Limbic Neuropeptidergic Modulators of Emotion and Their Therapeutic Potential for Anxiety and Post-Traumatic Stress Disorder.

Post-traumatic stress disorder (PTSD) is characterized by hypervigilance, increased reactivity to unpredictable versus predictable threat signals, deficits in fear extinction, and an inability to discriminate between threat and safety. First-line pharmacotherapies for psychiatric disorders have limited therapeutic efficacy in PTSD. However, recent studies have advanced our understanding of the roles of several limbic neuropeptides in the regulation of defensive behaviors and in the neural processes that are disrupted in PTSD. For example, preclinical studies have shown that blockers of tachykinin pathways, such as the Tac2 pathway, attenuate fear memory consolidation in mice and thus might have unique potential as early post-trauma interventions to prevent PTSD development. Targeting this pathway might also be beneficial in regulating other symptoms of PTSD, including trauma-induced aggressive behavior. In addition, preclinical and clinical studies have shown the important role of angiotensin receptors in fear extinction and the promise of using angiotensin II receptor blockade to reduce PTSD symptom severity. Additional preclinical studies have demonstrated that the oxytocin receptors foster accurate fear discrimination by facilitating fear responses to predictable versus unpredictable threats. Complementary human imaging studies demonstrate unique neural targets of intranasal oxytocin and compare its efficacy with well-established anxiolytic treatments. Finally, promising data from human subjects have demonstrated that a selective vasopressin 1A receptor antagonist reduces anxiety induced by unpredictable threats. This review highlights these novel promising targets for the treatment of unique core elements of PTSD pathophysiology.

Tachykinin antagonists ameliorate surgically induced impairment of gastrointestinal motility in rats.

The protective effects of tachykinin receptor antagonists: SR140333 (NK1 receptor), SR48968 (NK2 receptor), and SB222200 (NK3 receptor) were tested in rats against a surgically induced postoperative inhibition of gut motility, a common complication of abdominal surgery. The small intestinal transit of Evans blue was measured 24-h post-surgery in untreated rats and animals subjected to skin incision, laparotomy, or laparotomy followed by gut evisceration and manipulation. Surgical procedures were conducted under diethyl ether anesthesia. In comparison to untreated and ether-anesthetized rats, animals undergoing skin incision, laparotomy, or laparotomy with gut evisceration and manipulation showed a significant decrease in the intestinal transit of Evans blue. The pretreatment with NK1 (3-100 µg/kg), NK2 (3-30 µg/kg), and NK3 (10-300 µg/kg) blockers before surgery ameliorated the inhibitory effects of gut manipulation in a dose-dependent manner. Moreover, the submaximal and maximal doses of NK3 antagonists showed a trend toward reversing not only the inhibition caused by gut manipulation but also laparotomy. An additive effect of combining submaximal doses of NK1-3 blockers was observed in animals pretreated with NK1  + NK2 compared to single-agent NK1 and NK2 . Additionally, doublets: NK1  + NK3 or NK2  + NK3 and a triplet: NK1  + NK2  + NK3 proved to be more effective than NK2 antagonist alone. In contrast, NK1-3 blockers have not markedly affected the intestinal propulsion in untreated rats or animals subjected to skin incision or laparotomy. NK1-3 blockers ameliorated the suppressed small-bowel gut motility 24 post-surgery. Combined pretreatment with NK1-3 antagonists provided selective, additive benefits compared to single agents.

Tachykinin Antagonists Reverse Ischemia/Reperfusion Gastrointestinal Motility Impairment in Rats.

