Neurokinin-1 Receptor Research Articles

OR06-5 Fezolinetant for Treatment of Moderate-to-severe Vasomotor Symptoms Associated with Menopause: Results from a 52-week Study (Skylight 2)

Abstract Background SKYLIGHT 2 (NCT04003142) investigated safety and efficacy of fezolinetant (a neurokinin-3 receptor antagonist) on frequency and severity of moderate-to-severe vasomotor symptoms (VMS) and sleep disturbance. In this analysis, persistence of fezolinetant efficacy was investigated over 52 weeks. Methods This double-blind Phase 3 study randomized women aged ≥40–65 years with moderate-to-severe VMS associated with menopause (average of ≥7 hot flashes/day) to once-daily placebo or fezolinetant 30mg or 45mg for 12 weeks. Women completing 12 weeks entered an extension period, with those on placebo re-randomized to fezolinetant 30mg or 45mg (placebo/fezolinetant), and those originally on fezolinetant remaining on their dose for an additional 40-weeks. Fezolinetant efficacy was evaluated vs placebo for 12-weeks through change in VMS frequency, VMS severity, and Patient-reported Outcomes Measurement Information System Sleep Disturbance–Short Form 8b (PROMIS) Total Score. Persistence of efficacy for fezolinetant was evaluated descriptively (without statistical comparisons) over the extension period. Results The analysis comprised 484 women (fezolinetant 30mg n=166, fezolinetant 45mg n=167, placebo/fezolinetant 30mg n=76, placebo/fezolinetant 45mg n=75). Improvement in VMS frequency and severity observed through week 12 (statistically significant differences vs placebo) was maintained throughout the 52-week total study period for those receiving fezolinetant. Fezolinetant demonstrated further reductions in VMS frequency and severity from baseline to beyond week 12. For VMS frequency, there was a least squares (LS) mean (SE) baseline-to-week 12 reduction of –6.83 (0.39) VMS/day for fezolinetant 30mg and –7.50 (0.39) for 45mg, and a mean (SD) baseline-to-week 52 reduction of –8.03 (4.53) for fezolinetant 30mg and –8.48 (3.98) for 45mg. For VMS severity, LS mean (SE) baseline-to-week 12 reduction was –0.64 (0.06) for 30mg and –0.77 (0.06) for 45mg, and mean (SD) baseline-to-week 52 reduction was –0.83 (0.82) for fezolinetant 30mg, and –0.95 (0.78) for 45mg. Women re-randomized from placebo to fezolinetant experienced a reduction in frequency and severity of VMS consistent with that in women receiving fezolinetant throughout the study. Fezolinetant also reduced PROMIS-assessed sleep disturbance, with a LS mean (SE) baseline-to-week 12 reduction of –4.1 (0.5) for fezolinetant 30mg and –5.5 (0.5) for 45mg (statistically significant difference vs placebo for fezolinetant 45mg) and a mean (SD) baseline-to-week 52 reduction of – 6.3 (7.3) for fezolinetant 30mg and –5.7 (7.9) for 45mg. The safety profile observed for the 40-week extension period was consistent with that of the 12-week placebo-controlled period. Conclusion Fezolinetant 30mg and 45mg once daily were efficacious for treatment of moderate-to-severe VMS associated with menopause. Efficacy was persistent and reductions in VMS frequency were maintained during the extension period, at levels consistent with weeks 1 through 12. Fezolinetant 45mg improved sleep at week 12 and improvement was maintained through the active treatment extension period. No safety signals of concern were apparent for either fezolinetant dose. Presentation: Saturday, June 11, 2022 12:30 p.m. - 12:45 p.m.

Partial loss of arcuate kisspeptin neurons in female rats stimulates luteinizing hormone and decreases prolactin secretion induced by estradiol.

