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1.
J Neurophysiol ; 127(2): 397-404, 2022 02 01.
Article in English | MEDLINE | ID: mdl-34986062

ABSTRACT

Whether pinocembrin (PCN) could be used to alleviate hip fracture-induced pain is investigated in this research. Aged rats with hip fractures were treated with vehicle or 80 mg/kg/day PCN from week 3 to week 4. Then, hind paw mechanical allodynia, unweighting, warmth, and thickness were measured. The microglia and astrocytes activation and proliferation markers in the spinal dorsal horn were detected with real-time PCR and immunofluorescence staining. The relative expression of substance P and its receptor, tachykinin receptor 1 (Tacr1), was detected with enzyme-linked immunosorbent assay (ELISA) and Western blots. The antinociceptive effect of Tacr1 inhibitor LY303870 was also testified. PCN alleviated hip fracture-induced hind paw nociceptive (allodynia and unweighting) and vascular changes (warmth and thickness) in aged rats with diminished microglia and astrocytes activation and proliferation in the spinal dorsal horn. Upregulated substance P and Tacr1 were induced after hip fracture, which could be reversed by PCN treatment. Furthermore, LY303870 treatment partially reversed both spinal nociceptive sensitization and vascular changes after hip fracture. Substance P signaling contributes to the nociceptive and vascular changes observed in the hip fracture, which could be alleviated by PCN.NEW & NOTEWORTHY Substance P signaling contributes to the nociceptive and vascular changes observed in hip fracture, which could be alleviated by PCN.


Subject(s)
Aging , Flavanones/pharmacology , Hip Fractures/drug therapy , Neurokinin-1 Receptor Antagonists/pharmacology , Pain/drug therapy , Substance P/drug effects , Animals , Disease Models, Animal , Flavanones/administration & dosage , Hip Fractures/complications , Hip Fractures/metabolism , Indoles/pharmacology , Male , Neurokinin-1 Receptor Antagonists/administration & dosage , Nociceptive Pain/drug therapy , Nociceptive Pain/etiology , Nociceptive Pain/metabolism , Pain/etiology , Pain/metabolism , Piperidines/pharmacology , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects
2.
Physiol Rep ; 9(22): e15117, 2021 11.
Article in English | MEDLINE | ID: mdl-34806344

ABSTRACT

Endometriosis is the abnormal growth of endometrial tissue. The goals of the study are: (1) Is any correlation between endometriosis pain and neurotrophins in the serum, dorsal root ganglion (DRG), and peritoneal fluid (PF) in rat models of experimental endometriosis?, (2) Possible therapeutic effects of royal jelly (RJ) on pain scores, size of endometriotic lesion, and neurotrophic factors. Forty-eight Sprague Dawley female rats weighing 205.023 ± 21.54 g were maintained in a standard condition. The rats were randomly divided into one of the six groups: Control (no intervention), Sham-1 (remove of uterine horn), RJ (administration of 200 mg/kg/day RJ for 21 days), Endometriosis (induction of endometriosis), Treatment (induction of endometriosis+administration of 200 mg/kg/day RJ for 21 days), and Sham-2 (induction of endometriosis+administration of water). Formalin test performed for pain evaluation. The levels of Brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), substance P, and calcitonin gene-related peptide (CGRP) were measured by enzyme-linked immunosorbent assay. The mean pain scores in all three phases of the formalin test were significantly increased by endometriosis induction (p < 0.05). The concentrations of BDNF, NGF, and CGRP in DRG of the endometriosis group were significantly higher than these factors in the Control, Sham-1, and RJ groups (p < 0.05). RJ could significantly (p < 0.001) decrease the mean lesion size and the mean pain score in the late phase (p < 0.05). The present results determine that endometriosis pain may be related to nervous system neurotrophic factors. Treatment with RJ could decrease the size of endometriosis lesions as well as pain scores. The findings may shed light on other complementary and alternative remedies for endometriosis.


