2s and CD4+ T cells in the nasal mucosa, 24h post-NAC. EoP in nasal mucosa was significantly increased, while mature eosinophils were significantly decreased, 24h post-NAC in INCS versus placebo treatment arm. Following INCS treatment, IL-2, IL-4, IL-5 and IL-13 were significantly attenuated 24h post-NAC accompanied by significant improvement in upper airway function. Pre-treatment with INCS attenuates allergen-induced increases in ILC2s, CD4+ T cells and terminal differentiation of EoPs in the nasal mucosa of allergic rhinitis patients with mild asthma, with little systemic effect. Attenuation of HLA-DR expression by ILC2s may be an additional mechanism by which steroids modulate adaptive immune responses in the upper airways.

Intranasal adjuvant immunotherapy increases survival in murine metastatic Lymphangioleiomyomatosis (LAM)

Abstract Pulmonary lymphangioleiomyomatosis (LAM) is a slow progressing, metastasizing neoplasm primarily affecting women of reproductive age. LAM is characterized by the abnormal growth of smooth muscle-like cells leading to cystic destruction of the lungs. Rapamycin, the only FDA approved treatment for LAM, slows disease progression but patient responses are incomplete. Therefore there is a critical need for new LAM treatments. Research has shown that LAM has several characteristics of cancer including suspected immune suppression. We and others recently found that LAM may be treated using immune checkpoint inhibitors (ICI), a common cancer immunotherapy. Here, we investigate immune-activating adjuvants as local anti-LAM immunotherapies. Using an established murine model of metastatic LAM, we determined survival after twice weekly intranasal treatments of CpG, PolyI:C, or MPLA. We used flow cytometry and immunofluorescence to determine how adjuvants alter the immune response in LAM. We found that intranasal treatment with CpG and PolyI:C, but not MPLA, increased survival in mice with LAM. In more progressive LAM disease, we observed an increase in activated CD8 T cells, and a decrease in B cell, macrophage, and eosinophil infiltration in lungs of CpG treated vs untreated LAM mice. We also observed increased expression of MHC-II on alveolar macrophages but decreased numbers of migratory dendritic cells in CpG treated LAM lungs. These results suggest that CpG immunotherapy in LAM lungs activates cytotoxic lymphocytes while tempering other inflammatory cells like eosinophils. Our findings also suggest that LAM lungs may respond favorably to adjuvant immunotherapy, and that combination ICI-adjuvant therapy could be synergistic.

Synergy of oxytocin and citalopram in modulating Itgb3/Chl1 interplay: Relevance to sensitivity to SSRI therapy

Intranasal treatment with oxytocin showed beneficial effects in post-traumatic stress disorder and autism spectrum disorders; however, it was not investigated as much in depression. Keeping in mind the favorable effects of oxytocin on animal models of anxiety and depression, we postulated that synergy between prescribed first choice drugs, selective serotonin reuptake inhibitors (SSRIs) and oxytocin could improve the treatment outcome compared with SSRI monotherapy. Our previous in vitro genome-wide transcriptomic study on human lymphoblastoid cell lines exposed to paroxetine resulted in increase of integrin β3 (ITGB3) gene expression, and further, ITGB3/CHL1 expression ratio was hypothesized to influence the sensitivity to SSRIs. The aim of this report was to explore molecular mechanisms behind the antidepressant-like oxytocin effect, alone and in synergy with citalopram, on behavioral and molecular level in corticosterone treated rats, a paradigm used to model anxiety and depression in animals. Oxytocin treatment (1) ameliorated corticosterone-induced reduction of neurogenesis and number of parvalbumin-positive interneurons in the hippocampal CA1 region, (2) enhanced anxiolytic- and antidepressant-like effects of citalopram in the open field test, and (3) the SSRI/oxytocin synergy persisted in reversing the reduction of the Itgb3 gene expression and increased Itgb3/Chl1 ratio in the prefrontal cortices. These results support the existence of synergy between citalopram and oxytocin in reversing the molecular and behavioral changes induced by corticosterone treatment and point to possible molecular mechanisms behind antidepressant-like effect of oxytocin.

