Nanotechnological Advances for Nose to Brain Delivery of Therapeutics to Improve the Parkinson Therapy.

Blood-Brain Barrier (BBB) acts as a highly impermeable barrier, presenting an impediment to the crossing of most classical drugs targeted for neurodegenerative diseases including Parkinson's disease (PD). About the nature of drugs and other potential molecules, they impose unavoidable doserestricted limitations eventually leading to the failure of therapy. However, many advancements in formulation technology and modification of delivery approaches have been successful in delivering the drug to the brain in the therapeutic window. The nose to the brain (N2B) drug delivery employing the nanoformulation, is one such emerging delivery approach, overcoming both classical drug formulation and delivery-associated limitations. This latter approach offers increased bioavailability, greater patient acceptance, lesser metabolic degradation of drugs, circumvention of BBB, ample drug loading along with the controlled release of the drugs. In N2B delivery, the intranasal (IN) route carries therapeutics firstly into the nasal cavity followed by the brain through olfactory and trigeminal nerve connections linked with nasal mucosa. The N2B delivery approach is being explored for delivering other biologicals like neuropeptides and mitochondria. Meanwhile, this N2B delivery system is associated with critical challenges consisting of mucociliary clearance, degradation by enzymes, and drug translocations by efflux mechanisms. These challenges finally culminated in the development of suitable surfacemodified nano-carriers and Focused- Ultrasound-Assisted IN as FUS-IN technique which has expanded the horizons of N2B drug delivery. Hence, nanotechnology, in collaboration with advances in the IN route of drug administration, has a diversified approach for treating PD. The present review discusses the physiology and limitation of IN delivery along with current advances in nanocarrier and technical development assisting N2B drug delivery.

Morphology of GNAT3-immunoreactive chemosensory cells in the nasal cavity and pharynx of the rat.

Solitary chemosensory cells and chemosensory cell clusters are distributed in the pharynx and larynx. In the present study, the morphology and reflexogenic function of solitary chemosensory cells and chemosensory cell clusters in the nasal cavity and pharynx were examined using immunofluorescence for GNAT3 and electrophysiology. In the nasal cavity, GNAT3-immunoreactive solitary chemosensory cells were widely distributed in the nasal mucosa, particularly in the cranial region near the nostrils. Solitary chemosensory cells were also observed in the nasopharynx. Solitary chemosensory cells in the nasopharyngeal cavity were barrel like or slender in shape with long lateral processes within the epithelial layer to attach surrounding ciliated epithelial cells. Chemosensory cell clusters containing GNAT3-immunoreactive cells were also detected in the pharynx. GNAT3-immunoreactive cells gathered with SNAP25-immunoreactive cells in chemosensory clusters. GNAT3-immunoreactive chemosensory cells were in close contact with a few SP- or CGRP-immunoreactive nerve endings. In the pharynx, GNAT3-immunoreactive chemosensory cells were also attached to P2X3-immunoreactive nerve endings. Physiologically, the perfusion of 10 mM quinine hydrochloride (QHCl) solution induced ventilatory depression. The QHCl-induced reflex was diminished by bilateral section of the glossopharyngeal nerve, suggesting autonomic reflex were evoked by chemosensory cells in pharynx but not in nasal mucosa. The present results indicate that complex shape of nasopharyngeal solitary chemosensory cells may contribute to intercellular communication, and pharyngeal chemosensory cells may play a role in respiratory depression.

Cryosurgical Ablation for Treatment of Rhinitis: Two-Year Results of a Prospective Multicenter Study.