Subject(s)
Endometriosis/metabolism , Fatty Acids/pharmacology , Nerve Growth Factors/drug effects , Animals , Ascitic Fluid/drug effects , Ascitic Fluid/metabolism , Brain-Derived Neurotrophic Factor/drug effects , Brain-Derived Neurotrophic Factor/metabolism , Calcitonin Gene-Related Peptide/drug effects , Calcitonin Gene-Related Peptide/metabolism , Disease Models, Animal , Endometriosis/pathology , Female , Ganglia, Spinal/drug effects , Ganglia, Spinal/metabolism , Nerve Growth Factor/drug effects , Nerve Growth Factor/metabolism , Nerve Growth Factors/metabolism , Pain Measurement/drug effects , Rats , Substance P/drug effects , Substance P/metabolism
3.
Regul Toxicol Pharmacol ; 122: 104916, 2021 Jun.
Article in English | MEDLINE | ID: mdl-33711392

ABSTRACT

Cizolirtine, a substance-P and calcitonin gene-related peptide release modulator developed for the treatment of pain and urinary incontinence, was orally administered for 26-weeks to rats at dosages of 20, 60 and 200 mg/kg/day. Clinical signs were limited to post-dosing salivation and brown staining on head and muzzle. There were slight decreases in bodyweight gain and slight increases in water consumption among cizolirtine-treated animals. Slight increases in plasma alkaline phosphatase activity, and cholesterol and phospholipid concentrations were observed in mid- and/or high-dose animals. Low urinary volume, pH and sodium and potassium outputs were observed after 12-weeks, and low urinary pH, low sodium and high potassium outputs at end of treatment. Increased relative (to bodyweight) liver weight was observed in high-dose animals. Treated males and high-dose females showed a dose-related increase in the incidence and severity of periacinar hepatocytic hypertrophy and midzonal/periacinar hepatocytic fat vacuolization. Increased incidences of hepatic clear cell foci were observed in all cizolirtine-treated male groups and, to a lesser extent, in treated females. Ovaries of treated females showed a dose-dependent increased incidence of absent corpora lutea and, occasionally, follicular cysts. The dosages of 20 and 60 mg/kg/day were considered as the No-Observed-Adverse-Effect Levels for males and females, respectively.


Subject(s)
Analgesics/toxicity , Calcitonin Gene-Related Peptide/drug effects , Liver/drug effects , Pyrazoles/toxicity , Substance P/drug effects , Animals , Body Weight , Dose-Response Relationship, Drug , Drinking , Female , Hydrogen-Ion Concentration , Lipids/blood , Male , Organ Size , Rats , Rats, Sprague-Dawley , Sex Factors , Water-Electrolyte Balance
4.
Neurotherapeutics ; 18(2): 1360-1370, 2021 04.
Article in English | MEDLINE | ID: mdl-33449304

ABSTRACT

Oropharyngeal dysphagia is prevalent in age-related neurological disorders presenting with impaired efficacy and safety of swallowing due to a loss of muscle force and sensory deficits. Stimulating the oropharynx with capsaicin that mediates Substance P release is an emerging pharmacological treatment option which needs further scientific evidence. Our aim was to comprehensively evaluate the effect of capsaicin on biochemical, neurophysiological, and biomechanical parameters of swallowing function. In a randomized study on healthy individuals, the impact of orally administered capsaicinoids at different dosages and application durations in comparison to non-carbonated water was evaluated. Time course and magnitude of salivary Substance P increase were monitored. Magnetoencephalography was used to detect cortical swallowing network alterations. Modifications in swallowing biomechanics were measured applying high-resolution pharyngeal manometry. Capsaicinoids at 10 µmol/L improved swallowing efficacy as seen by a significant increase of pharyngeal contractile integral and upper esophageal sphincter activation and relaxation times in manometry. Significant improvement of precision in a challenging swallow task accompanied by a reduction in swallowing-related submental electromyographic power was observed with capsaicinoids preconditioning at 10 µmol/L over 5 min, but not with continuous stimulation. The cortical activation pattern remained unchanged after any intervention. A significant increase of salivary Substance P was not detected with 10 µmol/L but with 50 µmol/L and lasted for 15 min after application. Capsaicinoids mediate dose-dependent Substance P release and positively alter swallowing biomechanics in healthy subjects. The results provide supportive evidence for the value of natural capsaicinoids to improve swallowing function.