A comparison of administration of oral chloral hydrate with intranasal dexmedetomidine in sedation of children to perform electroencephalography

Background: Electroencephalography is a record of the electrical activity of the brain that is used to diagnose brain dysfunction and to determine the location of brain injury and to determine seizure activity. There is. The sedative medication used should not only have an effect on the brain’s electrical activity, but it also calms the baby. Since there have been no studies to compare the effects of intranasal oral hydrate and dexmedetomidine on sedation in children for electroencephalography, this study aimed to compare the effects of intranasal intravenous dexmedetomidine with intramuscular dexmedetomidine on electroencephalography in children. Methods: This clinical trial study was performed on 62 children candidates for electroencephalography in Imam Hossein Pediatric Hospital in Isfahan. Age, weight, and clinical data including sedation score, mean arterial pressure, respiratory rate, arterial oxygen saturation, and heart rate at pre-medication times, 15, 30, 45, and 60 minutes after drug administration. And analyzed. Results: The mean age of the children candidates for electroencephalography was 16.90 ± 1.32, out of which 35 (56.5%) were male. The results showed no significant difference between the two groups in terms of sedation, mean arterial pressure, respiratory rate, and percentage of arterial oxygen saturation (p> 0.05). But the difference between the two groups was statistically significant for the variable heart rate. Heart rate was significantly lower in group B (dexmedetomidine group) than in group A (oral chlorate hydrate group) (p-value = 0.032), and time as an influencing factor in changing mean sedimentation, mean arterial pressure, respiratory rate, and heart rate (p-value <0.05). But there was no significant effect on the change in arterial oxygen saturation percentage (p = 0.478). Conclusion: Chloral hydrate administration was more effective than intranasal dexmedetomidine treatment in maintaining heart rate but overall the results showed no significant difference between the two groups in terms of clinical data and child sedation score in the two groups. Was.

Comparison of Intranasal Steroid Application Using Nasal Saline Irrigation and a Mucosal Atomization Device to Treat Chronic Rhinosinusitis.

Introduction: Chronic rhinosinusitis (CRS) is a disease that can significantly reduce patients' quality of life (QoL). Intranasal steroid therapy is the most commonly used treatment for CRS. There are many evaluation tools dedicated to assessing CRS patients' QoL, but none of them evaluates QoL during local steroid therapy. Mucosal atomization devices (MADs) and nasal saline irrigation (NSI) are effective and safe methods of applying intranasal steroids for CRS patients. Materials and Methods: The sample population for this prospective study comprised 43 CRS patients. Following endoscopic sinus surgery, all participants received intranasal steroids administered via an MAD, followed by NSI for 1.5 months. Each participant completed the SNOT-22 (22-item Sino-Nasal Outcomes Test) score and a new questionnaire, the Complementary Topical Nasal Drug Delivery Questionnaire (the Complementary Questionnaire), at the end of 3 months of intranasal steroid therapy. Results: The patients' responses in both the SNOT-22 score and the Complementary Questionnaire revealed significant differences in their adverse experiences. The patients who received intranasal steroid treatment using NSI experienced more frequently delayed nasal drainage, higher frequency of ear symptoms, and facial pain/pressure, while those whose therapy was administered using an MAD reported complaints such as nasal irritation, nasal dryness, and postnasal drip with unpleasant taste/smell. Conclusion: We used the Complementary Questionnaire as an effective tool for assessment of the QoL of CRS patients. The SNOT-22 score and the Complementary Questionnaire make it possible to select an intranasal applicator tailored to a CRS patient's specific complaints.

Allergic rhinitis as a comorbid disease with Covid-19 infection

Allergic rhinitis (AR) is the most common disease (28.3%) among allergic pathology. Coronavirus disease 2019 (Covid-19) is characterized by a variety of clinical conditions ranging from mild symptoms to severe pneumonia and death. Nasal and ocular manifestations are included in the number of possible manifestations of Covid-19, therefore differential diagnosis of AR and coronavirus infection is important. The penetration of the Sars-CoV-2 virus occurs through the nasal and oral mucosa; scientists have paid close attention to the local immunity of these mucous membranes. Respiratory allergies have not been reported as risk factors for SARS- CoV-2 infection. Intranasal corticosteroids have a dose- dependent suppression of the expression of both ACE2 and the transmembrane protease, serine 2. Respiratory allergy (AR, asthma) and controlled exposure to allergens are associated with a significant decrease in ACE2 expression. Patients with Covid-19 infection need to continue intranasal corticosteroid treatment at the recommended dose for AR, as more frequent sneezing after cessation means more spread of SARS-CoV-2 infection. The importance of adhering to inhaled and intranasal corticosteroid therapy, which will achieve optimal control of upper and lower respiratory tract diseases, and may also provide protection against viral triggers, including SARS-CoV-2. Allergic rhinitis is not a contraindication for Covid-19 vaccination.