OBJECTIVES/HYPOTHESIS: To assess the long-term (12-24 months) safety and effectiveness of cryoablation of the posterior nasal nerve as treatment for chronic rhinitis. STUDY DESIGN: A multicenter, prospective, single-arm clinical study. METHODS: The study was conducted from February 2017 to April 2020. Study endpoints included change from baseline in the reflective Total Nasal Symptom Score (rTNSS), Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), physician assessment of improvement using the Clinical Global Impression-Improvement (CGI-I), and the incidence of treatment-related adverse events. RESULTS: Ninety-one participants completed the study through the initial 12-month study period. Sixty-two participants consented to the long-term follow-up with 57 completing the 24-month follow-up. Significant improvements in the total rTNSS were reflected in a median change from baseline of -3.0 or -4.0 at all timepoints (P < .001). Greater than 80.0% of participants achieved the minimum clinically important difference (MCID) of improvement by ≥1 point on the rTNSS at all follow-ups. Total RQLQ scores indicated significant improvement (P < .0001) in quality of life. Over 77% of participants achieved the MCID (≥0.5 points) for the total RQLQ score. According to the CGI-I, ≥83.0% experienced improvement at all but the 12-month visit (61.9%). One participant experienced two treatment-related serious adverse events (epistaxis and retained pledget). A total of 29 nonserious treatment-related AEs were reported in 23 participants; most events were transient and resolved with little to no intervention. CONCLUSIONS: Cryotherapy significantly and clinically improves rhinitis symptoms and quality of life with outcomes that are durable through 24 months after treatment. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1952-1957, 2021.

Effect of posterior nasal neurectomy on the suppression of allergic rhinitis.

OBJECTIVES: Recent guidelines have revealed that allergic rhinitis (AR) impairs quality of life. Neuropeptides play a central role in AR. The aim of this study was to determine the efficacy of posterior nasal neurectomy (PNN) for the treatment of AR and for the suppression of neuropeptides and type 2 cytokine expression. METHODS: In total, 77 patients undergoing PNN were recruited. Subjective symptoms, including sneezing and rhinorrhea, were elicited with a questionnaire using a 10 cm visual analogue scale (VAS). Nasal lavage fluid taken from a random sample of 17 patients both preoperatively and 1 year postoperatively was screened with enzyme-linked immunosorbent assays. RESULTS: Postoperative rhinorrhea (6.03 ± 1.31vs 2.12 ± 1.40, P < 0.001) and sneezing (5.53 ± 1.25vs 2.04 ± 1.29, P < 0.001) were significantly improved relative to the preoperative levels; the mean SP and NPY concentrations in the nasal lavage fluid were 91.6 ± 20.9 pg/ml and 71.5 ± 10.5 pg/ml, which decreased significantly to 52.9 ± 16.7 pg/ml and 31.8 ± 8.2 pg/ml, respectively, and the mean periostin and IL-5 concentrations were 215.2 ± 87.7 pg/ml and 984.5 ± 181.8 pg/ml, which decreased significantly to 146.1 ± 70.1 pg/ml and 281.6 ± 74.0 pg/ml, respectively. CONCLUSIONS: PNN was safe and well tolerated, and the symptom (sneezing and rhinorrhea) scores were significantly decreased by 1 year postoperatively.

Laser ablation of posterior nasal nerves for rhinitis.

BACKGROUND: Posterior nasal nerve (PNN) surgery, Radiofrequency (RF), and cryoablation have been described as alternative treatments for allergic and vasomotor rhinitis. We hypothesize that endoscopic (diode) laser ablation (ELA) is effective and less invasive than previously described methods. METHODS: An IRB approved prospective study was performed. Thirty-two patients with chronic rhinitis and nasal congestion resistant to medical management were recruited. Total Nasal Symptom Score (TNSS) measurements were used to assess symptom severity and treatment outcomes. ELA was performed bilaterally in the clinic with a 940 nm diode laser with CW 5 W output, under topical/local anesthesia in 21 patients, while the remaining 11 were treated under sedation in the operating room. The 400-micron uninitiated diode laser fiber tip with a malleable protective shaft was specially designed for PNN ablation. The fiber was pre-shaped according to the intranasal anatomy and endoscopically advanced toward the posterior middle meatus. Patients were followed up for the first 90 days after treatment. RESULTS: ELA was successfully completed in 97% of patients. No crusting, epistaxis, or other complications were observed. One patient could not be treated in the office due to limited endoscopic access. TNSS was reduced significantly after30 and 90 days (mean ± SD: 6.0 ± 0.7 prior to ablation, 2.3 ± 0.4 at 90 days, p < .001). Rhinitis and congestion scores decreased at 30 and 90 days after treatment compared to the baseline (p < .001). CONCLUSION: ELA of the PNN region is safe and well tolerated both in the office and ambulatory settings. Symptom scores were significantly decreased after 30 and 90 days. This new minimally invasive method appears to be a promising treatment method.