Subject(s)
Capsaicin/pharmacology , Cerebral Cortex/drug effects , Deglutition/drug effects , Esophageal Sphincter, Upper/drug effects , Pharynx/drug effects , Sensory System Agents/pharmacology , Substance P/drug effects , Adult , Biomechanical Phenomena , Capsaicin/analogs & derivatives , Cerebral Cortex/diagnostic imaging , Cerebral Cortex/physiology , Deglutition/physiology , Electromyography , Esophageal Sphincter, Upper/physiology , Female , Healthy Volunteers , Humans , Magnetoencephalography , Male , Manometry , Pharynx/physiology , Random Allocation , Saliva/chemistry , Saliva/drug effects , Substance P/metabolism , Young Adult
5.
BMC Complement Med Ther ; 20(1): 289, 2020 Sep 22.
Article in English | MEDLINE | ID: mdl-32962697

ABSTRACT

BACKGROUND: In recent years, it has been reported that Qinbai Qingfei Concentrated Pellet (QQCP) has the effect of relieving cough and reducing sputum. However, the therapeutic potentials of QQCP on post-infectious cough (PIC) rat models has not been elucidated. So the current study was aimed to scientifically validate the efficacy of QQCP in post infectious cough. METHODS: All rats were exposed to sawdust and cigarette smokes for 10 days, and intratracheal lipopolysaccharide (LPS) and capsaicin aerosols. Rats were treated with QQCP at dose of 80, 160, 320 mg/kg. Cough frequency was monitored twice a day for 10 days after drug administration. Inflammatory cell infiltration was determined by ELISA. Meanwhile, the histopathology of lung tissue and bronchus in rats were evaluated by hematoxylin-eosin staining (H&E). Neurogenetic inflammation were measured by ELISA and qRT-PCR. RESULTS: QQCP dose-dependently decreased the cough frequency and the release of pro-inflammatory cytokines TNF-α, IL-1ß, IL-6 and IL-8, but exerted the opposite effects on the secretion of anti-inflammatory cytokines IL-10 and IL-13 in BALF and serum of PIC rats. The oxidative burden was effectively ameliorated in QQCP-treated PIC rats as there were declines in Malondialdehyde (MDA) content and increases in Superoxide dismutase (SOD) activity in the serum and lung tissue. In addition, QQCP blocked inflammatory cell infiltration into the lung as evidenced by the reduced number of total leukocytes and the portion of neutrophils in the broncho - alveolar lavage fluid (BALF) as well as the alleviated lung damage. Furthermore, QQCP considerable reversed the neurogenetic inflammation caused by PIC through elevating neutral endopeptidase (NEP) activity and reducing Substance P (SP) and Calcitonin gene related peptide (CGRP) expression in BALF, serum and lung tissue. CONCLUSIONS: Our study indicated that QQCP demonstrated a protective role of PIC and may be a potential therapeutic target of PIC.


