Search Results (58)

Neuroendoscopy is a minimally invasive surgical technique used to treat brain pathologies such as hydrocephalus, arachnoid cysts, and skull base tumors. While it offers several advantages, including reduced tissue trauma and lower morbidity, it is associated with a high risk of postoperative nausea and vomiting (PONV). This paper provides a narrative review of the literature on the incidence, pathophysiology, and management of PONV in patients undergoing neuroendoscopic procedures. The review includes several studies published between 2001 and 2024, analyzing specific risk factors such as female gender, postoperative opioid use, extended endoscopic approaches, and cavernous sinus dissection. PONV prevention strategies include a multimodal approach combining total intravenous anesthesia (TIVA) with propofol, perioperative hydration, and pharmacological prophylaxis (5-HT3 receptor antagonists, NK1 antagonists, dexamethasone, and droperidol). Despite advances in surgical and anesthetic techniques, further research is needed to develop procedure-specific protocols and optimize PONV management in neuroendoscopy. Full article

Cisplatin (cis-diamminedichloro-platinum; CDDP) is a chemotherapeutic agent that frequently induces peripheral neuropathy characterized by mechanical allodynia. Herein, we aimed to determine the effects of valproic acid (VPA) on cisplatin-induced mechanical allodynia in rats and elucidate the underlying mechanisms. A single administration of VPA (150 mg/kg) transiently suppressed CDDP-induced mechanical allodynia, correlating with serum VPA concentrations. Repeated VPA administration before or after the onset of CDDP-induced mechanical allodynia significantly attenuated allodynia even after VPA discontinuation, suggesting fundamental treatment potential. Mechanistically, CDDP increased the expression of neurokinin 1 receptor (NK1R) mRNA in the dorsal horn of the spinal cord, and this increased expression was suppressed by repeated VPA administration. Treatment with an NK1R antagonist alleviated CDDP-induced mechanical allodynia, indicating the involvement of NK1R in allodynia. In vitro assays revealed that VPA did not affect the cytotoxicity of CDDP in Walker 256 cells, suggesting that VPA does not interfere with the antitumor activity of CDDP. Overall, repeated VPA administration may fundamentally ameliorate CDDP-induced peripheral neuropathy by suppressing the CDDP-induced increased NK1R expression without compromising the antitumor effects of CDDP. These findings provide insights into the potential use of VPA as a therapeutic agent for managing CDDP-induced peripheral neuropathy. Full article

The cornea, a highly innervated and avascular ocular tissue, relies on intricate neuro-immune interactions to maintain homeostasis. Among key neuromediators, substance P (SP)—a neuropeptide belonging to the tachykinin family—plays a dual role in corneal physiology and pathology. This review synthesizes current knowledge on SP’s involvement in corneal innervation, epithelial homeostasis, immune regulation, neovascularization, and wound healing, while highlighting its dichotomous effects in both promoting tissue repair and exacerbating inflammation. SP, primarily signaling through the neurokinin-1 receptor (NK1R), influences corneal epithelial proliferation, barrier function, and wound healing by modulating cytokines, chemokines, and growth factors. However, its overexpression is linked to pain sensitization, inflammatory keratitis, and corneal neovascularization, driven by interactions with immune cells (e.g., mast cells, neutrophils) and pro-angiogenic factors (e.g., VEGF). Clinical studies demonstrate altered SP levels in dry eye disease, neurotrophic keratitis, and post-refractive surgery, correlating with nerve damage and ocular surface dysfunction. Emerging therapies targeting SP pathways- such as NK1R antagonists (e.g., fosaprepitant) and SP-IGF-1 combinations-show promise for treating neurotrophic ulcers but face challenges due to SP’s context-dependent actions. Future research should clarify the roles of NK2R/NK3R receptors and optimize SP-based interventions to balance its reparative and inflammatory effects. Understanding SP’s multifaceted mechanisms could advance the development of therapies for corneal diseases, particularly those involving sensory neuropathy and immune dysregulation. Full article

KNDy (kisspeptine, neurokinin B, dynorphin) neurons, located in the hypothalamus, play a crucial role in the development of vasomotor symptoms (VSM) in menopausal women. Estrogen withdrawal during menopause leads to the hyperactivation of kisspeptin and neurokinin B (NKB) secretion, contributing to the onset of these symptoms. The identification of NKB/neurokinin B receptor (NK3R) signaling as a key mechanism in menopausal hot flashes has driven the development of NK3R antagonists. These antagonists restore the disrupted balance in KNDy neuron activity caused by estrogen deficiency, thereby reducing the frequency and severity of VMS. In 2023, the FDA approved fezolinetant, the first selective NK3R antagonist, for the treatment of moderate to severe VMS associated with menopause. Additionally, elinzanetant, a dual neurokinin-1 and neurokinin-3 receptor antagonist, has demonstrated promising results. The approval application for elinzanetant was supported by positive findings from the OASIS 1, 2, and 3 Phase III clinical studies. The dual antagonism of NK-1 and NK-3 receptors enhances its efficacy by alleviating menopause-related sleep disturbances and modulating peripheral vasodilatation. In this regard, elinzanetant represents a promising non-hormonal treatment that targets the underlying causes of VMS through NK-1 and NK-3 receptor pathways. The development of neurokinin B antagonist for VMS treatment exemplifies the impact of advanced pharmacological research on gynecological endocrinology. Full article