A preliminary report on the effect of gabapentin pretreatment on periprocedural pain during in-office posterior nasal nerve cryoablation.

BACKGROUND: Posterior nasal nerve (PNN) cryoablation is a novel surgical technique to address allergic and nonallergic rhinitis. Periprocedural pain has been reported after PNN cryoablation and there are no standardized protocols for optimal in-office local anesthesia. This study sought to evaluate the effect of gabapentin on patient discomfort following in-office PNN cryoablation. METHODS: Multi-institutional prospective analysis of patients undergoing in-office PNN cryoablation for allergic or nonallergic rhinitis between March 2018 and April 2019. Patients received local anesthesia with or without 600 mg oral gabapentin 1 hour preprocedure. Rhinitis diagnosis, demographics, and baseline disease-specific quality of life (mini-Rhinoconjunctivitis Quality of Life Questionnaire [RQLQ] and Total Nasal Symptom Score [TNSS]) were recorded. Patient discomfort was measured by the pain visual analogue scale (VAS) posttreatment and rated 0 to 10 on an ordinal scale. Fisher's exact and Wilcoxon 2-sample tests were used to evaluate differences between the 2 groups. RESULTS: A total of 26 patients were enrolled (gabapentin n = 15, control = 11). Baseline TNSS scores in the gabapentin vs control group were median [25th percentile to 75th percentile]) 10 (7.5 to 11.0) and 9 (6.0 to 10.0) (p = 0.35). Baseline Mini-RQLQ scores in gabapentin vs control groups were 3.21 (2.0 to 4.0) and 2.92 (2.78 to 4.35) (p = 0.51). The median VAS pain scores at 5, 20, and 30 minutes in the gabapentin vs control group were 0.0 (0.0 to 2.0) vs 3.0 (1.0 to 4.0), 2.0 (0.0 to 3.0) vs 8.0 (6.0 to 10.0), and 1.0 (0.0 to 1.0) vs 5.0 (4.0 to 6.0) (p = 0.02, p = 0.0043, and p = 0.003, respectively). CONCLUSION: Preprocedure gabapentin significantly reduces immediate and delayed postprocedural patient discomfort following PNN cryoablation.

Effect of non-invasive intranasal neurostimulation on tear volume, dryness and ocular pain.

PURPOSE: To evaluate the effect of one TrueTear session on change in tear volume and symptoms of dryness and ocular pain. METHODS: Retrospective interventional case series of patients seen in a dry eye clinic. Seventy-five individuals underwent an ocular surface examination and one session of neurostimulation. Outcome measures included objective change in tear volume measured via phenol red test, and subjective change in sensations of dryness and ocular pain measured on a 0-10 Numerical Rating Scale. RESULTS: The mean age of the 75 individuals was 59±13 years, and the majority were male (73%). Intranasal neurostimulation increased tear volume (mean 13.40±8.00 mm, p<0.0005) and reduced intensities of dryness (mean -2.85±2.79, p<0.0005) and ocular pain (mean -1.48±2.41, p<0.0005 for both). However, these effects were independent of one another as change in symptom report did not correlate with change in tear volume (r=-0.13, p=0.25 for dryness; r=0.07, p=0.56 for pain). In a multivariable model, the strongest predictors for increased tear volume were lower baseline tear volume (standardised beta (ß)=-0.50, p<0.0005) and absence of an autoimmune disease (ß=-0.36, p=0.001) (R2=0.30). The strongest predictors for reduced dryness and pain scores were lower baseline dryness and ocular pain scores. No complications related to neurostimulation were noted. CONCLUSION: Intranasal neurostimulation increased tear volume and reduced intensities of dryness and ocular pain, independently of one another.

Randomized, Controlled, Double-Masked, Multicenter, Pilot Study Evaluating Safety and Efficacy of Intranasal Neurostimulation for Dry Eye Disease.