Kisspeptin, neurokinin, and dynorphin (KNDy) neurons in the arcuate nucleus (ARC) control luteinizing hormone (LH) and prolactin (PRL) release, although their role in conveying the effects of estradiol (E2 ) to these hormones is not well understood. We performed a longitudinal evaluation of female rats in which KNDy neurons were ablated using a neurokinin-3 receptor agonist conjugated with saporin (NK3-SAP) to investigate the impact of the reduction of KNDy neurons on the E2 regulation of gonadal and PRL axes. NK3-SAP rats, bearing a moderate loss of ARC kisspeptin-immunoreactive (-IR) neurons (50%-90%), displayed irregular estrous cycles but essentially unaltered follicular development and a normal number of corpora lutea. Rats were then ovariectomized (OVX) and treated with a positive-feedback dose of E2 (OVX + E2 ). LH and PRL were measured in the tail blood by an enzyme-linked immunosorbent assay. The E2 -induced LH surge was amplified, whereas the PRL rise was decreased in NK3-SAP rats compared to Blank-SAP control. After 10 days of no hormonal treatment, basal LH levels were equally elevated in NK3-SAP and controls. Tyrosine hydroxylase (TH) phosphorylation in the median eminence, in turn, was increased in NK3-SAP rats, with no change in the number of ARC TH-IR neurons. Thus, KNDy neurons exert concurrent and opposite roles in the E2 -induced surges of LH and PRL. The partial loss of KNDy neurons disrupts ovarian cyclicity but does not preclude ovulation, consistent with the disinhibition of the LH preovulatory surge. Conversely, KNDy neurons tonically inhibit the enzymatic activity of tuberoinfundibular dopaminergic neurons, which appears to facilitate PRL release in response to E2 .

Electroacupuncture relieves hyperalgesia by regulating neuronal-glial interaction and glutamate transporters of spinal dorsal horns in rats with acute incisional neck pain.

Glial cells are involved in the analgesic effect of electroacupuncture (EA) in rats with chronic neurological pain. The objective of this study was to observe the role of neuronal-glial interaction and glutamate (Glu) transporters in EA-induced acute neck pain relief in rats. Male rats were placed into the following five groups: control, model, EA Futu (LI18), EA Hegu (LI4)-Neiguan (PC6), and EA Zusanli (ST36)-Yanglingquan (GB34). The incisional neck pain model was established by making a longitudinal incision along the midline of the neck. The thermal pain threshold (TPT) was measured using a radiation heat detector. The immunoactivities of glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (Iba-1), neurokinin-1 receptor (NK-1R), Glu aspartate transporter (GLAST), and Glu transporter-1 (GLT-1) in the dorsal horns (DHs) of the cervico-spinal cord (C2-C5) were detected using immunofluorescence histochemistry. The expression levels of GFAP, Iba-1, GLAST, and GLT-1 mRNAs were determined using quantitative real-time polymerase chain reaction (PCR). The TPT and levels of mRNAs expression and immunoactivity of GLT-1 and GLAST were significantly decreased, and those of Iba-1 and GFAP were significantly increased in the model group than those of the control group (P < 0.05). The activated microgliacytes were gathered around the NK-1R positive neurons, and co-expression of NK-1R and astrocytes was observed in the model group. EA LI18 significantly increased the TPT and expression of GLAST and GLT-1 mRNAs (P < 0.05) and notably decreased the number of Iba-1 positive cells and Iba-l mRNA expression (P < 0.05), whereas GLAST and GLT-1 antagonists inhibited the analgesic effect of EA LI18. However, these effects, except for the downregulation of Iba-1 mRNA, were not observed in the EA ST36-GB34 group. Fewer NK-1R-positive neurons were visible in the spinal DHs in the EA LI18 group, and the co-expression of NK-1R and astrocytes was also lower than that in the three EA groups. Electroacupuncture of LI18 had an analgesic effect in rats with neck incisions, which may be related to its functions in suppressing the neuronal-glial cell interaction through NK-1R and upregulating the expression of GLAST and GLT-1 in the spinal DHs.

Involvement of neurokinin-1 receptors in the autonomic nervous system in colorectal distension-induced cardiovascular suppression in rats.

Situational syncope, which includes rectally mediated reflexes, is defined as syncope induced by a specific situation. Its pathogenesis generally involves disorders of the autonomic nervous system. However, the mechanisms and preventive strategies are not yet well understood. Therefore, we hypothesized that a tachykinin neurokinin-1 receptor might be involved in the autonomic nervous system, and that a neurokinin-1 receptor antagonist could mitigate reflex syncope. This study used a rat model in which the reflex was induced by afferent vagal stimulation with colorectal distension (CRD). In the study, the rats were divided into three groups: non-CRD, CRD, and CRD with a neurokinin-1 receptor antagonist. First, we examined the effect of fosaprepitant, a neurokinin-1 receptor antagonist, on the circulatory response in this model. We then determined the brain regions that showed increased numbers of c-Fos immunoreactive cells in the respective groups. Our results suggest that the colorectal distension procedure reduced blood pressure and that fosaprepitant lowered this response. In addition, the number of c-Fos immunoreactive cells was increased in the caudal ventrolateral medullary region with colorectal distension, and this number was decreased by the administration of fosaprepitant. In conclusion, fosaprepitant might be involved in the vagal reflex pathway and potentially suppress the circulatory response to colorectal distension.