BACKGROUND: Supraceliac aortic clamping and unclamping produces ischemia-reperfusion (I/R) injury of the splanchnic organs. The protective effects of tachykinin receptor antagonists, SR140333 (NK1 receptor), SR48968 (NK2 receptor), and SB222200 (NK3 receptor), against I/R-induced inhibition of intestinal motility were tested in rats. MATERIAL AND METHODS: The intestinal transit of Evans blue was measured in untreated rats and animals subjected to skin incision, I/R (1 h superior mesenteric artery occlusion followed by 24 h reperfusion) or sham operation. Surgical procedures were conducted under diethyl ether anesthesia. RESULTS: The gastrointestinal transit has not been markedly affected in rats, which were anesthetized or subjected to skin incision in comparison with untreated animals. In contrast, a sham operation and I/R have significantly reduced the intestinal motility. Pretreatment with NK1-3 blockers (SR140333 [3-30 µg/kg]; SR48968 [3-100 µg/kg]; and SB222200 [10-100 µg/kg]) reversed dose dependently the effects of I/R to the level observed after sham operation only. A combination of NK1+NK2+NK3 inhibitors exerted an additive effect compared with NK1 and NK2 antagonists used as single agents. Similarly, combined NK1+NK2 were more effective than NK2 alone. Sham operation and I/R have shifted the in vitro carbachol concentration-response curves to the right in comparison with untreated animals, a phenomenon partially reversed by NK1-NK3 pretreatment. CONCLUSIONS: Single-agent and combined treatment with NK1-3 antagonists markedly attenuated the gastrointestinal dysmotility evoked by I/R injury. The pretreatment with NK3 blocker proved to be the most active in this experimental setting.

The Neuropeptide Tac2 Controls a Distributed Brain State Induced by Chronic Social Isolation Stress.

Chronic social isolation causes severe psychological effects in humans, but their neural bases remain poorly understood. 2 weeks (but not 24 hr) of social isolation stress (SIS) caused multiple behavioral changes in mice and induced brain-wide upregulation of the neuropeptide tachykinin 2 (Tac2)/neurokinin B (NkB). Systemic administration of an Nk3R antagonist prevented virtually all of the behavioral effects of chronic SIS. Conversely, enhancing NkB expression and release phenocopied SIS in group-housed mice, promoting aggression and converting stimulus-locked defensive behaviors to persistent responses. Multiplexed analysis of Tac2/NkB function in multiple brain areas revealed dissociable, region-specific requirements for both the peptide and its receptor in different SIS-induced behavioral changes. Thus, Tac2 coordinates a pleiotropic brain state caused by SIS via a distributed mode of action. These data reveal the profound effects of prolonged social isolation on brain chemistry and function and suggest potential new therapeutic applications for Nk3R antagonists.

Occurrence of substance P and neurokinin receptors during the early phase of spinal fusion.

Spinal fusion is widely used for patients with spinal disorders; however, patients often suffer from back pain following fusion surgery. Substance P (SP) acts as a pain neurotransmitter via the sensory nerve afferent fibres up to the spinal cord, and is involved in the conduction and modulation of pain. The use of specific SP neurokinin receptor (NKR) antagonists may decrease postoperative pain. In the present study, the effects of alterations in the quantity of SP and NKRs in the early spinal fusion process were investigated. The results of the present study revealed that SP and NKRs began to appear 1 week post­surgery in fibrous tissues. The abundance of SP and NKRs peaked at 3 weeks post­surgery; the majority of SP and NKRs were distributed around the allograft and the new microvessels. In conclusion, SP and NKRs are involved in early spinal fusion, a finding that may facilitate the development of novel strategies to promote spinal fusion from a neurogenesis perspective.

Magnesium enhances the beneficial effects of NK1 antagonist administration on blood-brain barrier permeability and motor outcome after traumatic brain injury.

The current study investigated whether adding magnesium to an NK1 tachykinin receptor antagonist after traumatic brain injury would enhance efficacy to further reduce blood-brain barrier permeability and improve functional recovery compared to either treatment alone. Sprague-Dawley rats were injured using the impact acceleration model of diffuse brain injury, and received either no treatment, MgSO4 (30 mg/kg IV), the NK1 antagonist n-acetyl L tryptophan (2.5 mg/kg IP), or both agents combined. Animals were then killed at either 1, 5, or 24 h postinjury for determination of blood-brain barrier permeability using previously administered Evans blue dye or assessed for functional outcome over a 1-week period using the rotarod motor test. As expected, both MgSO4 and n-acetyl L tryptophan significantly reduced blood-brain barrier permeability and improved functional outcome. However, combined n-acetyl L tryptophan and MgSO4 was more effective at reducing blood-brain barrier permeability (P < 0.05) and improving functional outcome (P < 0.001) compared to the individual compounds. Our results demonstrate that combination therapy with magnesium and an NK1 antagonist may be a more effective therapy for TBI than either compound administered alone.

