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Salvatore Salomone - One of the best experts on this subject based on the ideXlab platform.
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Behavioural and neurochemical changes induced by stress-related conditions are counteracted by the Neurokinin-2 Receptor antagonist saredutant.
The international journal of neuropsychopharmacology, 2013Co-Authors: Alessandra Tamburella, Andrea Navarria, Valentina Cicirata, Gian Marco Leggio, Vincenzo Micale, Claudio Bucolo, Filippo Drago, Salvatore SalomoneAbstract:These experiments were undertaken to assess the mechanisms underlying the antidepressant-like effects of the Neurokinin-2 (NK(2)) Receptor antagonist saredutant (SR48968) in rats tested in the forced swim test (FST), by analysing hippocampal brain-derived neurotrophic factor (BDNF) and plasma corticosterone [as index of hypothalamic-pituitary-adrenal (HPA) axis activity]. Male Wistar rats received three intraperitoneal injections over 24 h of vehicle, saredutant (5 mg/kg), citalopram (15 mg/kg), clomipramine (50 mg/kg). Rats were subjected to restraint stress (4 h) 24 h prior to the FST procedure. This stress procedure increased immobility and decreased swimming behaviour in the FST; furthermore, it lowered hippocampal BDNF protein expression and increased plasma corticosterone levels. Saredutant and clomipramine or citalopram, used here as positive controls, reduced the immobility time in the FST both under basal conditions and after stress exposure. This effect was not attributable to changes in locomotion, because locomotor activity was unchanged when assessed in the open field test. Pretreatment with para-cholorophenylalanine (150 mg/kg, 72 h and 48 h prior to FST) abolished the effect of citalopram and saredutant on immobility time. At neurochemical level, saredutant attenuated activation of HPA axis in stressed animals more than clomipramine or citalopram. The behavioural effects of saredutant support the hypothesis that NK(2) Receptor activity is involved in stress-related disorders. These effects of saredutant may be related to normalization of the HPA axis. Moreover, saredutant increases BDNF expression in the hippocampus, confirming the role of NK(2) Receptor blockade in BDNF activation following stressor application.
Lesley Marson - One of the best experts on this subject based on the ideXlab platform.
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Prokinetic effects of Neurokinin-2 Receptor agonists on the bladder and rectum of rats with acute spinal cord transection
European Journal of Pharmacology, 2017Co-Authors: Lesley Marson, M. Katofiasc, K. B. Thor, Edward C. Burgard, Nadia M.j. RupniakAbstract:Abstract The suitability of various Neurokinin-2 (NK2) Receptor agonists and routes of administration to elicit on-demand voiding of the bladder and bowel, as future therapy for individuals with spinal cord injury, was examined using a rat model. The current study examined the feasibility of alternative routes of administration, which are more practical for clinical use than intravenous (IV) administration. Voiding and isovolumetric cystometry were recorded in anesthetized, acutely spinalized, female rats after IV, subcutaneous (SC), intramuscular (IM), intranasal (IN), or sublingual (SL) administration of [Lys5,MeLeu9,Nle10]-NKA(4−10) (LMN-NKA). Administration of LMN-NKA (1–10 μg/kg IV; 10−300 μg/kg SC or IM; 15–1000 μg/kg IN or 300–1500 μg/kg SL) elicited rapid-onset, short-duration, dose-related increases in bladder pressure and voiding with the rank order for time of both onset and duration being IV
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Pharmacodynamic evaluation of Lys^5, MeLeu^9, Nle^10-NKA_(4–10) prokinetic effects on bladder and colon activity in acute spinal cord transected and spinally intact rats
Naunyn-Schmiedeberg's Archives of Pharmacology, 2017Co-Authors: F. Aura Kullmann, M. Katofiasc, K. B. Thor, Lesley MarsonAbstract:The purpose of this study was to determine feasibility of a novel therapeutic approach to drug-induced voiding after spinal cord injury (SCI) using a well-characterized, peptide, Neurokinin 2 Receptor (NK_2 Receptor) agonist, Lys^5, MeLeu^9, Nle^10-NKA_(4–10) (LMN-NKA). Cystometry and colorectal pressure measurements were performed in urethane-anesthetized, intact, and acutely spinalized female rats. Bladder pressure and voiding were monitored in response to intravenous LMN-NKA given with the bladder filled to 70% capacity. LMN-NKA (0.1–300 μg/kg) produced dose-dependent, rapid (
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Pharmacodynamic evaluation of Lys5, MeLeu9, Nle10-NKA(4-10) prokinetic effects on bladder and colon activity in acute spinal cord transected and spinally intact rats.