Purpose: We assess the safety and effectiveness of intranasal neurostimulation to promote tear production via the nasolacrimal pathway in subjects with dry eye disease. Methods: A multicenter, randomized, controlled, double-masked pilot study was conducted in adults with dry eye diagnosis and at least one eye with corneal fluorescein staining ≥2 in at least one region or a sum of all regions ≥5 (National Eye Institute grading), basal Schirmer test score ≤10 mm, a cotton-swab stimulated Schirmer score ≥7 mm higher, and an Ocular Surface Disease Index score ≥23. Subjects were randomized to receive active intranasal neurostimulation or sham control intranasal stimulation 4 to 8 times per day. Assessments were scheduled before (unstimulated) and during (stimulated) device application at days 0, 7, 14, 30, and 90. The primary effectiveness endpoint was stimulation-induced change in Schirmer test (with anesthesia) score. Primary safety measure was incidence of device-related adverse events (AEs). Results: Fifty-eight subjects were randomized at nine sites in Australia and New Zealand; 56 completed the 90-day study. Stimulation-induced change in Schirmer score was significantly greater with active intranasal (mean ± SEM, 9.0 ± 2.0) than sham control intranasal stimulation (0.4 ± 0.6; P < 0.001) at day 90. Similar results were observed at days 0, 7, 14, and 30 (P < 0.001). No serious device-related AEs were observed. Mild nosebleed, the most common device-related AE, was reported in five (16.7%) subjects. Conclusions: Intranasal neurostimulation was effective in inducing acute tear production after 90 days of use and generally was well tolerated in subjects with dry eye disease.

Characterization of tear production in subjects with dry eye disease during intranasal tear neurostimulation: Results from two pivotal clinical trials.

PURPOSE: The intranasal tear neurostimulator (ITN) activates the nasolacrimal pathway, which is involved with basal and bolus tear secretion. These studies characterized the acute and long-term effectiveness of the ITN in stimulating tear production in subjects with dry eye disease (DED). METHODS: Study 1: Randomized, double-masked, dual-controlled, 1-day crossover. Study 2: Single-arm, open-label, 180-day prospective cohort. Eligible subjects had basal unstimulated Schirmer test (with anesthesia) ≤10 mm and intranasal cotton swab-stimulated Schirmer test at least 7 mm greater in the same eye, and Ocular Surface Disease Index® ≥13 and ≥ 23, in Studies 1 and 2, respectively. Study 1: Subjects (n = 48) received three randomized test applications: active intranasal, extranasal (active control), and sham intranasal (inactive control) stimulation, 3 min/application with 1-hour minimum between applications. Primary outcome measure was the difference in Schirmer test scores during active intranasal and control applications. Study 2: Subjects (n = 97) performed intranasal neurostimulation for ≤3 min/application, 2-10 times/day. Primary outcome measure was the difference in Schirmer scores (stimulated minus unstimulated) at day 180. Both studies recorded device-related adverse events (AEs). RESULTS: Study 1: Schirmer scores (mean ±â€¯SEM) were significantly greater (p < 0.0001) with active intranasal (25.3 ±â€¯1.5 mm) vs extranasal (9.5 ±â€¯1.2 mm) and sham (9.2 ±â€¯1.1 mm) applications. Study 2: Schirmer scores were significantly greater (p < 0.0001) with ITN stimulation vs unstimulated at day 180 (17.3 ±â€¯1.3 mm vs 7.9 ±â€¯0.7 mm). No serious device-related AEs were reported in either study. CONCLUSION: The ITN was well-tolerated and effective in stimulating tear production with acute and long-term use in DED. CLINICALTRIALS. GOV IDENTIFIER: NCT02680158 and NCT02526290.

Neurostimulation in dry eye disease-past, present, and future.