Background: Diffuse intrinsic pontine glioma (DIPG) is a devastating childhood brainstem tumor. The median survival of DIPG is 16–24 months independent of the treatment received. Therefore, new therapeutic strategies against DIPG are urgently needed. Substance P (SP) peptide, through the neurokinin neurokinin-1 receptor (NK-1R), is involved in glioma progression. It induces glioma cell proliferation by activating MAPKs (p38 MAPK, ERK1/2, and JNK), c-Myc, AP-1, and NF-κB and induces antiapoptotic effects via PI3K/Akt/mTOR in glioma cells. SP favors glycogen breakdown that is essential for glycolysis. The SP/NK-1R system also regulates the migration and invasion of glioma cells, stimulates angiogenesis, and triggers inflammation which contributes to glioma progression. Moreover, all glioma cells express NK-1R, and NK-1R is essential for the viability of glioma cells and not of normal cells. In contrast, in glioma, NK-1R antagonists, such as the drug aprepitant, penetrate the brain and reach therapeutic concentrations, thereby inhibiting mitogenesis, inducing apoptosis, and inhibiting the breakdown of glycogen in glioma cells. In addition, they inhibit angiogenesis and exert antimetastatic and anti-inflammatory effects. The combination of radiotherapy with NK-1R antagonists produces radiosensitization and radioneuroprotection, reduces both peritumoral- and radiation-induced inflammation, and also provides antinausea and antivomiting effects. Objective: This review updates the involvement of the SP/NK-1R system in glioma promotion and progression and the potential clinical application of NK-1R antagonist drugs in DIPG therapy. Conclusions: NK-1R plays a crucial role in glioma progression and NK-1R antagonists such as aprepitant could be used in combination with radiotherapy as a potent therapeutic strategy for the treatment of patients with DIPG. Full article

We recently developed a series of nalfurafine analogs (TK10, TK33, and TK35) that may serve as non-addictive candidate analgesics. These compounds are mixed-action agonists at the kappa and delta opioid receptors (KOR and DOR, respectively) and produce antinociception in a mouse warm-water tail-immersion test while failing to produce typical mu opioid receptor (MOR)-mediated side effects. The warm-water tail-immersion test is an assay of pain-stimulated behavior vulnerable to false-positive analgesic-like effects by drugs that produce motor impairment. Accordingly, this study evaluated TK10, TK33, and TK35 in a recently validated assay of pain-related behavioral depression in mice that are less vulnerable to false-positive effects. For comparison, we also evaluated the effects of the MOR agonist/analgesic hydrocodone (positive control), the neurokinin 1 receptor (NK1R) antagonist aprepitant (negative control), nalfurafine as a selective KOR agonist, SNC80 as a selective DOR agonist, and a nalfurafine/SNC80 mixture. Intraperitoneal injection of dilute lactic acid (IP lactic acid) served as a noxious stimulus to depress vertical and horizontal locomotor activity in male and female ICR mice. IP lactic acid-induced locomotor depression was alleviated by hydrocodone but not by aprepitant, nalfurafine, SNC80, the nalfurafine/SNC80 mixture, or the KOR/DOR agonists. These results suggest that caution is warranted in advancing mixed-action KOR/DOR agonists as candidate analgesics. Full article

Accidents caused by Bothrops jararaca (Bj) snakes result in several local and systemic manifestations, with pain being a fundamental characteristic. The inflammatory process responsible for hyperalgesia induced by Bj venom (Bjv) has been studied; however, the specific roles played by the peripheral and central nervous systems in this phenomenon remain unclear. To clarify this, we induced hyperalgesia in rats using Bjv and collected tissues from dorsal root ganglia (DRGs) and spinal cord (SC) at 2 and 4 h post-induction. Samples were labeled for Iba-1 (macrophage and microglia), GFAP (satellite cells and astrocytes), EGR1 (neurons), and NK1 receptors. Additionally, we investigated the impact of minocycline, an inhibitor of microglia, and GR82334 antagonist on Bjv-induced hyperalgesia. Our findings reveal an increase in Iba1 in DRG at 2 h and EGR1 at 4 h. In the SC, markers for microglia, astrocytes, neurons, and NK1 receptors exhibited increased expression after 2 h, with EGR1 continuing to rise at 4 h. Minocycline and GR82334 inhibited venom-induced hyperalgesia, highlighting the crucial roles of microglia and NK1 receptors in this phenomenon. Our results suggest that the hyperalgesic effects of Bjv involve the participation of microglial and astrocytic cells, in addition to the activation of NK1 receptors. Full article