Preclinical Safety Evaluation of Intranasally Delivered Human Mesenchymal Stem Cells in Juvenile Mice.

Simple SummaryThe concept of utilizing mesenchymal stem cells for the treatment of central nervous system disorders has progressed from preclinical studies to clinical trials. While promising, the effectiveness of cell therapy is hampered by the route used to deliver cells into the brain. In this context, intranasal cell administration has boomed over the past few years as an effective cell delivery method. However, comprehensive safety studies are required before translation to the clinic. Our study shed light on how intranasally administrated mesenchymal stem cells may be used to safely treat neurological disorders.Mesenchymal stem cell (MSC)-based therapy is a promising therapeutic approach in the management of several pathologies, including central nervous system diseases. Previously, we demonstrated the therapeutic potential of human adipose-derived MSCs for neurological sequelae of oncological radiotherapy using the intranasal route as a non-invasive delivery method. However, a comprehensive investigation of the safety of intranasal MSC treatment should be performed before clinical applications. Here, we cultured human MSCs in compliance with quality control standards and administrated repeated doses of cells into the nostrils of juvenile immunodeficient mice, mimicking the design of a subsequent clinical trial. Short- and long-term effects of cell administration were evaluated by in vivo and ex vivo studies. No serious adverse events were reported on mouse welfare, behavioral performances, and blood plasma analysis. Magnetic resonance study and histological analysis did not reveal tumor formation or other abnormalities in the examined organs of mice receiving MSCs. Biodistribution study reveals a progressive disappearance of transplanted cells that was further supported by an absent expression of human GAPDH gene in the major organs of transplanted mice. Our data indicate that the intranasal application of MSCs is a safe, simple and non-invasive strategy and encourage its use in future clinical trials.

The impact of influenza pulmonary infection and inflammation on vagal bronchopulmonary sensory neurons.

Influenza A virus (IAV) is rapidly detected in the airways by the immune system, with resident parenchymal cells and leukocytes orchestrating viral sensing and the induction of antiviral inflammatory responses. The airways are innervated by heterogeneous populations of vagal sensory neurons which also play an important role in pulmonary defense. How these neurons respond to IAV respiratory infection remains unclear. Here, we use a murine model to provide the first evidence that vagal sensory neurons undergo significant transcriptional changes following a respiratory IAV infection. RNA sequencing on vagal sensory ganglia showed that IAV infection induced the expression of many genes associated with an antiviral and pro-inflammatory response and this was accompanied by a significant increase in inflammatory cell recruitment into the vagal ganglia. Assessment of gene expression in single-vagal sensory neurons confirmed that IAV infection induced a neuronal inflammatory phenotype, which was most prominent in bronchopulmonary neurons, and also evident in some neurons innervating other organs. The altered transcriptome could be mimicked by intranasal treatment with cytokines and the lung homogenates of infected mice, in the absence of infectious virus. These data argue that IAV pulmonary infection and subsequent inflammation induces vagal sensory ganglia neuroinflammation and this may have important implications for IAV-induced morbidity.

Evaluation of the intranasal steroid treatment outcomes in adenoid tissue hypertrophy with or without allergic rhinitis

PurposeTo compare the intranasal steroid (INS) treatment outcomes in patients with adenoid tissue hypertrophy (ATH) with or without allergic rhinitis (AR). Materials and methodsMedical records of 96 children diagnosed with ATH were retrospectively examined. The pediatric version of the Score for Allergic Rhinitis (SFAR) questionnaire was used to determine the AR status of the patients and classify them. The children were divided into two groups based on the questionnaire: Group 1, low probability of AR (SFAR<9); and Group 2, high probability of AR (SFAR≥9). Intranasal mometasone furoate (100 μg/mL) was used to treat ATH for at least 3 months. The severity of nasal obstruction and snoring was evaluated using the visual analog scale (VAS) score, the adenoid/choana (A/C) ratios before and after treatment were compared, and the rate of patient referral to surgery was recorded among groups. ResultsThe change in the A/C ratio within the group between before and after treatment was significant (both P < 0.001). However, the reduction in the adenoid size was more significant in Group 1 than in Group 2 (P = 0.025). A significant improvement in the VAS scores was observed between before and after treatment in both groups (P < 0.001). Furthermore, the rate of surgical referral of Group 1 was significantly lower than that of Group 2 (P = 0.035). ConclusionsINS treatment was found more successful for reducing A/C ratio in ATH without AR. Related with this, when considering the INS treatment for ATH, AR status should be kept in mind for predicting the treatment success.