Neuromodulation is a novel approach that utilizes electrical signals, pharmaceutical agents, or other forms of energy to modulate abnormal neural function through neurostimulation. Neurostimulation is a novel technique that uses electrical currents to stimulate the nervous system. During the recent few decades, neuromodulation has gained significant attention, in particular for the treatment of chronic neurological diseases, due to its success in treating patients unresponsive to conventional pharmacological therapies. Dry eye disease (DED) is a chronic, multifactorial disease that affects millions of people worldwide. Recent data have demonstrated that neurosensory abnormalities contribute to the pathogenesis of DED. Current mainstays of dry eye therapy include lubrication, tear retention, and anti-inflammatory therapies, among others. The recent development of intranasal neurostimulation therapy for DED utilizes the nasolacrimal reflex as an alternative pathway, not only to increase tear production via increased lacrimation, but also to target other tear film components, such as mucin and meibum secretion, promoting tear film homeostasis. This review aims to describe the different types of neuromodulation devices available and their application for non-ocular diseases, as well as to review recent advances and literature on ocular neurostimulation.

Análisis semántico y gramatical de los términos latinos de los ramos terminales del nervio nasociliar / Semantic and grammatical analysis of latin terms of the terminal branches of the nasociliary nerve

RESUMEN: La necesidad de unificar criterios respecto a los nombres de las estructuras anatómicas ha sido una permanente preocupación de los anatomistas del mundo, de tal manera que a partir de 1895 se inicia un proceso de estandarización y normalización de la terminología anatómica mundial. Se publica la Nomina Anatomica tratando de nominar las estructuras con un solo nombre en latín y se suprime los epónimos y homónimos. En la actualidad la Terminologia Anatomica sustituye a la Nomina Anatomica, con las mismas características, pero con la adición del término en el idioma de cada país. Sin embargo, persisten algunos errores desde la elaboración de la Nomina Anatomica y que se mantienen en Terminologia Anatomica, derivados tanto de la estructura gramatical latina, principalmente en el número y género, así como de la descripción de algunas estructuras anatómicas. Este es el caso de los ramos del nervio nasociliar, específicamente del ramo etmoidal anterior y del ramo infratroclear. Para el efecto se realizó una revisión de la descripción del nervio nasociliar y sus ramos terminales, se compararon entre sí y con los nombres que aparecen en la Terminologia Anatomica, para verificar que tanto la descripción como la construcción gramatical latina sean correctas. Se encontraron errores en la estructuración gramatical y jerárquica del ramo nasal interno, así como la supresión de los ramos palpebrales superior e inferior del nervio infratroclear, por lo que proponemos el cambio del término codificado con A14.2.01.031 a Ramus nasalis internus y la adición de los nombres Ramus palpebralis superior y Ramus palpebralis inferior.

SUMMARY: The need to unify criteria regarding the names of anatomical structures has been a permanent concern of anatomists worldwide. Therefore, and beginning in 1895 a standardization and normalization process of world anatomical terminology was initiated. The Nomina Anatomica is published in an attempt to name the structures with a single name in Latin and the eponyms and homonyms are deleted. Today the Terminologia Anatomica replaces the Nomina Anatomica, with the same characteristics, but with the addition of the term in the language of each country. Nevertheless, some errors persist from the Nomina Anatomica that remain in Terminologia Anatomica, derived from both the Latin grammatical structure, mainly in the number and gender, as well as the description of some anatomical structures. This is the case of the nasociliary nerve branches, specifically the anterior ethmoidal branch and the infratroclear branch. For this purpose, a review of the description of the nasociliary nerve and its terminal branches was made, they were compared between each other, and with the names that appear in the Terminologia Anatomica, to verify that both the description and the Latin grammatical construction are correct. Errors were found in the grammatical and hierarchical structure of the internal nasal branch, as well as the suppression of the upper and lower palpebral branches of the infratrochlear nerve. Therefore, we propose the change of the coded term with A14.2.01.031 to "Ramus nasalis internus" and the addition of the names "Ramus palpebralis superior" and "Ramus palpebralis inferior".

Restoration of the nasopharyngeal response after bilateral sectioning of the anterior ethmoidal nerve in the rat.