MCRT, a chimeric peptide based on morphiceptin and PFRTic-NH2, regulates the depressor effects induced by endokinin A/B.

The interactions of the chimeric peptide MCRT (YPFPFRTic-NH2), based on morphiceptin and neuropeptide FF derivative PFRTic-NH2, on the effects of endokinin A/B (EKA/B) on mean arterial blood pressure of the urethane-anaesthetized rat have been investigated in the absence and presence of tachykinin receptor antagonists, naloxone and NO synthase inhibitors. While MCRT produced dose dependent decreases in mean arterial pressure, in its presence only a small but statistically insignificant decreases in the magnitude and the time course of the depressor effect of EKA/B (10nmol/kg) were observed. MCRT had little influence on the depressor effect of EKA/B (1 nmol/kg), but strongly potentiated that of EKA/B (100nmol/kg). The tachykinin NK1 receptor antagonist SR140333B (1mg/kg) and the NK3 antagonist SR142891 (2.79mg/kg) both reduced the hypotensive effects of EKA/B and MCRT alone and blocked those of the two peptides in combination. The NK2 antagonist GR159897 (4mg/kg) partially blocked the depressor effects of EKA/B and MCRT alone. Naloxone (2mg/kg) completely blocked the depressor effect of MCTR, but partially blocked that of EKA/B. The NO synthase inhibitor l-NAME (50mg/kg) partially blocked the depressor effects of EKA/B, MCRT, and EKA/B + MCRT. These results could help to better understand the role of tachykinin receptors, opioid receptors and neuropeptide FF receptors in cardiovascular system.

Interactions Between Neurokinin B and Kisspeptin in Mediating Estrogen Feedback in Healthy Women.

CONTEXT: Kisspeptin and neurokinin B (NKB) are obligate for normal gonadotropin secretion, but their hierarchy is unexplored in normal women. OBJECTIVE: To investigate the interaction between kisspeptin and NKB on estrogen-regulated LH secretion. DESIGN: Women were treated with neurokinin-3 receptor (NK3R) antagonist followed by transdermal estradiol to induce LH secretion 48 hours later, with kisspeptin-10 or vehicle infusion during estrogen administration in a 2-way crossover study. SETTING: Clinical research facility. PATIENTS OR OTHER PARTICIPANTS: Healthy females with regular menses. INTERVENTION(S): NK3R antagonist AZD4901 40 mg twice daily orally was taken from cycle day 4-6 for 6 days (n = 10, with 10 no treatment controls). Transdermal estradiol patches (200 µg/d) were applied after 5 days of NK3R antagonist treatment. At 24-hour estradiol treatment, women were randomized to 7-hour kisspeptin-10 (4 µg/kg/h) or vehicle iv infusion, with the alternate infusion in a subsequent cycle. MAIN OUTCOME MEASURE(S): Plasma gonadotropin and estradiol secretion. RESULTS: After an initial suppression, LH secretion was increased 48 hours after estradiol treatment. Kisspeptin-10 increased LH secretion during the inhibitory phase, and LH remained elevated beyond the discontinuation of kisspeptin-10 infusion. NK3R antagonist decreased LH pulse frequency (0.5 ± 0.2 vs 0.7 ± 0.2 pulses/h, P < .05) and stimulated FSH response to kisspeptin-10 infusion (10.7 ± 11.0 vs 5.0 ± 3.6 IU/L, P < .05) with a nonsignificant rise in LH. The duration of LH response was blunted, with LH being lower at 48 hours (7.5 ± 4.8 vs 15.0 ± 11.4 IU/L, P < .05). CONCLUSIONS: These data demonstrate that NKB signaling regulates GnRH/LH secretion in normal women, and is predominantly proximal to kisspeptin in mediating estrogenic positive and negative feedback on LH secretion.

Inhibition of tachykinin NK1 receptor using aprepitant induces apoptotic cell death and G1 arrest through Akt/p53 axis in pre-B acute lymphoblastic leukemia cells.