Open, prospective, multicenter study on postoperative intranasal phototherapy in nasal polyposis.

The therapeutic effect of ultraviolet (UV) light is generally attributed to its immunosuppressive and immunomodulatory effects. Since chronic inflammation is the major factor in the development of nasal polyposis, we have previously used mixed ultraviolet-visible light (mUV-VIS, Rhinolight®) phototherapy for the treatment of nasal polyps. In the present open, multicenter study, our aim was to delineate whether mUV-VIS applied postoperatively in vivo together with intranasal steroid treatment could reduce the recurrence of nasal polyps. After functional endoscopic sinus surgery, one group of patients received mUV-VIS light together with standard intranasal steroid (mometason furoate 2×200 μg) application for a 12-week treatment period, whereas the other patient group obtained only intranasal steroid for the same duration. We recorded nasal endoscopy images and obtained demographical and clinical data, total nasal score (TNS), and nasal obstruction symptom evaluation (NOSE). We performed acoustic rhinometry and measured nasal inspiratory peak flow. Follow-up was 12months. We found that the recurrence of nasal polyps was significantly diminished, and based on video-endoscopic measurements, the size and grade of recurrent polyps were significantly smaller in the phototherapy-receiving group. Nasal obstruction values and NOSE were significantly better throughout the follow-up period in the mUV-VIS light-treated group than in the intranasal steroid monotreatment group. Rhinophototherapy together with standard nasal steroid application may have a supportive role in the treatment of recurrent bilateral nasal polyps.

ACE-2-interacting Domain of SARS-CoV-2 (AIDS) Peptide Suppresses Inflammation to Reduce Fever and Protect Lungs and Heart in Mice: Implications for COVID-19 Therapy

COVID-19 is an infectious respiratory illness caused by the virus strain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and until now, there is no effective therapy against COVID-19. Since SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) for entering into host cells, to target COVID-19 from therapeutic angle, we engineered a hexapeptide corresponding to the ACE2-interacting domain of SARS-CoV-2 (AIDS) that inhibits the association between receptor-binding domain-containing spike S1 and ACE-2. Accordingly, wild type (wt), but not mutated (m), AIDS peptide inhibited SARS-CoV-2 spike S1-induced activation of NF-κB and expression of IL-6 in human lungs cells. Interestingly, intranasal intoxication of C57/BL6 mice with recombinant SARS-CoV-2 spike S1 led to fever, increase in IL-6 in lungs, infiltration of neutrophils into the lungs, arrhythmias, and impairment in locomotor activities, mimicking some of the important symptoms of COVID-19. However, intranasal treatment with wtAIDS, but not mAIDS, peptide reduced fever, protected lungs, improved heart function, and enhanced locomotor activities in SARS-CoV-2 spike S1-intoxicated mice. Therefore, selective targeting of ACE2-to-SARS-CoV-2 interaction by wtAIDS may be beneficial for COVID-19.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1007/s11481-020-09979-8.

Intranasal treatment of lixisenatide attenuated emotional and olfactory symptoms via CREB-mediated adult neurogenesis in mouse depression model.

Convergent lines of evidence indicate a striking correlation between olfactory deficits and depressive symptoms. However, the effectiveness of intranasal treatment of antidepressant or other neurotrophic agents remains poorly understanding. Here in this study, we created depression mouse model and explored the antidepressant effects of GLP-1 analog lixisenatide (LXT) with intranasal treatment. Consecutive intranasal treatment of LXT remarkably reduced the depressive and anxiety behaviors. Meanwhile, it also improved the olfactory memory and olfactory sensitivity. Immunofluorescent analysis demonstrated the LXT improved the adult neurogenesis in olfactory system and hippocampus. Inhibition of adult neurogenesis with TMZ caused the compromised effects of LXT in improving emotional and olfactory functions, suggesting the vital role of adult neurogenesis in LXT induced depression therapeutic effects. Treatment of LXT resulted in the increased phosphorylation of CREB protein in hippocampal tissue, indicating CREB plays important roles in antidepressant effects of LXT intranasal treatment. Inhibiting CREB with chemical approach decreased effects of LXT in reserving depression induced emotional and olfactory functions. In conclusion, our study suggests intranasal treatment of LXT could be a potential antidepressant to improve the olfactory functions as well as the emotional behaviors.