Traumatic brain injuries represent a leading cause of death and disability in the paediatric and adult populations. Moderate-to-severe injuries are associated with blood–brain barrier dysfunction, the development of cerebral oedema, and neuroinflammation. Antagonists of the tachykinin NK1 receptor have been proposed as potential agents for the post-injury treatment of TBI. We report on the identification of EUC-001 as a potential clinical candidate for development as a novel TBI therapy. EUC-001 is a selective NK1 antagonist with a high affinity for the human NK1 receptor (Ki 5.75 × 10⁻¹⁰ M). It has sufficient aqueous solubility to enable intravenous administration, whilst still retaining good CNS penetration as evidenced by its ability to inhibit the gerbil foot-tapping response. Using an animal model of TBI, the post-injury administration of EUC-001 was shown to restore BBB function in a dose-dependent manner. EUC-001 was also able to ameliorate cerebral oedema. These effects were associated with a significant reduction in post-TBI mortality. In addition, EUC-001 was able to significantly reduce functional deficits, both motor and cognitive, that normally follow a severe injury. EUC-001 is proposed as an ideal candidate for clinical development for TBI. Full article

Innate immunity is essential for the anti-microbial defense, but excessive immune activation may cause severe disease. In this study, immunotherapy was shown to prevent excessive innate immune activation and restore the anti-bacterial defense. E. coli-infected Asc^−/− mice develop severe acute cystitis, defined by IL-1 hyper-activation, high bacterial counts, and extensive tissue pathology. Here, the interleukin-1 receptor antagonist (IL-1RA), which inhibits IL-1 hyper-activation in acute cystitis, was identified as a more potent inhibitor of inflammation and NK1R- and substance P-dependent pain than cefotaxime. Furthermore, IL-1RA treatment inhibited the excessive innate immune activation in the kidneys of infected Irf3^−/− mice and restored tissue integrity. Unexpectedly, IL-1RA also accelerated bacterial clearance from infected bladders and kidneys, including antibiotic-resistant E. coli, where cefotaxime treatment was inefficient. The results suggest that by targeting the IL-1 response, control of the innate immune response to infection may be regained, with highly favorable treatment outcomes, including infections caused by antibiotic-resistant strains. Full article

Neuroinflammation is considered to be a significant component in a range of neuropathologies. Unfortunately, whilst its role is well recognised, the options for therapeutic intervention are limited. As such, there is a need to identify novel targets in order to increase treatment options. Given its role as both a neurotransmitter and an immune modulator, substance P (SP) and its NK1 receptor (NK1R) have been widely studied as a potential therapeutic target. There is evidence that NK1R antagonists may exert beneficial effects in a range of conditions, including traumatic brain injury and stroke. Blocking the NK1R has been shown to reduce blood–brain barrier dysfunction, reduce cerebral oedema, and reduce the levels of pro-inflammatory cytokines. These actions are associated with improved survival and functional outcomes. The NK1R has also been shown to be involved in the inflammatory reaction to CNS infection, and hence antagonists may have some benefit in reducing infection-driven inflammation. However, the NK1R may also play a role in the host immune response to infection, and so here, the potential beneficial and detrimental effects need to be carefully balanced. The purpose of this review is to provide a summary of evidence for the involvement of the NK1R in acute CNS inflammation, particularly in the context of traumatic brain injury and stroke. Full article

Binding of substance P to the tachykinin NK1 receptor is involved in numerous physiological and pathophysiological processes ranging from modulation of sensory and motor function to inflammation, cancer, and brain injury, amongst others. NK1 antagonists therefore have enormous potential as a therapeutic intervention in a wide variety of human disease states, albeit that the clinical potential is yet to be fully realised. In the current review, the role of substance P in the pathophysiology of traumatic brain injury (TBI) will be discussed, summarising both experimental and clinical observations in mild, moderate, and severe TBI. In addition, the potential for NK1 antagonists to be a valuable therapeutic intervention against chronic traumatic encephalopathy (CTE) after repeated concussive brain injury as well as raised intracranial pressure (ICP) following severe TBI will be addressed, highlighting the various pathophysiological processes that are attenuated by the intervention. Full article