Neurokinin 3 receptor antagonist-induced adipocyte activation improves obesity and metabolism in PCOS-like mice

AimsNeurokinin-B (NKB)-Neurokinin-3-receptor (NK3R) pathway is remarkably sensitive to energy equilibrium; however, its role in metabolic regulation remains unexplored in polycystic ovary syndrome (PCOS). Therefore, this work aimed to investigate the role of NK3R antagonists (NK3Ra) on metabolic dysfunction and obesity in in vitro and in vivo PCOS models. Main methodsFirst, an observational study using serum samples collected from 19 PCOS patients was performed. Second, prospective case-control experimental studies where NK3Ra (SB222200) was used to treat PCOS-like mice (BALB/c mice), ovariectomized+estrogen implanted obese mice (C57BL/6J mice) and 3T3-L1 murine preadipocytes were carried out to investigate its effect on metabolism in vivo and in vitro. The fat volumes, serum biochemical indexes, adipokines and inflammatory cytokines, metabolism-related gene expression and the concentrations of ATP, NAD+, NADPH…etc. were studied. Key findingsWe found a positive correlation between serum NKB and lipid metabolism indicators in PCOS women. Using the mouse models, we demonstrated that administration of NK3Ra regulates serum adipokines, inhibits weight gain with a marked decrease in fat volume, adipocyte size, and inflammatory cytokines, and promotes oxidative metabolism and energy consumption. NK3Ra reduces lipid accumulation in mature murine adipocytes by inhibiting the expression of peroxisome proliferator- activated receptor gamma (PPAR-γ) and fatty acid binding protein 4 (FABP4) genes. NK3Ras also enhances oxidative metabolism and energy consumption by maintaining intracellular redox homeostasis. SignificanceThis study backs the use of NK3Ras as a potential therapeutic for PCOS since it ameliorates both reproductive and metabolic aberrations.

The Neurokinin-1 Receptor: Structure Dynamics and Signaling

Substance P (SP), the first isolated neuropeptide, belongs to the family of tachykinin peptides and is the natural ligand of neurokinin-1 receptors (NK-1R), also named SP receptors. The undecapeptide activates the receptor after specifically binding to the protein and triggers intracellular signals leading to different biochemical events and subsequent physiological responses. This study reviews the main architectural features of this receptor, its interaction with natural and synthetic ligands, and the functional conformational states adopted after interacting with ligands and effector G proteins. The analysis of the main intracellular signaling pathways turned on by the activation of NK-1 receptors reveals the participation of different proteins supporting metabolic changes and genetic and epigenetic regulations. Furthermore, the analysis of receptor occupancy and receptor downregulation and internalization represents a complex and estimable field for basic and clinical research focused on the role of SP in physiopathology. Profound knowledge of the structural dynamics of NK-1R may help develop and assay new selective synthetic non-peptide antagonists as potential therapeutic agents applied to various pathologies and symptoms.

The Effect of Blocking Neurokinin-1 Receptor by Aprepitant on the Inflammatory and Apoptosis Pathways in Human Ovarian Cancer Cells.

Ovarian cancer is the seventh most common cancer globally, and the second most common cancer among women with significant mortality. Toward this end, it is shown that substance P (SP) is involved in tumor initiation and progression through the neurokinin-1 receptor (NK1R). However, the exact molecular mechanism of the SP/NK1R system in ovarian cancer is not yet fully clarified. In this in vitro study, we decided to investigate the effect of the SP/NK1R system and blockage of NK1R by its specific antagonist (Aprepitant) on the proliferation of ovarian cancer cells as well as the alteration of inflammatory pathways. Our results revealed that Aprepitant stimulated apoptotic cell death and attenuated inflammation of ovarian cancer cells through the NF-kB and P53 signaling pathways. After treatment with Aprepitant, the expression of downstream anti-apoptotic genes related to the NF-kB pathway (survivine and bcl2) was decreased. However, we indicated the positive effect of SP on the proliferation of ovarian cancer cells by inducing the expression of NF-kB protein and NF-kB anti-apoptotic target genes. Moreover, Pro-apoptotic p53 target genes (P21 and Bax) were increased through aprepitant treatment, while SP attenuated these genes' expression. Besides, ROS generation in ovarian cancer cells after treatment with SP induced, while blocking of NK1R with Aprepitant reduced the level of ROS generation. Given this, our data suggest that this NK1R might be used as an important therapeutic target in ovarian cancer and Aprepitant could be considered a new drug in ovarian cancer therapy.