Increasing number of genetic and cancer biology studies indicated a prominent role for tachykinin NK1 receptor (NK1R) in cancer cell growth and survival. Considering the fact that neoplastic lymphoid precursors in acute lymphoblastic leukemia (ALL) carry a three- to four-fold NK1R expression as compared to normal lymphocytes, using NK1R antagonist seems to be noteworthy in the treatment of ALL patients. In this study, we found that inhibition of NK1R with aprepitant, a selective high-affinity antagonist of the human NK1R, exerts cytotoxic and anti-proliferative effects against pre-B ALL-derived Nalm-6 cells either as single drug or in combination with doxorubicin. Our data showed that treatment of the cells with the inhibitor resulted in apoptotic cell death, at least partly, through abrogation of PI3K/Akt pathway, as revealed by the reduction of phospho/total Akt ratio. In agreement with the inhibitory effect on Akt, we also found that aprepitant increased the expression level of p21 and p27, which in turn leads to the induction of G1 cell cycle arrest. Overall, this study recommends mechanistic pathways by which inhibition of NK1R can augment apoptotic cell death through a plausible p53-dependent pathway rather than NF-κB-depended mechanism in pre-B ALL cells; however, further studies are needed to better characterize the application of NK1R inhibition in clinical cancer treatment.

Analysis of the Expression of Tachykinins and Tachykinin Receptors in the Rat Uterus During Early Pregnancy.

The peptides of the tachykinin family participate in the regulation of reproductive function acting at both central and peripheral levels. Our previous data showed that treatment of rats with a tachykinin NK3R antagonist caused a reduction of litter size. In the present study, we analyzed the expression of tachykinins and tachykinin receptors in the rat uterus during early pregnancy. Uterine samples were obtained from early pregnant rats (Days 1-9 of pregnancy) and from nonpregnant rats during the proestrus stage of the ovarian cycle, and real-time quantitative RT-PCR, immunohistochemistry, and Western blot studies were used to investigate the pattern of expression of tachykinins and tachykinin receptors. We found that all tachykinins and tachykinin receptors were locally synthesized in the uterus of early pregnant rats. The expression of substance P, neurokinin B, and the tachykinin receptors NK1R and NK3R mRNAs and proteins underwent major changes during the days around implantation and they were widely distributed in implantation sites, being particularly abundant in decidual cells. These findings support the involvement of the tachykinin system in the series of uterine events that occur around embryo implantation in the rat.

Neuropeptide Receptor Ligands for the Treatment of Schizophrenia: Focus on Neurotensin and Tachykinins.

There is a wealth of evidence that various neuropeptides and their receptor ligands modulate schizophrenia- related behaviors in preclinical animal models, suggesting that neuropeptide systems may represent potential novel therapeutic targets for the treatment of schizophrenia. In particular, neurotensin and tachykinins have been the subject of significant research efforts, generating compelling preclinical data in the schizophrenia field. However, clinical studies with notably selective tachykinin NK3 receptor antagonists in schizophrenia have been disappointing, and they were unable to confirm the promising therapeutic potential from animal studies, thereby questioning the therapeutic utility of these compounds for this condition. This article reviews preclinical and clinical findings on ligands for neurotensin and tachykinin receptors in schizophrenia, and provides possible explanations for the failure so far to develop small-molecule neuropeptide ligands for the treatment of schizophrenia.

Targeting tachykinin receptors for the treatment of functional gastrointestinal disorders with a focus on irritable bowel syndrome.

BACKGROUND: Tachykinins (TKs) are a family of endogenous peptides widely expressed in the central and in the peripheral nervous systems as well as in the gastrointestinal (GI) tract. They act as full agonists at three different membrane receptors neurokinin (NK) 1, NK2, and NK3, which are G protein-coupled receptors and in the GI tract are expressed both on neurons and effector cells. PURPOSE: This article reviews the literature concerning the role of TKs in the GI tract function in physiological and pathological conditions and their potential relevance in the treatment of functional GI disorders with particular reference to irritable bowel syndrome (IBS). The efficacy of NK1 antagonists in chemotherapy-induced and postoperative nausea and vomiting is well established. While pharmacodynamic studies have reported conflicting and negative results concerning the effects of NK1 and of NK3 antagonists, respectively, on the GI tract function in humans, clinical studies applying the NK3 antagonist talnetant in IBS-D were negative. Pharmacodynamic studies applying NK2 antagonists have suggested a role for antagonism of NK2 receptors in modulation of GI chemical-induced altered motility and of stress-induced altered bowel habits. Clinical studies and in particular a recently completed Phase 2 study have reported that the NK2 antagonist ibodutant is effective and safe in treating symptoms of D-IBS, especially in females.