The preclinical inhibitor GS441524 in combination with GC376 efficaciously inhibited the proliferation of SARS-CoV-2 in the mouse respiratory tract

ABSTRACT The unprecedented coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a serious threat to global public health. Development of effective therapies against SARS-CoV-2 is urgently needed. Here, we evaluated the antiviral activity of a remdesivir parent nucleotide analog, GS441524, which targets the coronavirus RNA-dependent RNA polymerase enzyme, and a feline coronavirus prodrug, GC376, which targets its main protease, using a mouse-adapted SARS-CoV-2 infected mouse model. Our results showed that GS441524 effectively blocked the proliferation of SARS-CoV-2 in the mouse upper and lower respiratory tracts via combined intranasal (i.n.) and intramuscular (i.m.) treatment. However, the ability of high-dose GC376 (i.m. or i.n. and i.m.) was weaker than GS441524. Notably, low-dose combined application of GS441524 with GC376 could effectively protect mice against SARS-CoV-2 infection via i.n. or i.n. and i.m. treatment. Moreover, we found that the pharmacokinetic properties of GS441524 is better than GC376, and combined application of GC376 and GS441524 had a synergistic effect. Our findings support the further evaluation of the combined application of GC376 and GS441524 in future clinical studies.

Oxytocin alters leukogram composition in

Context Transportation, a common practice in cattle production, activates the hypothalamo-pituitary-adrenal (HPA) axis, ultimately increasing glucocorticoids and altering the cellular immune system in cattle. Oxytocin attenuates the HPA axis in mammals. Intra-nasal oxytocin supplementation has been investigated in human and rodent models, revealing anxiolytic effects. The aim of this study was to assess the ability of exogenous oxytocin to mitigate stress and inflammatory responses in transported cattle. Aims We hypothesised that Bos indicus cattle treated with intra-nasal oxytocin would demonstrate more stable cortisol and inflammatory responses when subjected to handling and 6 h of road transportation compared with cattle treated with intra-nasal saline. Methods Thirty, Bos indicus steers were allocated to one of three treatments: (1) intra-nasal sterile saline and held in the yard for 6 h (S-NT; n = 10), (2) intra-nasal sterile saline and transported for 6 h (S-T; n = 10), and (3) intra-nasal oxytocin (0.3 IU/kg bodyweight) and transported for 6 h (OXT-T; n = 10). Blood was collected at 0, 6, 48, and 72 h and analysed for haematological parameters, cortisol, glucose and lactate. Key results A treatment × time effect (P &lt; 0.05) was detected for lymphocytes and basophils, such that oxytocin helped maintain baseline counts. A treatment × time effect was detected for neutrophils and eosinophils such that counts were greater and lesser, respectively, directly following transport (P &lt; 0.01) for transported treatments. Total leukocyte counts were not different between treatments (P = 0.96). No differences were observed between treatments or over time for plasma cortisol concentration (P = 0.46). A treatment × time interaction (P &lt; 0.03) was detected for bodyweight such that transportation, independent of intra-nasal treatment, resulted in increased weight loss compared with the non-transported treatment. Conclusion Oxytocin altered circulating basophils in Bos indicus cattle exposed to short-duration transport. Although no effect on the HPA axis was detected via changes in cortisol concentration, road transport induced some signs of an acute inflammatory response directly following transportation. Implications Providing exogenous oxytocin improved the maintenance and recovery of some cellular immune system parameters in Bos indicus steers subject to short duration transport and more research is needed to explicate a more comprehensive understanding of such effects.

Oxytocin in young children with Prader-Willi syndrome: Results of a randomized, double-blind, placebo-controlled, crossover trial investigating 3 months of oxytocin.