Subject(s)
Cough/drug therapy , Drugs, Chinese Herbal/pharmacology , Neprilysin/drug effects , Substance P/drug effects , Animals , Biomarkers/metabolism , Cytokines/metabolism , Disease Models, Animal , Male , Rats , Rats, Sprague-Dawley
6.
Pharmacol Biochem Behav ; 198: 173034, 2020 11.
Article in English | MEDLINE | ID: mdl-32910929

ABSTRACT

In the spinal cord, γ-aminobutyric acid (GABA) interneurons play an essential role in antinociception. However, not all actions of GABA favor antinociception at the supraspinal level. We previously reported that gabaculine, which increases endogenous GABA in the synaptic clefts, induces loss of the righting reflex (LORR) that is one indicator of hypnosis, but not immobility in response to noxious stimulus. A slow pain is transmitted to the spinal cord via C fibers and evokes substance P (SP) release from their terminals. However, the antinociceptive effects of gabaculine are still unknown. Our study examined whether the analgesic effects of the opioid morphine or the α2-adrenoceptor agonist dexmedetomidine, whose actions are mediated through facilitation of the descending analgesic pathway, are affected by gabaculine-induced LORR. We also explored the effects of GABA receptor agonists on SP release from cultured dorsal root ganglion (DRG) neurons. All drugs were administered systemically to mice. To assess antinociception, loss of nociceptive response (analgesia) and immobility were evaluated. DRG cells were dissected from rats. Gabaculine produced no analgesia. Either morphine or dexmedetomidine in combination with gabaculine induced immobility; however, the doses of each drug required to induce immobility were much higher than those required to induce analgesia. Capsaicin significantly increased SP release from DRG cells, but a high concentration (1 mM) of the GABA receptor agonist muscimol, propofol, gaboxadol, or baclofen did not inhibit the capsaicin-induced SP release, suggesting that their antinociceptive effects were not through this mechanism. Thus, the gabaculine-induced LORR may inhibit the descending analgesic pathway.


Subject(s)
Analgesics/pharmacology , Cyclohexanecarboxylic Acids/pharmacology , Dexmedetomidine/pharmacology , Morphine/pharmacology , Reflex, Righting/drug effects , Adrenergic alpha-2 Receptor Agonists/pharmacology , Analgesics/metabolism , Animals , Baclofen/pharmacology , GABA Agonists/pharmacology , Ganglia, Spinal/drug effects , Male , Mice , Muscimol/pharmacology , Neural Pathways/drug effects , Neurons/drug effects , Pain Measurement/drug effects , Rats , Signal Transduction/drug effects , Spinal Cord/drug effects , Substance P/drug effects , Substance P/metabolism
7.
Pharmacology ; 105(11-12): 723-728, 2020.
Article in English | MEDLINE | ID: mdl-32694256

ABSTRACT

This study aimed to investigate whether the consecutive administration of methotrexate affects 5-hydroxytryptamine (5-HT) synthesis in the rat small intestine. Rats received methotrexate at a dose of 12.5 mg/kg intraperitoneally on 4 consecutive days. NG-nitro-L-arginine methyl ester (L-NAME) was given subcutaneously to inhibit nitric oxide (NO) synthase. Methotrexate moderately altered 5-HT synthesis, whereas the combined administration of methotrexate and L-NAME significantly changed 5-HT synthesis in the rat ileal tissue. These results suggest that endogenous NO has an antagonistic role in the induction of 5-HT synthesis in rats following the consecutive administration of methotrexate.


Subject(s)
Enzyme Inhibitors/pharmacology , Intestine, Small/drug effects , Intestine, Small/metabolism , Methotrexate/pharmacology , Nitric Oxide/metabolism , Serotonin/biosynthesis , Animals , Drug Administration Schedule , Enzyme Inhibitors/administration & dosage , Injections, Intraperitoneal , Intestinal Diseases/chemically induced , Intestine, Small/pathology , Male , Methotrexate/administration & dosage , NG-Nitroarginine Methyl Ester/administration & dosage , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , RNA, Messenger/metabolism , Rats , Rats, Wistar , Substance P/drug effects , Substance P/metabolism , Tachykinins/drug effects , Tachykinins/genetics , Tachykinins/metabolism , Tryptophan Hydroxylase/drug effects , Tryptophan Hydroxylase/genetics , Tryptophan Hydroxylase/metabolism
8.
Rev Assoc Med Bras (1992) ; 65(9): 1188-1192, 2019.
Article in English | MEDLINE | ID: mdl-31618336