Naunyn-schmiedebergs Archives of Pharmacology, 2016Co-Authors: F. Aura Kullmann, M. Katofiasc, K. B. Thor, Lesley MarsonAbstract:The purpose of this study was to determine feasibility of a novel therapeutic approach to drug-induced voiding after spinal cord injury (SCI) using a well-characterized, peptide, Neurokinin 2 Receptor (NK2 Receptor) agonist, Lys5, MeLeu9, Nle10-NKA(4–10) (LMN-NKA). Cystometry and colorectal pressure measurements were performed in urethane-anesthetized, intact, and acutely spinalized female rats. Bladder pressure and voiding were monitored in response to intravenous LMN-NKA given with the bladder filled to 70% capacity. LMN-NKA (0.1–300 μg/kg) produced dose-dependent, rapid (
Alessandra Tamburella - One of the best experts on this subject based on the ideXlab platform.
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Behavioural and neurochemical changes induced by stress-related conditions are counteracted by the Neurokinin-2 Receptor antagonist saredutant.
The international journal of neuropsychopharmacology, 2013Co-Authors: Alessandra Tamburella, Andrea Navarria, Valentina Cicirata, Gian Marco Leggio, Vincenzo Micale, Claudio Bucolo, Filippo Drago, Salvatore SalomoneAbstract:These experiments were undertaken to assess the mechanisms underlying the antidepressant-like effects of the Neurokinin-2 (NK(2)) Receptor antagonist saredutant (SR48968) in rats tested in the forced swim test (FST), by analysing hippocampal brain-derived neurotrophic factor (BDNF) and plasma corticosterone [as index of hypothalamic-pituitary-adrenal (HPA) axis activity]. Male Wistar rats received three intraperitoneal injections over 24 h of vehicle, saredutant (5 mg/kg), citalopram (15 mg/kg), clomipramine (50 mg/kg). Rats were subjected to restraint stress (4 h) 24 h prior to the FST procedure. This stress procedure increased immobility and decreased swimming behaviour in the FST; furthermore, it lowered hippocampal BDNF protein expression and increased plasma corticosterone levels. Saredutant and clomipramine or citalopram, used here as positive controls, reduced the immobility time in the FST both under basal conditions and after stress exposure. This effect was not attributable to changes in locomotion, because locomotor activity was unchanged when assessed in the open field test. Pretreatment with para-cholorophenylalanine (150 mg/kg, 72 h and 48 h prior to FST) abolished the effect of citalopram and saredutant on immobility time. At neurochemical level, saredutant attenuated activation of HPA axis in stressed animals more than clomipramine or citalopram. The behavioural effects of saredutant support the hypothesis that NK(2) Receptor activity is involved in stress-related disorders. These effects of saredutant may be related to normalization of the HPA axis. Moreover, saredutant increases BDNF expression in the hippocampus, confirming the role of NK(2) Receptor blockade in BDNF activation following stressor application.
C.a. Maggi - One of the best experts on this subject based on the ideXlab platform.