ContextPrader‐Willi syndrome (PWS) is characterized by hypothalamic dysfunction, hyperphagia and a typical behavioural phenotype, with characteristics of autism spectrum disorder (ASD) like stubbornness, temper tantrums and compulsivity. It has been suggested that the oxytocin system in patients with PWS is dysfunctional. In ASD, intranasal oxytocin treatment has favourable effects on behaviour.ObjectiveTo evaluate the effects of 3 months of twice daily intranasal oxytocin (dose range 16‐40 IU/day), compared to placebo, on behaviour and hyperphagia in children with PWS.DesignRandomized, double‐blind, placebo‐controlled, crossover study in the Dutch PWS Reference Center.PatientsTwenty‐six children with PWS aged 3‐11 years.Main outcome measures(Change in) behaviour and hyperphagia measured by Oxytocin Questionnaire and Dykens hyperphagia questionnaire.ResultsIn the total group, no significant effects of oxytocin on social behaviour or hyperphagia were found. However, in boys, the Oxytocin Questionnaire scores improved significantly during oxytocin treatment, compared to a deterioration during placebo (4.5 (−0.8 to 15.3) vs. −4.0 (−11.3 to 0.8), P = .025). The Dykens hyperphagia questionnaire scores remained similar during oxytocin treatment, while there was a deterioration during placebo (0.0 (−0.8 to 4.3) vs. −3.5 (−6.0 to 0.0), P = .046). Patients with a deletion had significant improvements in both questionnaire scores during oxytocin treatment, but deteriorations during placebo. Oxytocin treatment was well tolerated, and there were no serious adverse events.ConclusionsIntranasal oxytocin treatment has positive effects on social and eating behaviour in 3‐11 years aged boys with PWS and in children with a deletion without safety concerns. Intranasal oxytocin in children with PWS might be considered, but individual effects should be carefully evaluated and treatment discontinued if no effects are found.

Changes in endogenous oxytocin levels after intranasal oxytocin treatment in adult men with autism: An exploratory study with long-term follow-up

Intranasal administration of the neuropeptide oxytocin (OT) is increasingly explored as a potential treatment for targeting the core symptoms of autism spectrum disorder (ASD). Previously, interactions of exogenously administered OT with its endogenous production have been demonstrated following single-dose administrations. However, the impact of repeated, long-term OT use on endogenous salivary OT levels is unknown. In this double-blind, randomized, placebo-controlled study with between-subject design, 34 adult men with ASD were either assigned to a four-week treatment of once-daily intranasal OT administrations (24 IU) or placebo. Salivary OT samples were obtained before and after the treatment period as well as at two follow-up sessions, four weeks and one year after cessation of the treatment. Receiving OT intranasally but not placebo reliably increased endogenous salivary levels of OT immediately post-treatment and at the follow-up session four weeks post treatment, indicating an interaction between exogenously administered OT and its endogenous production. Notably, increases in salivary OT at the four-week follow-up session were most pronounced in individuals with larger behavioral improvements in ASD social symptoms. These results suggest that OT's positive effects on social behaviors may lead to a self-perpetuating elevation of OT levels through a feed-forward triggering of its own release. Together, the current investigation provides initial evidence that repeated intranasal administration of OT can induce long-lasting changes in endogenous salivary OT levels, presumably through a positive spiral of OT release.

Involvement of Bradykinin Receptor 2 in Nerve Growth Factor Neuroprotective Activity.

Neurotrophin nerve growth factor (NGF) has been demonstrated to upregulate the gene expression of bradykinin receptor 2 (B2R) on sensory neurons, thus facilitating nociceptive signals. The aim of the present study is to investigate the involvement of B2R in the NGF mechanism of action in nonsensory neurons in vitro by using rat mixed cortical primary cultures (CNs) and mouse hippocampal slices, and in vivo in Alzheimer’s disease (AD) transgenic mice (5xFAD) chronically treated with NGF. A significant NGF-mediated upregulation of B2R was demonstrated by microarray, Western blot, and immunofluorescence analysis in CNs, indicating microglial cells as the target of this modulation. The B2R involvement in the NGF mechanism of action was also demonstrated by using a selective B2R antagonist which was able to reverse the neuroprotective effect of NGF in CNs, as revealed by viability assay, and the NGF-induced long-term potentiation (LTP) in hippocampal slices. To confirm in vitro observations, B2R upregulation was observed in 5xFAD mouse brain following chronic intranasal NGF treatment. This study demonstrates for the first time that B2R is a key element in the neuroprotective activity and synaptic plasticity mediated by NGF in brain cells.