The Potential In Vitro Inhibitory Effects of Neurokinin-1 Receptor (NK-1R) Antagonist, Aprepitant, in Osteosarcoma Cell Migration and Metastasis.

Background Osteosarcoma, the most frequent osteogenic malignancy, has become a serious public health challenge due to its high morbidity rates and metastatic potential. Recently, the neurokinin-1 receptor (NK-1R) is proved to be a promising target in cancer therapy. This study is aimed at determining the effect of aprepitant, a safe and Food and Drug Administration (FDA) approved NK-1R antagonist, on osteosarcoma cell migration and metastasis, and to explore its underlying mechanism of action. Methods Colorimetric MTT assay was employed to assess cell viability and cytotoxicity. A wound-healing assay was used to examine migration ability. The desired genes' protein and mRNA expression levels were measured by western blot assay and quantitative real-time PCR (qRT-PCR), respectively. Gelatinase activity was also measured by zymography. Results We found that aprepitant inhibited MG-63 osteosarcoma cell viability in a dose-dependent manner. We also observed that aprepitant inhibited the migrative phenotype of osteosarcoma cells and reduced the expression levels and activities of matrix metalloproteinases (MMP-2 and MMP-9). Aprepitant also reduced the expression of an angiogenic factor, VEGF protein, and NF-κB as an important transcriptional regulator of metastasis-related genes. Conclusion Collectively, our observations indicate that aprepitant modulates the metastatic behavior of human osteosarcoma cells, which may be applied to an effective therapeutic approach for patients with metastatic osteosarcoma.

K+ channel Kv4.1 is expressed in the nociceptors/secondary nociceptive neurons and participates in pain regulation.

Kv4 channels are key components controlling neuronal excitability at membrane potentials below action potential thresholds. It remains elusive whether Kv4.1 participates in pain regulation. We raised a Kv4.1 antibody to map Kv4.1+ neurons in the superficial dorsal horn of the spinal cord and dorsal root ganglion (DRG) of rats. Behavioural, biochemical and immunohistochemical methods were used to examine whether the activity of Kv4.1+ neurons or Kv4.1 expression level is altered after peripheral nerve injury. In lamina I of the spinal cord, Kv4.1 immunoreactivity (IR) was detected in neurokinin-1 receptor positive (NK1R)+ projection neurons (the secondary nociceptive neurons) and NK1R+ excitatory interneurons. Kv4.1, KChIP2 and DPP10 were co-expressed in these neurons. Peripheral nerve injury evoked by lumbar spinal nerve ligation (SNL) immediately induced phosphorylated extracellular regulated protein kinase (pERK, an indicator of enhanced neuronal activity) in lamina I Kv4.1+ neurons and lamina II Kv4.2/Kv4.3+ neurons of the spinal cord. Furthermore, Kv4.1 appeared in 59.9% of DRG neurons with variable sizes. Kv4.1 mRNA and protein levels in DRG neurons were gradually decreased after SNL. Following intrathecal injection of Kv4.1 antisense oligodeoxynucleotide (ASO) into naive rats, Kv4.1 protein level was reduced in the DRG, and mechanical but not thermal hypersensitivity was induced. Kv4.1 appears in the secondary nociceptive neurons, and peripheral nerve injury increases the activity of these neurons. Kv4.1 expression in DRG neurons (including half of the nociceptors) is gradually reduced after peripheral nerve injury, and knockdown of Kv4.1 in DRG neurons induces pain. Thus, Kv4.1 participates in pain regulation. Based on the expression of Kv4.1 and Kv4.3 in the nociceptors, Kv4.1 in the secondary nociceptive neurons, Kv4.1 in spinal lamina I excitatory interneurons that regulate the activity of the secondary nociceptive neurons, as well as Kv4.2 and Kv4.3 in spinal lamina II excitatory interneurons that also regulate the activity of the secondary nociceptive neurons, developing Kv4 activators or genetic manipulation to increase Kv4 channel activity in these pain-related Kv4+ neurons will be useful in future pain therapeutics.