Innovative pharmacotherapies for women with overactive bladder: where are we now and what is in the pipeline?

INTRODUCTION AND HYPOTHESIS: The impressive prevalence of overactive bladder (OAB) and the relevant limitations of current treatments urge the need for novel therapeutic approaches. METHODS: A systematic literature and web search was performed to identify investigational drugs that entered the early and late phases of clinical development for women with OAB symptoms. RESULTS: Approved pharmacological therapies for OAB (antimuscarinics, beta-3 agonists, and botulinum toxin) are evolving with the development of alternative administration methods, combination strategies, and novel compounds, expected to improve effectiveness, bladder selectivity, and dose flexibility. A wealth of investigational compounds, developed with both public and companies' indoor nonclinical disease-oriented studies, entered the early and late stages of clinical development in the last decade. Most non-anticholinergic compounds in ongoing clinical trials target central and peripheral neurotransmitter receptors involved in neurological modulation of micturition, nonadrenergic-noncholinergic mechanisms, cyclic nucleotide metabolism, different subtypes of ion channels or peripheral receptors of prostaglandins, vanilloids, vitamin D3, and opioids. Fascinating advances are ongoing also in the field of genetic therapy. CONCLUSIONS: New pharmaceutical formulations and drug combinations are expected to be available in the next decade in order to overcome the limitations of current drugs for OAB. Although proof-of-concept, patient-oriented studies yielded disappointing results for several tentative drugs, a lot of clinical research is ongoing that is expected to provide clinicians with novel therapeutic agents in the near future.

Cooperativity to increase Turing pattern space for synthetic biology.

It is hard to bridge the gap between mathematical formulations and biological implementations of Turing patterns, yet this is necessary for both understanding and engineering these networks with synthetic biology approaches. Here, we model a reaction-diffusion system with two morphogens in a monostable regime, inspired by components that we recently described in a synthetic biology study in mammalian cells.1 The model employs a single promoter to express both the activator and inhibitor genes and produces Turing patterns over large regions of parameter space, using biologically interpretable Hill function reactions. We applied a stability analysis and identified rules for choosing biologically tunable parameter relationships to increase the likelihood of successful patterning. We show how to control Turing pattern sizes and time evolution by manipulating the values for production and degradation relationships. More importantly, our analysis predicts that steep dose-response functions arising from cooperativity are mandatory for Turing patterns. Greater steepness increases parameter space and even reduces the requirement for differential diffusion between activator and inhibitor. These results demonstrate some of the limitations of linear scenarios for reaction-diffusion systems and will help to guide projects to engineer synthetic Turing patterns.

Pharmacophore modeling, virtual screening, and in vitro testing reveal haloperidol, eprazinone, and fenbutrazate as neurokinin receptors ligands.

Neurokinin receptors (NKRs) have been shown to be involved in many physiological processes, rendering them promising novel drug targets, but also making them the possible cause for side effects of several drugs. Aiming to answer the question whether the binding to NKRs could have a share in the side effects or even the desired effects of already licensed drugs, we generated a set of ligand-based common feature pharmacophore models based on the structural information about subtype-selective and nonselective NKR antagonists and screened an in-house database mainly composed of licensed drugs. The prospective pharmacological investigations of the virtual hits haloperidol, eprazinone, and fenbutrazate confirmed them to be NKR ligands in vitro. By the identification of licensed drugs as so far unknown NKR ligands, this study contributes to establishing an activity profile of the investigated compounds and confirms the presented pharmacophore models as useful tools for this purpose.

Irritable bowel syndrome: new findings in pathophysiological and therapeutic field.