In response to stimulation of the nasal passages with volatile ammonia vapors, the nasopharyngeal reflex produces parasympathetically mediated bradycardia, sympathetically mediated increased peripheral vascular tone, and apnea. The anterior ethmoidal nerve (AEN), which innervates the anterior nasal mucosa, is thought to be primarily responsible for providing the sensory afferent signals that initiate these protective reflexes, as bilateral sectioning causes an attenuation of this response. However, recent evidence has shown cardiovascular responses to nasal stimulation with ammonia vapors are fully intact 9 days after bilateral AEN sectioning, and are similar to control animals without bilaterally sectioned AENs. To investigate this restoration of the nasopharyngeal response, we recorded the cardiorespiratory responses to nasal stimulation with ammonia vapors immediately after, and 3 and 9 days after, bilateral AEN sectioning. We also processed brainstem tissue for Fos to determine how the restoration of the nasopharyngeal response would affect the activity of neurons in the medullary dorsal horn (MDH), the part of the ventral spinal trigeminal nucleus caudalis region that receives primary afferent signals from the nose and nasal passages. We found 3 days after bilateral AEN sectioning the cardiorespiratory responses to nasal stimulation are partially restored. The bradycardic response to nasal stimulation is significantly more intense 3 days after AEN sectioning compared to Acute AEN sectioning. Surprisingly, 3 days after AEN sectioning the number of Fos-positive neurons within MDH decreased, even though the cardiorespiratory responses to nasal stimulation intensified. Collectively these findings indicate that, besides the AEN, there are alternate sensory pathways that can activate neurons within the trigeminal nucleus in response to nasal stimulation. The findings further suggest trigeminal neuronal plasticity involving these alternate sensory pathways occurs in as few as 3 days after bilateral AEN sectioning. Finally, activation of even a significantly reduced number of MDH neurons is sufficient to initiate the nasopharyngeal response.

Substance P represents a novel first-line defense mechanism in the nose.

BACKGROUND: Neuropeptides, such as substance P (SP), have long been seen as mediators of widespread continuous airway inflammation, a process known as neurogenic inflammation. However, this has been difficult to demonstrate clinically, suggesting an alternative role for these signaling molecules. OBJECTIVES: We sought to examine the role of SP in nasal infection by assessing the release of SP in response to viral stimulation and characterizing the effects of SP on innate immunity, with the latter reflected in changes in local Toll-like receptor (TLR) expression. METHODS: The distribution of SP and TLRs in the nasal mucosa and local airway neurons was assessed with immunohistochemistry. The TLR7 agonists R-837 and R-848 were used to mimic a viral insult in the upper airways represented by primary human nasal epithelial cells (HNECs) and murine nasal epithelial cells (MNECs) and isolated murine trigeminal ganglial neurons. SP release from HNECs, MNECs, and trigeminal ganglial neurons was quantified with EIA. The effects of SP on TLR expression on HNECs were determined by using flow cytometry and confocal microscopy. RESULTS: SP was released from the sensory neurons, MNECs, and HNECs within 15 minutes of local TLR7 stimulation. Subsequently, stimulation with SP induced upregulation of TLR expression in HNECs within 30 minutes through induction of TLR movement within HNECs. Upregulation of TLR expression was not evident when cells were treated with the neurokinin 1 receptor antagonist aprepitant before SP stimulation. CONCLUSIONS: This highlights a novel role for sensory neuropeptides as acute and local mediators of pathogen-driven inflammation, rapidly priming innate immune defenses in the airway.

Intranasal Drug Delivery: A Non-Invasive Approach for the Better Delivery of Neurotherapeutics.

BACKGROUND: The convoluted pathophysiology of brain disorders along with penetration issue of drugs to brain represents major hurdle that requires some novel therapies. The blood-brain barrier (BBB) denotes a rigid barrier for delivery of therapeutics in vivo; to overcome this barrier, intranasal delivery is an excellent strategy to deliver the drug directly to brain via olfactory and trigeminal nerve pathways that originate as olfactory neuro-epithelium in the nasal cavity and terminate in brain. METHOD: Kind of therapeutics like low molecular weight drugs can be delivered to the CNS via this route. In this review, we have outlined the anatomy and physiological aspect of nasal mucosa, certain hurdles, various strategies including importance of muco-adhesive polymers to increase the drug delivery and possible clinical prospects that partly contribute in intranasal drug delivery. RESULTS: Exhaustive literature survey related to intranasal drug delivery system revealed the new strategy that circumvents the BBB, based on non-invasive concept for treating various CNS disorders. Numerous advantages like prompt effects, self-medication through wide-ranging devices, and the frequent as well protracted dosing are associated with this novel route. CONCLUSION: Recently few reports have proven that nasal to brain drug delivery system bypasses the BBB. This novel route is associated with targeting efficiency and less exposure of therapeutic substances to non-target site. Nevertheless, this route desires much more research into the safe transferring of therapeutics to the brain. Role of muco-adhesive polymer and surface modification with specific ligands are area of interest of researcher to explore more about this.