Ionic signalling mechanisms involved in neurokinin-3 receptor-mediated augmentation of fear-potentiated startle response in the basolateral amygdala.

The tachykinin peptides include substance P (SP), neurokinin A and neurokinin B, which interact with three G-protein-coupled neurokinin receptors, NK1Rs, NK2Rs and NK3Rs, respectively. Whereas high densities of NK3Rs have been detected in the basolateral amygdala (BLA), the functions of NK3Rs in this brain region have not been determined. We found that activation of NK3Rs by application of the selective agonist, senktide, persistently excited BLA principal neurons. NK3R-elicited excitation of BLA neurons was mediated by activation of a non-selective cation channel and depression of the inwardly rectifying K+ (Kir) channels. With selective channel blockers and knockout mice, we further showed that NK3R activation excited BLA neurons by depressing the G protein-activated inwardly rectifying K+ (GIRK) channels and activating TRPC4 and TRPC5 channels. The effects of NK3Rs required the functions of phospholipase Cβ (PLCβ), but were independent of intracellular Ca2+ release and protein kinase C. PLCβ-mediated depletion of phosphatidylinositol 4,5-bisphosphate was involved in NK3R-induced excitation of BLA neurons. Microinjection of senktide into the BLA of rats augmented fear-potentiated startle (FPS) and this effect was blocked by prior injection of the selective NK3R antagonist SB218795, suggesting that activation of NK3Rs in the BLA increased FPS. We further showed that TRPC4/5 and GIRK channels were involved in NK3R-elicited facilitation of FPS. Our results provide a cellular and molecular mechanism whereby NK3R activation excites BLA neurons and enhances FPS. KEY POINTS: Activation of NK3 receptors (NK3Rs) facilitates the excitability of principal neurons in rat basolateral amygdala (BLA). NK3R-induced excitation is mediated by inhibition of GIRK channels and activation of TRPC4/5 channels. Phospholipase Cβ and depletion of phosphatidylinositol 4,5-bisphosphate are necessary for NK3R-mediated excitation of BLA principal neurons. Activation of NK3Rs in the BLA facilitates fear-potentiated startle response. GIRK channels and TRPC4/5 channels are involved in NK3R-mediated augmentation of fear-potentiated startle.

Quantitative spatial analysis reveals that the local axons of lamina I projection neurons and interneurons exhibit distributions that predict distinct roles in spinal sensory processing.

Our knowledge about the detailed wiring of neuronal circuits in the spinal dorsal horn (DH), where initial sensory processing takes place, is still very sparse. While a substantial amount of data is available on the somatodendritic morphology of DH neurons, the laminar and segmental distribution patterns and consequential function of individual axons are much less characterized. In the present study, we fully reconstructed the axonal and dendritic processes of 10 projection neurons (PNs) and 15 interneurons (INs) in lamina I of the rat, to reveal quantitative differences in their distribution. We also performed whole-cell patch-clamp recordings to test the predicted function of certain axon collaterals. In line with our earlier qualitative description, we found that lamina I INs in the lateral aspect of the superficial DH send axon collaterals toward the medial part and occupy mostly laminae I-III, providing anatomical basis for a lateromedial flow of information within the DH. Local axon collaterals of PNs were more extensively distributed including dorsal commissural axon collaterals that might refer to those reported earlier linking the lateral aspect of the left and right DHs. PN collaterals dominated the dorsolateral funiculus and laminae IV-VI, suggesting propriospinal and ventral connections. Indeed, patch-clamp recordings confirmed the existence of a dorsoventral excitatory drive upon activation of neurokinin-1 receptors that, although being expressed in various lamina I neurons, are specifically enriched in PNs. In summary, lamina I PNs and INs have almost identical dendritic input fields, while their segmental axon collateral distribution patterns are distinct. INs, whose somata reside in lamina I, establish local connections, may show asymmetry, and contribute to bridging the medial and lateral halves of the DH. PNs, on the other hand, preferably relay their integrated dendritic input to deeper laminae of the spinal gray matter where it might be linked to other ascending pathways or the premotor network, resulting in a putative direct contribution to the nociceptive withdrawal reflex.

The current and emerging treatment landscape for chronic cough.