Irritable bowel syndrome (IBS) is a high prevalence disease, whose symptoms are reported by a large number of young adults with significant effects on quality of life and social costs. Traditionally, IBS has been treated with dietary and lifestyle modification, fiber supplementation, psychological and pharmacological therapy. Since its complex and multifactorial etiopathogenesis is only partially known, therapeutic choices may be difficult and not always effective. New research efforts focused on the role of relationship between central nervous system and gut disorders (brain-gut axis), altered composition of gut microbiota (e.g. an eight times increased risk for IBS after Salmonella infection), immune activation with an increased number of T lymphocytes and mast cells associated with mucosa as well as an increased level of pro-inflammatory cytokines (IL-10 and IL-12, suggesting Th1 polarization), visceral hypersensitivity causing perception of pain even for minimal abdominal distension. Based on these findings, new possibilities of treatment are emerging with encouraging outcomes. Attention is directed to drugs that showed good tolerability profile and poor systemic absorption, which may make them suitable for repeated or long term treatments, as frequently required in patients with IBS. They have been successfully used drugs such as tachykinin receptors antagonists, tryptophan hydroxylase inhibitors, bile acid sequestrants, µ agonist and δ antagonist opioid receptors. Recent studies are discussed in this review, focusing both on new therapeutic approaches and innovative adaptation of previously available treatments.

Mechanisms of action of otilonium bromide (OB) in human cultured smooth muscle cells and rat colonic strips.

BACKGROUND: The pharmacological properties of otilonium bromide (OB) have been investigated using different experimental models, techniques, and conditions, and consequently, the results are not always easy to compare. The aim of the present work was to investigate the pharmacological properties of OB in human cultured colonic smooth muscle cells (HCSMCs), which is the main target of the drug 'in vivo'. Rat colonic strips were used to confirm the pharmacological properties. METHODS: Human cultured colonic smooth muscle cells were studied using the calcium imaging technique. Microelectrodes and muscle bath experiments were performed in rat colonic strips. KEY RESULTS: Otilonium bromide (OB) concentration dependently inhibited nifedipine-sensitive calcium transients induced by KCl (EC50  = 3.6 µM) and BayK8644 (EC50  = 4.0 µM). All the following experiments were performed in the presence of nifedipine. In HCSMC, carbachol-induced calcium transients were inhibited by OB (EC50  = 8.4 µM). Carbachol evoked 1-a smooth muscle depolarization (10 mV) that was antagonized by 100 µM OB; and 2-a contraction that was inhibited by OB (EC50  = 13.0 µM). 'Non-nitrergic (L-NNA 1 mM) non-purinergic (MRS2500 1 µM)' conditions were used to elicit endogenous excitatory responses. Electrical field stimulation caused 1-an atropine-sensitive excitatory junction potential that was inhibited by OB (EC50  = 8.9 µM) and 2-an atropine-sensitive contraction that was inhibited by OB (EC50  = 7.3 µM). In HCSMC, neurokinin A (NKA) and CaCl2 induced calcium transients that were inhibited by OB (NKA: EC50  = 11.7 µM; CaCl2 : EC50  = 17.5 µM). CONCLUSIONS & INFERENCES: Otilonium bromide causes inhibition of L-/T-type calcium channels, muscarinic, and tachykininergic responses that acting together explain the pharmacological properties of the compound.

Chronic treatment with otilonium bromide induces changes in L-type Ca²âº channel, tachykinins, and nitric oxide synthase expression in rat colon muscle coat.

BACKGROUND: Otilonium bromide (OB) is a quaternary ammonium derivative used for the treatment of intestinal hypermotility and is endowed with neurokinin2 receptor (NK2r) antagonist and Ca²âº channel blocker properties. Therefore, the possibility that OB might play a role in the neurokinin receptor/Substance-P/nitric oxide (NKr/SP/NO) circuit was investigated after chronic exposition to the drug. METHODS: Rats were treated with OB 2-20 mg kg⁻¹ for 10 and 30 days. In the proximal colon, the expression and distribution of muscle NOsynthase 1 (NOS1), NK1r, NK2r, SP and Cav 1.2 subunit (for L-type Ca²âº channel) and the spontaneous activity and stimulated responses to NK1r and NK2r agonists were investigated. KEY RESULTS: Immunohistochemistry showed a redistribution of NK1r and L-type Ca²âº channel in muscle cells with no change of NK2r at 30 days, a significant increase in muscle NOS1 expression at 10 days and a significant decrease in the SP content early in the ganglia and later in the intramuscular nerve fibers. Functional studies showed no change in spontaneous activity but a significant increase in maximal contraction induced by NK1r agonist. CONCLUSIONS & INFERENCES: Chronic exposition to OB significantly affects the NKr/SP/NO circuit. The progressive decrease in SP-expression might be the consequence of the persistent presence of OB, the increase of NOS1 expression in muscle cells at 10 days in an attempt to guarantee an adequate NO production, and, at 30 days, the redistribution of the L-type Ca²âº channel and NK1r as a sign to compensate the drug channel block by re-cycling both of them. The physiological data suggest NK1r hypersensitivity.