Prolonged denervation induces remodeling of nasal mucosa in rat model of posterior nasal neurectomy.

BACKGROUND: The posterior nasal nerve is the dominant source of the parasympathetic, sympathetic, and sensory fibers that innervate the nasal respiratory mucosa. Therefore, a posterior nasal neurectomy (PNN) induces denervation of the nasal mucosa and relieves the nasal symptoms of intractable rhinitis. PNN depletes nerve fibers, choline acetyltransferase, and neuropeptides in nasal respiratory mucosa, and reduces nasal secretion. However, the histological and symptomatic changes over an extended period after PNN remain unknown. METHODS: Using a rat model of PNN via the transorbital approach, we investigated chronological changes of nasal morphology, innervation, and secretion over a 48-week postoperative period after PNN. RESULTS: The respiratory nasal mucosa exhibited squamous metaplasia, lymphocyte and plasma cell infiltration, basement membrane thickening, loss of cilia, and hyperplasia of the mucus gland in thickened epithelium with increased connective tissue from 24 weeks after PNN. These changes resemble the characteristics of remodeling in chronic rhinosinusitis. DNA microarray and quantitative polymerase chain reaction analysis revealed that mucin 5ac, interleukin 13, and brain-derived neurotrophic factor messenger RNA (mRNA) were upregulated in PNN-treated mucosa compared to untreated mucosa. During this period, nerve fibers including sensory, sympathetic, and parasympathetic fibers gradually reinnervated the mucosa from 12 weeks after PNN. However, nasal secretion was decreased even at 48 weeks after PNN probably due to the prolonged absence of choline acetyltransferase. CONCLUSION: Prolonged denervation induces remodeling of the nasal mucosa. Although the depleted nerves were partially reinnervated a few months after PNN, nasal secretion was still suppressed, partly due to a sustained deficiency of acetylcholine synthesis.

Increase of Mast Cell-Nerve Association and Neuropeptide Receptor Expression on Mast Cells in Perennial Allergic Rhinitis.

OBJECTIVES: Mast cells (MCs) and nerves play an important role in allergic rhinitis (AR), but little is known about their crosstalk in AR. The aim of this study was to investigate MC-nerve interaction in the human nasal mucosa during AR. METHODS: The association between MCs and nerves, the expression of neuropeptide receptors (neurokinin 1 receptor [NK1R], neurokinin 2 receptor [NK2R], calcitonin gene-related peptide receptor [CGRPR], and MrgX2) on MCs, and protease-activated receptor 2 (PAR2) and tyrosine receptor kinase A (TrkA) on nerve fibres in the human nasal mucosa were investigated with immunofluorescence and real-time PCR. RESULTS: The association between MCs and nerves was found to be significantly increased, although the numbers of MCs and nerve fibres were unchanged during AR. MCs expressing tryptase-chymase (MCtc) were frequently associated with nerve fibres and these contacts increased significantly in AR. Neuropeptide receptors NK1R, NK2R, and CGRPR were firstly found to be largely localised on MCs. The number of MCs expressing NK1R and NK2R, but not CGRPR, was significantly increased in AR. Interestingly, MCtc mostly expressed these neuropeptide receptors. The newly discovered tachykinin receptor MrgX2 was not expressed on nasal MCs, but was expressed on gland cells and increased in AR. Additionally, tachykinergic nerve fibres were found to express PAR2 or TrkA as receptors for MCs. CONCLUSIONS: This study revealed for the first time an increase of MC-nerve association and neuropeptide receptor expression on MCs during AR as well as nerve fibres containing receptors for MCs. These results suggest that targeting or controlling airway sensory nerve function as a modulator of MCs may prevent allergic airway inflammation such as AR.