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the Neurokinin 2 Receptor antagonist ibodutant improves overall symptoms abdominal pain and stool pattern in female patients in a phase ii study of diarrhoea predominant ibs
Gut, 2017Co-Authors: Jan Tack, K Schumacher, G Tonini, Simona Scartoni, A Capriati, C.a. MaggiAbstract:Background Tachykinins have been implicated in the pathophysiology of IBS with diarrhoea (IBS-D). Our aim was to study the efficacy and safety of ibodutant, a selective Neurokinin-2 (NK2) Receptor antagonist, in patients with IBS-D. Methods This multinational double-blind, placebo-controlled study recruited 559 patients with IBS-D according to Rome III criteria. After a 2-week treatment-free run-in, patients were randomised to ibodutant 1 mg, 3 mg, 10 mg or placebo once daily for eight consecutive weeks. Responders were those with a combined response of satisfactory relief (weekly binary question yes/no) of overall IBS symptoms and abdominal pain/discomfort on ≥75% weeks (primary end point). Secondary end points included abdominal pain and stool pattern. Data were also analysed according to US Food and Drug Administration (FDA)-approved interim end points (improvement of pain and stool consistency). Safety was assessed by monitoring adverse events and laboratory tests. Prespecified statistical analysis involved the whole group as well as gender subgroups. Results Demographics and baseline characteristics were comparable for all treatment arms. In the overall population, responsiveness tended to increase with escalating ibodutant doses. In the prespecified analysis by gender, ibodutant 10 mg demonstrated significant superiority over placebo in females (p=0.003), while no significant effect occurred in males. This was confirmed for secondary end points and for the responder analysis according to FDA-approved end points. The tolerability and safety of ibodutant was excellent at all doses. Conclusions Ibodutant showed dose-dependent efficacy response in IBS-D, reaching statistical significance at the 10 mg dose in female patients. The safety and tolerability profile of ibodutant was similar to placebo. Trial registration number NCT01303224.
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Stimulation of neuropeptide release from sensory and enteric neurons in the guinea-pig by α-latrotoxin
Neuroscience, 1995Co-Authors: S.a. Waterman, C.a. MaggiAbstract:Abstract α-Latrotoxin, from black widow spider venom, stimulates exocytosis of small synaptic vesicles at central and peripheral synapses. However, it is widely accepted that neuropeptide-containing large dense-core vesicles are insensitive to the toxin. In the present study, we investigated whether α-latrotoxin releases neuropeptides from primary afferent and enteric neurons. The guinea-pig renal pelvis is innervated by primary sensory neurons containing tachykinins and calcitonin gene-related peptide, but has no functional cholinergic or noradrenergic motor innervation. α-Latrotoxin increased the amplitude of spontaneous myogenic contractions of the renal pelvis, and this effect was prevented by prior capsaicin desensitization and by antagonists at Neurokinin-1 and Neurokinin-2 Receptors. In the presence of the latter antagonists, α-latrotoxin decreased the amplitude of the contractions, and this is likely to be mediated by calcitonin gene-related peptide. Thus, α-latrotoxin releases tachykinins and calcitonin gene-related peptide from capsaicin-sensitive sensory neurons in the renal pelvis. The circular muscle of the guinea-pig distal colon is innervated by excitatory and inhibitory motor neurons, which use a number of transmitters. In the presence of antagonists to block each of the known transmitters apart from the tachykinins, α-latrotoxin increased the amplitude of spontaneous contractions; this effect was prevented by the prior addition of Neurokinin-1 and Neurokinin-2 Receptor antagonists. Thus, α-latrotoxin stimulates the release of tachykinins from excitatory motor neurons in the myenteric plexus of the distal colon. In conclusion, this study demonstrates that α-latrotoxin is able to evoke the release of neuropeptides from both sensory and enteric neurons. This suggests that exocytosis of large dense-core vesicles shares more of the features of exocytosis of small synaptic vesicles than has previously been appreciated.
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Evidence for a role of tachykinins as sensory transmitters in the activation of micturition reflex.