Cough serves a protective physiologic function as a vital defensive reflex preventing aspiration. However, exposure to viral infections or other triggers induces, in some individuals, a chronic cough (CC) that causes a significant symptomatic burden. Most cases of CC are due to conditions that respond to appropriate therapeutic trials (upper airway cough syndrome; asthma; reflux). Unfortunately, a significant subgroup of patients will have refractory CC, which does not respond to treatment of known underlying causes of CC. Currently, available therapeutic options for refractory CC are inadequate due to limited efficacy and frequently intolerable adverse effects. Current professional society guideline recommendations are discussed, and a promising pipeline of antitussive drugs in development is introduced, including purinergic 2X3 receptor antagonists, neurokinin-1 receptor antagonists, oral mixed ĸ-opioid receptor agonists/µ-opioid receptor antagonists, and voltage-gated sodium channel blockers.

Respiratory deficits in a female rat model of Parkinson's disease.

What is the central question of this study? How does the 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease model affect the respiratory response in female rats? What effect does ovariectomy have on that response? What is the main finding and its importance? The results suggest a protective effect of ovarian hormones in maintaining normal neuroanatomical integrity of the medullary respiratory nucleus in females. It was observed that ovariectomy alone reduced neurokinin-1 density in the pre-Bötzinger complex and Bötzinger complex, and there was an incremental effect of 6-OHDA and ovariectomy on retrotrapezoid nucleus neurons. Emerging evidence indicates that the course of Parkinson's disease (PD) includes autonomic and respiratory deficiencies in addition to the classical motor symptoms. The prevalence of PD is lower in women, and it has been hypothesized that neuroprotection by ovarian hormones can explain this difference. While male PD animal models present changes in the central respiratory control areas, as well as ventilatory parameters under normoxia and hypercapnia, little is known about sex differences regarding respiratory deficits in this disease background. This study aimed to explore the neuroanatomical and functional respiratory changes in intact and ovariectomized (OVX) female rats subjected to chemically induced PD via a bilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA). The respiratory parameters were evaluated by whole-body plethysmography, and the neuroanatomy was monitored using immunohistochemistry. It was found that dopaminergic neurons in the substantia nigra and neurokinin-1 receptor density in the rostral ventrolateral respiratory group, Bötzinger and pre-Bötzinger complex were reduced in the chemically induced PD animals. Additionally, reduced numbers of Phox2b neurons were only observed in the retrotrapezoid nucleus of PD-OVX rats. Concerning respiratory parameters, in OVX rats, the resting and hypercapnia-induced tidal volume (VT ) is reduced, and ventilation ( ) changes independently of 6-OHDA administration. Notably, there is a reduction in the number of retrotrapezoid nucleus Phox2b neurons and hypercapnia-induced respiratory changes in PD-OVX animals due to a 6-OHDA and OVX interaction. These results suggest a protective effect induced by ovarian hormones in neuroanatomical changes observed in a female experimental PD model.

Therapeutic efficacy of topical blockade of substance P in experimental allergic red eye

PurposeAllergic conjunctivitis is the most common cause leading to ocular redness (OR). Herein, using an animal model of allergic OR, we evaluated the therapeutic efficacy of topical blockade of substance P (SP) in treating red eye. MethodsAllergic OR was induced in guinea pigs with topical histamine. Ocular SP was blocked using a specific SP receptor (neurokinin-1 receptor, NK1R) antagonist, L-703,606, via topical application 10 min before or 10 min after histamine instillation. Animal eyes were examined and a series of images were taken for up to 60 min post-OR induction. The severity of redness was analyzed using the quantitative ocular redness index (ORI). At the end of clinical examination, conjunctival tissues were collected for histological examination of conjunctival blood vessels and infiltrating eosinophils and neutrophils. In addition, SP concentration was quantified in the tear fluid and expression levels of inflammatory cytokines were assessed in the conjunctival tissues. ResultsTopical histamine application successfully induced red eye, evidenced by the significantly increased ORI during the observation period, with peak values at 10 min, along with significantly increased levels of SP in the tears. Topical treatment with L-703,606, either before histamine application or at the time of peak ORI, effectively reduced ORI and suppressed conjunctival blood vessel dilation, along with decreased eosinophil and neutrophil infiltration, and inflammatory cytokine expression in the conjunctiva, as well as reduced SP levels in the tears. ConclusionsTopical blockade of SP effectively prevents and treats allergy-related ocular redness by suppressing blood vessel dilation and allergic inflammation.