[Involvement of endogenous tachykinins in the development of jejunal mucosa injury induced by on-steroidal anti-inflammatory drugs]. / Udzial endogennych tachykinin w powstawaniu uszkodzen blony sluzowej jelita czczego wywolanych niesterydowymi lekami przeciwzapalnymi.

UNLABELLED: Previous studies have shown that tachykinins, the largest family of neuropeptides, affect the development of mucosal damage in the stomach and colon. The aim of the study was to assess the influence of tachykinins receptors antagonists on the development of the mucosa injury in the proximal and distal jejunum. MATERIAL AND METHODS: Mucosal damage was induced by administration of non-steroidal anti inflammatory drugs (NSAIDs), indomethacin, celecoxib or combination of indomethacin plus celecoxib given intragastrically. NK-1 receptor antagonist (SR 140333), NK-2 receptor antagonist (SR 48968) and NK-3 receptor antagonist (SR 142801) were administered intraperitoneally twice, 30 min before treatment with NSAID and again 24 h later, 30 min before the end of the experiment. RESULTS: Administration of indomethacin, a relatively selective inhibitor for cyclooxygenase-1 (COX-1), induced mucosal lesions in the jejunum. Lesions area in the distal jejunum was 8-fold bigger than in the proximal jejunum. This effect was associated with a significant reduction in mucosal blood flow and an increase in mucosal concentration of pro-inflammatory interleukin-1beta (IL-1beta). Celecoxib, selective inhibitor for COX-2 failed to induce mucosal lesions and did not affect the mucosal blood flow and IL-1beta concentration in the proximal and distal jejunum. In rats treated with a combination of indomethacin plus celecoxib, ulcers reached maximal area. This effect was associated with the highest concentration of mucosal IL-1beta and maximal reduction in mucosal blood flow. Administration of NK-1 receptor antagonist, SR 140333 reduced jejunal damage induced by indomethacin given alone or in combination with celecoxib. This effect was associated with significant reduction in mucosal concentration of IL-1beta. Effect of SR 140333 on mucosal blood flow was statistically insignificant. Neither NK-2 nor NK-3 receptor inhibitor affected mucosal blood flow, IL-1beta concentration area of NSAIDs-induced mucosal damage in the jejunum. CONCLUSIONS: Blockade of NK-1 receptor protects the jejunum against NSAIDs-induced mucosal injury and reduces local inflammation. This observation indicates the involvement of endogenous tachykinins in deleterious effects of NSAID.

Substance P antagonists as a novel intervention for brain edema and raised intracranial pressure.

Increased intracranial pressure (ICP) following acute brain injury requires the accumulation of additional water in the intracranial vault. One source of such water is the vasculature, although the mechanisms associated with control of blood-brain barrier permeability are unclear. We have recently shown that acute brain injury, such as neurotrauma and stroke, results in perivascular accumulation of the neuropeptide, substance P. This accumulation is associated with increased blood-brain barrier permeability and formation of vasogenic edema. Administration of a substance P antagonist targeting the tachykinin NK1 receptor profoundly reduced the increased blood-brain barrier permeability and edema formation, and in small animal models of acute brain injury, improved functional outcome. In a large, ovine model of experimental traumatic brain injury, trauma resulted in a significant increase in ICP. Administration of an NK1 antagonist caused a profound reduction in post--traumatic ICP, with levels returning to normal within 4 h of drug administration. Substance P NK1 antagonists offer a novel therapeutic approach to the treatment of acute brain injury.