ABSTRACT

OBJECTIVE: We aimed to explore the effects of neuropeptides ghrelin, obestatin, and vasoactive intestinal peptide (VIP) on seizures and plasma concentrations of neuroinflammation biomarkers including calcitonin gene-related peptide (CGRP), substance-P (SP), and interleukin-1 beta (IL-1ß) in pentylenetetrazol-induced seizures in rats. METHODS: Ghrelin (80 µg/kg), obestatin (1 µg/kg), VIP (25 ng/kg) or saline were administered to rats intraperitoneally 30 min before pentylenetetrazole (PTZ, 50 mg/kg) injections. Stages of epileptic seizures were evaluated by Racine's scale, and plasma CGRP, SP, and IL-1ß concentrations were measured using ELISA. RESULTS: Both obestatin and VIP shortened onset-time of generalized tonic-clonic seizure, respectively, moreover VIP also shortened the onset-time of first myoclonic-jerk induced by PTZ. While PTZ increased plasma CGRP, SP and IL-1ß concentrations, ghrelin reduced the increases evoked by PTZ. While VIP further increased PTZ-evoked CGRP levels, it diminished IL-1ß concentrations. However, obestatin did not change CGRP, SP, and IL-1ß concentrations. CONCLUSION: Our results suggest that ghrelin acts as an anticonvulsant, obestatin acts as a proconvulsant, and VIP has dual action on epilepsy. Receptors of those neuropeptides may be promising targets for epilepsy treatment.


Subject(s)
Convulsants , Neuropeptides , Pentylenetetrazole , Peptide Hormones , Seizures , Animals , Male , Biomarkers/blood , Calcitonin Gene-Related Peptide/blood , Calcitonin Gene-Related Peptide/drug effects , Convulsants/adverse effects , Disease Models, Animal , Ghrelin/pharmacology , Inflammation , Interleukin-1beta/blood , Interleukin-1beta/drug effects , Myoclonus , Neuropeptides/drug effects , Pentylenetetrazole/adverse effects , Peptide Hormones/pharmacology , Random Allocation , Rats, Wistar , Seizures/chemically induced , Seizures/metabolism , Substance P/blood , Substance P/drug effects , Time Factors , Vasoactive Intestinal Peptide/pharmacology
9.
Neurourol Urodyn ; 38(8): 2159-2169, 2019 11.
Article in English | MEDLINE | ID: mdl-31541501

ABSTRACT

AIM: We investigated the effects of Ba-Wei-Die-Huang-Wan (BWDHW) on ketamine-induced cystitis (KIC) in a rat model. METHODS: Female Sprague-Dawley rats were distributed into three groups: control (saline), ketamine (25 mg/kg/day for 28 days), or ketamine (25 mg/kg/day for 28 days) plus BWDHW (90 mg/kg/day, started from day 14). Functional magnetic resonance imaging (fMRI), metabolic cage study, and cystometry were evaluated. Bladder histology was evaluated. Western blots of the bladder proteins were carried out. RESULTS: Compared with controls, ketamine-treated rats showed stronger fMRI intensity in the periaqueductal gray area and bladder overactivity in the bladder functional study, but the ketamine/BWDHW-treated rats did not. Furthermore, ketamine breached the uroplakin III membrane at the apical surface of the urothelium, enhanced substance P spread over the urothelium, induced suburothelial hemorrhage and monocyte/macrophage infiltration, and caused interstitial fibrosis deposition. By contrast, the BWDHW-treated rats exhibited less substance P spread, lower suburothelial monocyte/macrophage infiltration, and lower interstitial fibrosis deposition. The ketamine group showed significant overexpression of neuroreceptors in the bladder mucosa (the transient receptor potential vanilloid 1 and M2 - and M3 -muscarinic receptors) and detrusor (M2 - and M3 -muscarinic receptors); inflammatory mediators in the detrusor (interleukin-1ß [IL-1ß], IL-6, tumor necrosis factor-α, nuclear factor-κB, cyclooxygenase-2, and intercellular adhesion molecule-1); and fibrogenesis molecules in the detrusor (transforming growth factor-ß1, collagen I, collagen III, and fibronectin). However, no significant changes were noted between the ketamine/BWDHW and control groups. CONCLUSION: BWDHW could exert therapeutic effects by inhibiting the upregulation of neuroreceptors, modulating inflammatory mediators, suppressing fibrogenesis, and ameliorating bladder overactivity in rats with KIC.