A Potential Role for Substance P in West Nile Virus Neuropathogenesis.

Of individuals who develop West Nile neuroinvasive disease (WNND), ~10% will die and >40% will develop long-term complications. Current treatment recommendations solely focus on supportive care; therefore, we urgently need to identify novel and effective therapeutic options. We observed a correlation between substance P (SP), a key player in neuroinflammation, and its receptor Neurokinin-1 (NK1R). Our study in a wild-type BL6 mouse model found that SP is upregulated in the brain during infection, which correlated with neuroinvasion and damage to the blood–brain barrier. Blocking the SP/NK1R interaction beginning at disease onset modestly improved survival and prolonged time to death in a small pilot study. Although SP is significantly increased in the brain of untreated WNND mice when compared to mock-infected animals, levels of WNV are unchanged, indicating that SP likely does not play a role in viral replication but may mediate the immune response to infection. Additional studies are necessary to define if SP plays a mechanistic role or if it represents other mechanistic pathways.

Managed care considerations for the treatment of chronic cough.

Chronic cough (CC), defined as a daily cough lasting longer than 8 weeks in adults, is a common condition in the United States. CC is a diagnosis of exclusion associated with a substantial economic burden related to increased healthcare and medication utilization, decreased work productivity, a greater incidence of cough-related comorbidities, and reduced quality of life. CC treatment guidelines recommend stepwise treatment with specific nonpharmacologic therapies and pharmacologic agents. However, many patients may still have incomplete or no symptom relief, encounter response attenuation over time, or experience intolerable adverse effects. New targeted therapies for refractory CC are currently under development, including the purinergic 2X3 receptor antagonists gefapixant, BLU-5937, and sivopixant (S-600918) and the neurokinin-1 receptor antagonist orvepitant. These targeted agents may have improved efficacy and safety profiles, helping fill unmet treatment needs. If approved, managed care organizations must develop formulary placement and utilization management criteria based on clinical guideline recommendations, expert opinion, and cost-effectiveness analyses to support the clinically appropriate use of these targeted therapies for best patient outcomes.

The Efficacy and Safety of Adding Olanzapine to Triple Drugs Regimen to Prevent Chemotherapy-induced Nausea and Vomiting: A systematic Review and Meta-analysis of RCTs

Chemotherapy-induced nausea and vomiting (CINV) is a complication of highly emetogenic chemotherapy (HEC) agents. The present meta-analysis was conducted to quantify and analyze the efficacy and safety of adding olanzapine to a Neurokinin Receptor Antagonist (NKRA) based triple-drug regimen in preventing HEC-induced CINV. Electronic database searches in PUBMED and Cochrane library was conducted using MeSH search terms “olanzapine” and “chemotherapy-induced nausea and vomiting.” Randomized or cross-over trials comparing the efficacy of “olanzapine + NKRA based triple-drug regimen” vs. “placebo + NKRA based triple-drug regimen” in patients of age &gt; 18 years with any malignancy receiving HEC were considered under inclusion criteria. Complete Response (CR) for the delayed (25–120 h) phase of CINV in patients receiving HEC agents was the primary outcome measure analyzed. Outcome measures were estimated by calculating the Risk Difference (RD) values and their 95% Confidence Intervals (CI). The Mantel-Haenszel method and both fixed and random effect models were used in the analysis by Revman 5.4.1 soft- ware. An additional 14% (RD: 0.14, 95% CI: 0.09 to 0.19) of patients treated with olanzapine + triple-drug regimen had a statistically significant higher CR in the delayed phase when compared to placebo + NKRA-based triple-drug regimen. Adding olanzapine at 10mg to the triple-drug regimen significantly improves delayed phase CR rates by 16% and delayed phase ‘no significant nausea’ rates by 30%. Results need to be interpreted cautiously in the background of response variations and limited trials included in our analysis

Substance P Exacerbates the Inflammatory and Pro-osteoclastogenic Responses of Murine Osteoclasts and Osteoblasts to Staphylococcus aureus.