The substance P (SP)/neurokinin-1 receptor (NK-1R) system is involved in cancer progression. NK-1R, activated by SP, promotes tumor cell proliferation and migration, angiogenesis, the Warburg effect, and the prevention of apoptosis. Tumor cells overexpress NK-1R, which influences their viability. A typical specific anticancer strategy using NK-1R antagonists, irrespective of the tumor type, is possible because these antagonists block all the effects mentioned above mediated by SP on cancer cells. This review will update the information regarding using NK-1R antagonists, particularly Aprepitant, as an anticancer drug. Aprepitant shows a broad-spectrum anticancer effect against many tumor types. Aprepitant alone or in combination therapy with radiotherapy or chemotherapy could reduce the sequelae and increase the cure rate and quality of life of patients with cancer. Current data open the door to new cancer research aimed at antitumor therapeutic strategies using Aprepitant. To achieve this goal, reprofiling the antiemetic Aprepitant as an anticancer drug is urgently needed. Full article

In recent years, numerous approaches have been developed to comprehend the molecular alterations underlying thyroid cancer (TC) oncogenesis and explore novel therapeutic strategies for TC. It is now well established that the neurokinin-1 receptor (NK-1R) is overexpressed in cancer cells and that NK-1R is essential for the viability of cancer cells. The binding of substance P (SP) to NK-1R in neoplastic cells plays a pivotal role in cancer progression by promoting neoplastic cell growth, protecting tumor cells from apoptosis, triggering invasion and metastasis through the enhanced migration of cancer cells, and stimulating endothelial cell proliferation for tumor angiogenesis. Remarkably, all types of human TC (papillary, follicular, medullary, anaplastic), as well as metastatic lesions, exhibit the overexpression of SP and NK-1R compared to the normal thyroid gland. TC cells synthesize and release SP, which exerts its multiple functions through autocrine, paracrine, intracrine, and neuroendocrine processes, including the regulation of tumor burden. Consequently, the secretion of SP from TC results in increased SP levels in plasma, which are significantly higher in TC patients compared to controls. Additionally, NK-1R antagonists have demonstrated a dose-dependent antitumor action. They impair cancer cell proliferation on one side and induce apoptosis of tumor cells on the other side. Furthermore, it has been demonstrated that NK-1R antagonists inhibit neoplastic cell migration, thereby impairing both invasiveness and metastatic abilities, as well as angiogenesis. Given the consistent overexpression of NK-1R in all types of TC, targeting this receptor represents a promising therapeutic approach for TC. Therefore, NK-1R antagonists, such as the drug aprepitant, may represent novel drugs for TC treatment. Full article

Transient receptor potential ankyrin 1 (TRPA1) channels are expressed on the surface of different cell types, including immune cells. However, TRPA1’s role in the context of innate and adaptive immune responses has not been fully elucidated so far. In this study, we aimed at investigating the expression and function of TRPA1 channels on NK cells. Among NK cells, TRPA1 was highly expressed by the CD56^dimCD16⁺ subpopulation, but not by CD56^brightCD16⁻ cells, as detected by FACS. TRPA1 activation with the potent ligand allyl isothiocyanate (AITC) induces intracellular calcium flux in CD56^dimCD16⁺ cells, which was prevented by the TRPA1 antagonist HC-030031. AITC treatment increased the membrane around NKp44 and strongly decreased CD16 and CD8 expression, while CD158a, CD159a, NKG2d, NKp46 were substantially unaffected. Importantly, AITC increased the granzyme production and CD107 expression and increased NK cell-mediated cytotoxicity towards the K562 cell line and two different melanoma cell lines. In parallel, TRPA1 activation also plays regulatory roles by affecting the survival of NK cells to limit uncontrolled and prolonged NK cell-mediated cytotoxicity. Our results indicate that the activation of TRPA1 is an important regulatory signal for NK cells, and agonists of TRPA1 could be used to strengthen the tumor response of the immune system. Full article

Aprepitant is the first member of a relatively new antiemetic drug class called NK₁ receptor antagonists. It is commonly prescribed to prevent chemotherapy-induced nausea and vomiting. Although it is included in many treatment guidelines, its poor solubility causes bioavailability issues. A particle size reduction technique was used in the commercial formulation to overcome low bioavailability. Production with this method consists of many successive steps that cause the cost of the drug to increase. This study aims to develop an alternative, cost-effective formulation to the existing nanocrystal form. We designed a self-emulsifying formulation that can be filled into capsules in a melted state and then solidified at room temperature. Solidification was achieved by using surfactants with a melting temperature above room temperature. Various polymers have also been tested to maintain the supersaturated state of the drug. The optimized formulation consists of Capryol^TM 90, Kolliphor^® CS20, Transcutol^® P, and Soluplus^®; it was characterized by DLS, FTIR, DSC, and XRPD techniques. A lipolysis test was conducted to predict the digestion performance of formulations in the gastrointestinal system. Dissolution studies showed an increased dissolution rate of the drug. Finally, the cytotoxicity of the formulation was tested in the Caco-2 cell line. According to the results, a formulation with improved solubility and low toxicity was obtained. Full article