Subject(s)
Cystitis/chemically induced , Drugs, Chinese Herbal/pharmacology , Ketamine/adverse effects , Urinary Bladder, Overactive/chemically induced , Urinary Bladder/drug effects , Urothelium/drug effects , Animals , Collagen/drug effects , Collagen/metabolism , Cyclooxygenase 2/drug effects , Cyclooxygenase 2/metabolism , Cystitis/metabolism , Cystitis/pathology , Cystitis/physiopathology , Female , Fibronectins/drug effects , Fibronectins/metabolism , Functional Neuroimaging , Intercellular Adhesion Molecule-1/drug effects , Intercellular Adhesion Molecule-1/metabolism , Interleukin-1beta/drug effects , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Magnetic Resonance Imaging , NF-kappa B/drug effects , NF-kappa B/metabolism , Periaqueductal Gray/diagnostic imaging , Rats , Rats, Sprague-Dawley , Receptors, Muscarinic/drug effects , Receptors, Muscarinic/metabolism , Sensory Receptor Cells , Substance P/drug effects , Substance P/metabolism , TRPV Cation Channels/drug effects , TRPV Cation Channels/metabolism , Transforming Growth Factor beta1/drug effects , Transforming Growth Factor beta1/metabolism , Tumor Necrosis Factor-alpha/drug effects , Tumor Necrosis Factor-alpha/metabolism , Urinary Bladder/metabolism , Urinary Bladder/pathology , Urinary Bladder/physiopathology , Urinary Bladder, Overactive/metabolism , Urinary Bladder, Overactive/pathology , Urinary Bladder, Overactive/physiopathology , Urothelium/metabolism
10.
Respir Physiol Neurobiol ; 266: 54-65, 2019 08.
Article in English | MEDLINE | ID: mdl-31055188

ABSTRACT

Respiratory frequency plasticity is a long-lasting increase in breathing frequency due to a perturbation. Mechanisms underlying respiratory frequency are poorly understood, and there is little evidence of frequency plasticity in neonates. This hybrid review/research article discusses available literature regarding frequency plasticity and highlights potential research opportunities. Also, we include data demonstrating a model of frequency plasticity using isolated neonatal rat brainstem-spinal cord preparations. Specifically, substance P (SubP) application induced a long-lasting (>60 min) increase in spontaneous respiratory motor burst frequency, particularly in brainstem-spinal cords with the pons attached; there were no male/female differences. SubP-induced frequency plasticity is dependent on the application pattern, such that intermittent (rather than sustained) SubP applications induce more frequency plasticity. SubP-induced frequency plasticity was blocked by a neurokinin-1 receptor antagonist. Thus, the newborn rat respiratory control system has the capacity to express frequency plasticity. Identifying mechanisms that induce frequency plasticity may lead to novel methods to safely treat breathing disorders in premature and newborn infants.