Staphylococcus aureus infections of bone tissue are associated with inflammatory bone loss. Resident bone cells, including osteoblasts and osteoclasts, can perceive S. aureus and produce an array of inflammatory and pro-osteoclastogenic mediators, thereby contributing to such damage. The neuropeptide substance P (SP) has been shown to exacerbate microbially induced inflammation at sites such as the gut and the brain and has previously been shown to affect bone cell differentiation and activity. Here we demonstrate that the interaction of SP with its high affinity receptor, neurokinin-1 receptor (NK-1R), expressed on murine osteoblasts and osteoclasts, augments the inflammatory responses of these cells to S. aureus challenge. Additionally, SP alters the production of pro- and anti-osteoclastogenic factors by bacterially challenged bone cells and their proteolytic functions in a manner that would be anticipated to exacerbate inflammatory bone loss at sites of infection. Furthermore, we have demonstrated that the clinically approved NK-1R antagonist, aprepitant, attenuates local inflammatory and pro-osteoclastogenic mediator expression in an in vivo mouse model of post-traumatic staphylococcal osteomyelitis. Taken together, these results indicate that SP/NK-1R interactions could play a significant role in the initiation and/or progression of damaging inflammation in S. aureus bone infections and suggest that the repurposing of currently approved NK-1R antagonists might represent a promising new adjunct therapy for such conditions.

Dual orexin receptor blocker suvorexant attenuates hypercapnic ventilatory augmentation in mice

Suvorexant (Belsomra(R)), a dual orexin receptor antagonist widely used in the treatment of insomnia, inhibits the arousal system in the brain. However, the drug’s ventilatory effects have not been fully explored. This study aims to investigate the expression of orexin receptors in respiratory neurons and the effects of suvorexant on ventilation. Immunohistology of brainstem orexin receptor OX2R expression was performed in adult mice (n = 4) in (1) rostral ventral respiratory group (rVRG) neurons projecting to the phrenic nucleus (PhN) retrogradely labeled by Fluoro-Gold (FG) tracer, (2) neurons immunoreactive for paired like homeobox 2b (Phox2b) in the parafacial respiratory group/retrotrapezoid nucleus (pFRG/RTN), and (3) neurons immunoreactive for neurokinin 1 receptor (NK1R) and somatostatin (SST) in the preBötzinger complex (preBötC). Additionally, we measured in vivo ventilatory responses to hyperoxic hypercapnia (5% CO2) and hypoxia (10% O2) before and after suvorexant pretreatment (10 and cumulative 100 mg/kg) in unrestrained mice (n = 10) in a body plethysmograph. We found the OX2R immunoreactive materials in pFRG/RTN Phox2b and preBötC NK1R/SST immunoreactive neurons but not in FG-labeled rVRG neurons, which suggests the involvement of orexin in respiratory control. Further, suvorexant expressly suppressed the hypercapnic ventilatory augmentation, otherwise unaffecting ventilation. Central orexin is involved in shaping the hypercapnic ventilatory chemosensitivity. Suppression of hypercapnic ventilatory augmentation by the orexin receptor antagonist suvorexant calls for caution in its use in pathologies that may progress to hypercapnic respiratory failure, or sleep-disordered breathing. Clinical trials are required to explore the role of targeted pharmacological inhibition of orexin in ventilatory pathologies.

Upregulated expression of substance P and NK1R in blood monocytes and B cells of patients with allergic rhinitis and asthma.

Increased expression of substance P (SP) and neurokinin-1 receptor (NK1R) has been noticed in patients with allergic rhinitis (AR) and allergic asthma (AA). However, little is known of the expression of SP and NK1R in monocytes and B cells of AR and AA. In the present study, the expression levels of SP and NK1R were determined by flow cytometry and mouse AR and AA models. The results showed that both percentages of SP+ monocytes and SP+ B cells, and mean fluorescence intensity (MFI) of SP in monocytes were elevated in the blood of AA and AR combined with AA (ARA) patients. Similarly, the percentages of NK1R+ monocytes were elevated in the blood of AR, AA, and ARA patients. Allergens Artemisia sieversiana wild allergen extract (ASWE), house dust mite extract (HDME), and Platanus pollen allergen extract (PPE) increased the expression density of SP molecules (determined by MFI) in an individual monocyte of AR patients. HDME and PPE appeared to enhance SP and NK1R expression in the B cells of ARA and AR patients. In the mouse AR and AA models, the percentages of NK1R+ monocytes and B cells were elevated in blood following OVA (ovalbumin) sensitization and challenge. Knocking out the FcεRI molecule completely abolished the OVA-induced upregulation of expression of NK1R in monocytes and B cells of AA mice. In conclusion, upregulated expressions of SP and NK1R may contribute to the pathogenesis of airway allergy.