Neuroscience, 1993Co-Authors: Alessandro Lecci, Sandro Giuliani, Claude Garret, C.a. MaggiAbstract:Abstract The possible involvement of tachykinin Neurokinin-1 and Neurokinin-2 Receptors in the activation of various micturition-related reflexes was assessed by the intrathecal administration of selective Neurokinin-1 or Neurokinin-2 Receptor antagonists at lumbosacral spinal cord level in urethane-anaesthetized rats. The effect of the glutamate N-methyl- d -aspartate Receptor antagonist, 2-amino-5-phosphonovaleric acid, was also investigated for comparison. The effect of antagonists was investigated on: (i) the chemonociceptive vesicovesical reflex activated by topical application of capsaicin onto the urinary bladder; (ii) the distension-induced micturition reflex produced by transvesical filling with saline; (iii) distension-induced rhythmic bladder contractions in isovolumetric conditions (urethra-ligated rats); (iv) (iv) the somatovesical excitatory reflex caused by noxious perineal pinching. The Neurokinin-2 Receptor selective antagonists MEN 10,376 and SR 48,968 were ineffective in the three models in all doses tested. Selective Neurokinin-1 Receptor antagonists blocked the chemonociceptive reflex produced by topical application of capsaicin with the rank order of potency (lowest effective dose in brackets): GR 82,334 (1nmol/rat)> RP 67,580 (10nmol/rat) > (±)CP 96,345 (100 nmol/rat). Unlike GR 82,334, RP 67,580 (10nmol/rat) and (±)CP 96,345 (100nmol/rat) were also effective on the distension-induced micturition reflex elicited by transvesical filling. Similarly, distension-induced rhythmic contractions were inhibited by RP 67,580 (10 nmol/rat) and (±)CP 96,345 (100 nmol/rat) whereas the effect of GR 82,334 was not significant. RP 68,651, the enantiomer of RP 67,580 devoid of Neurokinin-1 Receptor blocking activity, was inactive in both models. 2-Amino-5-phosphonovateric acid (250 nmol/rat) blocked the three types of vesicoexcitatory reflexes. Intravenous administration of (±)CP 96,345, RP 67,580 or 2-amino-5-phosphonovateric acid at the same doses proven effective after the intrathecal route, had no effect on distension-induced rhythmic contractions. To ascertain whether the effect of Neurokinin-1 Receptor antagonists or 2-amino-5-phosphonovaleric acid may be related to a blockade of tachykinins released from capsaicin-sensitive primary afferent neurons, the effect of RP 67,580 was investigated on the distension-evoked micturition reflex in capsaicin-pretreated rats. Capsaicin pretreatment (50 mg/kg, subcutaneously, four days before) increased bladder capacity. RP 67,580 was no longer effective in capsaicin-pretreated rats. In contrast, 2-amino-5-phosphonovateric acid produced a further increase in bladder capacity in capsaicin-pretreated rats. We conclude that tachykinin Neurokinin-1 but not Neurokinin-2 Receptors are involved in the activation of vesicoexcitatory micturition-related reflexes in the rat spinal cord. The ineffectiveness of RP 67,580 following capsaicin-pretreatment indicates that the role of Neurokinin-1 Receptors is restricted to capsaicin-sensitive afferents. By contrast, the role of N-methyl- d -aspartate Receptors in spinal regulation of micturition-related reflexes is not restricted to modulation of afferent input from capsaicin-sensitive sensory neurons.