Denervation of nasal mucosa induced by posterior nasal neurectomy suppresses nasal secretion, not hypersensitivity, in an allergic rhinitis rat model.

The posterior nasal nerve is the dominant source of the parasympathetic, sympathetic, and sensory fibers that innervate the nasal respiratory mucosa. Therefore, a posterior nasal neurectomy (PNN) is thought to induce denervation of the nasal mucosa and relieve the nasal symptoms of allergic rhinitis. However, the underlying mechanisms and therapeutic action of PNN remain unknown. To investigate the impact of PNN-induced denervation of the nasal mucosa on allergic rhinitis, we developed a rat model of PNN and examined the effects of PNN on allergic rhinitis in ovalbumin-sensitized rats. This rat model of PNN was characterized by the depletion of nerve fibers, choline acetyltransferase, and neuropeptides (eg, substance P, calcitonin gene-related peptide, vasoactive intestinal peptide, and neuropeptide Y) in the nasal respiratory mucosa. These animals exhibited nasal gland and goblet cell hypertrophy in the septal mucosa and atrophy of the submucosal gland in the lateral nasal wall, as well as reduced nasal secretion due to deficient acetylcholine synthesis. In an ovalbumin-sensitized model of allergic rhinitis, PNN also induced the depletion of nerve fibers, choline acetyltransferase, and neuropeptides in the nasal mucosa and suppressed nasal secretion. However, PNN did not affect mucosal thickening, eosinophil and mast cell infiltration, interleukin-4 and interferon-γ mRNA expression, and allergic symptoms (ie, sneezing and nasal scratching). These results suggest that the peripheral nerves and corresponding neuropeptides regulate nasal secretion, but not hypersensitivity, in allergic rhinitis, and that allergic rhinitis-related mucosal reactions occur in a highly denervated mucosa after PNN. Posterior nasal neurectomy may be a therapeutic option for the treatment of hyperrhinorrhea, but not allergic rhinitis hypersensitivity.

Identification of the cold receptor TRPM8 in the nasal mucosa.

BACKGROUND: The transient receptor potential channel melastatin 8 (TRPM8) has been proposed to be a cold receptor. However, its distribution and physiologic role in the nose is not yet fully explored. OBJECTIVE: We investigated the expression of TRPM8 in human nasal mucosa and its function when using the TRPM8 agonist. METHODS: Immunohistochemistry was used to study TRPM8 receptors in the nasal mucosa from patients with and those without allergic rhinitis (AR). By using isometric contraction studies, we also tested the effectiveness of the TRPM8 agonist menthol on nasal mucosa. Changes in nasal mucosal contractility in response to the application of the adrenergic agent methoxamine were also measured. We explored the effect of menthol on electrical field stimulation (EFS) induced nasal mucosal contractions. RESULTS: TRPM8 immunoreactivity was present principally in the nasal cilia, epithelium, and subepithelium around the glands. Except for nerve fibers, no obvious TRPM8-immunoreactive cells were detected in connective tissues. The immunoreactivity revealed no significant difference between patients with AR and those without AR. Adding menthol had a negligible effect on the basal tension of the nasal mucosa, but higher doses of menthol had a significant spasmolytic effect on nasal mucosa precontracted with methoxamine. Menthol inhibited the spike contraction induced by EFS, even at low doses. CONCLUSIONS: The finding of the TRPM8 immunoreactivity underlines the important physiologic role of the nose in temperature regulation, both in patients with allergy and those without allergy. Isometric contraction studies demonstrate the role of TRPM8 in regulating nasal patency and airway resistance. The antiadrenergic effect of menthol showed an effect apparently opposite that of clinical observations, that we usually feel decongested after menthol inhalation. The underlying mechanisms deserve further investigation, and the TRPM8 antagonists deserve consideration for treatment of rhinitis in a therapeutic trial.