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The role of Neurokinin and N-methyl-d-aspartate Receptors in synaptic transmission from capsaicin-sensitive primary afferents in the rat spinal cord in vitro
Neuroscience, 1993Co-Authors: Istvan Nagy, C.a. Maggi, A. Dray, Clifford J. Woolf, L. UrbanAbstract:Abstract The rat spinal cord with connected dorsal root ganglia was used to study Neurokinin and N -methyl- d -aspartate Receptors involved in the sensory synaptic transmission of dorsal horn cells. Selective C-fibre excitation was produced by capsaicin (200–500 nM) administered to the dorsal root ganglions. Sixty-nine per cent of dorsal horn cells responded with a postsynaptic depolarization and enhanced synaptic activity, recorded via intracellular electrodes, to capsaicin-activated primary afferent input. Dorsal horn neurons activated by the capsaicin-evoked input were also excited by a 1-min perfusion of the Neurokinin-1 Receptor agonists substance P methyl ester or GR73 632 and by the Neurokinin-2 agonist Neurokinin-A. These cells were also depolarized by N -methyl- d -aspartate. Responses to substance P methyl ester and GR73 632 were selectively reduced by the Neurokinin-1 Receptor antagonist CP96 345, and responses to Neurokinin-A were completely blocked by the Neurokinin-2 Receptor antagonist MEN 10 376. The depolarization evoked by N -methyl- d -aspartate was not altered by either of the antagonists, but was completely blocked by the selective N -methyl- d -aspartate Receptor antagonist (−)-2-amino-5-phosphonovaleric acid. Capsaicin-evoked responses in the dorsal horn were inhibited by MEN 10 376 (63 ± 13% inhibition) but no significant change was observed with CP96 345. The N -methyl- d -aspartate Receptor antagonist (−)-2-amino-5-phosphonovaleric acid consistently inhibited the capsaicin-induced response by 76 ± 14%. Combination of (−)-2-amino-5-phosphonovaleric acid and MEN 10 376 produced an almost complete abolition of the capsaicin-evoked depolarization. However, when (−)-2-amino-5-phosphonovaleric acid and CP96 345 were perfused together there was no alteration from the response to (−)-2-amino-5-phosphonovaleric acid alone. These data suggest that activation of dorsal horn neurons by polymodal nociceptors, the most abundant type of capsaicin sensitive C-fibres, involve mainly Neurokinin-2 rather than Neurokinin-1 Receptors. A strong N -methyl- d -aspartate Receptor-mediated component is also involved. The N -methyl- d -aspartate and Neurokinin-2 Receptors may be co-activated by nociceptive input and act together to produce slow synaptic potentials and prolonged excitability changes.
Andrea Navarria - One of the best experts on this subject based on the ideXlab platform.
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Behavioural and neurochemical changes induced by stress-related conditions are counteracted by the Neurokinin-2 Receptor antagonist saredutant.
The international journal of neuropsychopharmacology, 2013Co-Authors: Alessandra Tamburella, Andrea Navarria, Valentina Cicirata, Gian Marco Leggio, Vincenzo Micale, Claudio Bucolo, Filippo Drago, Salvatore SalomoneAbstract:These experiments were undertaken to assess the mechanisms underlying the antidepressant-like effects of the Neurokinin-2 (NK(2)) Receptor antagonist saredutant (SR48968) in rats tested in the forced swim test (FST), by analysing hippocampal brain-derived neurotrophic factor (BDNF) and plasma corticosterone [as index of hypothalamic-pituitary-adrenal (HPA) axis activity]. Male Wistar rats received three intraperitoneal injections over 24 h of vehicle, saredutant (5 mg/kg), citalopram (15 mg/kg), clomipramine (50 mg/kg). Rats were subjected to restraint stress (4 h) 24 h prior to the FST procedure. This stress procedure increased immobility and decreased swimming behaviour in the FST; furthermore, it lowered hippocampal BDNF protein expression and increased plasma corticosterone levels. Saredutant and clomipramine or citalopram, used here as positive controls, reduced the immobility time in the FST both under basal conditions and after stress exposure. This effect was not attributable to changes in locomotion, because locomotor activity was unchanged when assessed in the open field test. Pretreatment with para-cholorophenylalanine (150 mg/kg, 72 h and 48 h prior to FST) abolished the effect of citalopram and saredutant on immobility time. At neurochemical level, saredutant attenuated activation of HPA axis in stressed animals more than clomipramine or citalopram. The behavioural effects of saredutant support the hypothesis that NK(2) Receptor activity is involved in stress-related disorders. These effects of saredutant may be related to normalization of the HPA axis. Moreover, saredutant increases BDNF expression in the hippocampus, confirming the role of NK(2) Receptor blockade in BDNF activation following stressor application.