Subject(s)
Brain Stem/physiology , Growth and Development/physiology , Neuronal Plasticity/physiology , Neurotransmitter Agents/pharmacology , Respiratory Rate/physiology , Spinal Cord/physiology , Substance P/pharmacology , Animals , Animals, Newborn , Brain Stem/drug effects , Neuronal Plasticity/drug effects , Rats , Respiratory Rate/drug effects , Spinal Cord/drug effects , Substance P/drug effects
11.
Neuroreport ; 30(4): 288-294, 2019 03 06.
Article in English | MEDLINE | ID: mdl-30676543

ABSTRACT

Chemotherapy-induced peripheral neuropathic pain is a major dose-limiting and therapy-limiting adverse effect that is particularly difficult to treat. Puerarin, a major active ingredient of traditional Chinese plant medicine Gegen, is commonly used in the treatment of myocardial and cerebral ischemia. However, the effects of puerarin on neuropathic pain are still unknown. Therefore, the aim of this study is to examine the effects of puerarin on neuropathic pain. In this study, the effects of puerarin were tested in-vivo on a rat model of paclitaxel-induced peripheral neuropathic pain (PIPNP). The results show that a single injection of puerarin produced short-term analgesic effect on pre-established PIPNP, as indicated by decreased mechanical allodynia and thermal hyperalgesia in comparison with paclitaxel-treated rats. Repeated doses of puerarin, given during PIPNP induction, prevented the development of PIPNP. This prophylactic effect of puerarin was associated with suppressed paclitaxel-induced transient receptor potential vanilloid 1, calcitonin gene-related peptide and substance P up-regulation in the dorsal root ganglia. These findings revealed the therapeutic potential of puerarin in treating and preventing chemotherapy-induced peripheral neuropathic pain.


Subject(s)
Antineoplastic Agents, Phytogenic/toxicity , Isoflavones/pharmacology , Neuralgia/chemically induced , Neuralgia/metabolism , Paclitaxel/toxicity , Animals , Calcitonin Gene-Related Peptide/drug effects , Calcitonin Gene-Related Peptide/metabolism , Male , Rats , Rats, Sprague-Dawley , Substance P/drug effects , Substance P/metabolism , TRPV Cation Channels/drug effects , TRPV Cation Channels/metabolism
12.
Int J Mol Sci ; 21(1)2019 Dec 30.
Article in English | MEDLINE | ID: mdl-31906003

ABSTRACT

Targeted delivery of potent inhibitor of cytokine/pain-mediator into inflammatory or pain-sensing cells is a promising avenue for treating chronic pain, a world-wide major healthcare burden. An unmet need exists for a specific and effective delivery strategy. Herein, we describe a new approach using sortase to site-specifically ligate a non-toxic botulinum neurotoxin D (BoNT/D) core-therapeutic (synaptobrevin-cleaving protease and translocation domains) to cell-specific targeting ligands. An engineered core-therapeutic was efficiently ligated to IL-1ß ligand within minutes. The resultant conjugate specifically entered into cultured murine primary macrophages, cleaved synaptobrevin 3 and inhibited LPS/IFN-γ evoked IL-6 release. Likewise, a CGRP receptor antagonist ligand delivered BoNT/D protease into sensory neurons and inhibited K+-evoked substance P release. As cytokines and neuropeptides are major regulators of inflammation and pain, blocking their release by novel engineered inhibitors highlights their therapeutic potential. Our report describes a new and widely-applicable strategy for the production of targeted bio-therapeutics for numerous chronic diseases.


Subject(s)
Botulinum Toxins/pharmacology , Chronic Pain/drug therapy , Protein Engineering/methods , Animals , Botulinum Toxins/genetics , Cell Survival/drug effects , Cytokines , Macrophages , Mice , Neuropeptides , Peptide Hydrolases/metabolism , RAW 264.7 Cells , Rats , Rats, Sprague-Dawley , Sensory Receptor Cells/drug effects , Substance P/drug effects , Vesicle-Associated Membrane Protein 1/metabolism , Vesicle-Associated Membrane Protein 3
13.
Neurogastroenterol Motil ; 30(9): e13397, 2018 09.
Article in English | MEDLINE | ID: mdl-30043538

ABSTRACT

BACKGROUND: We have recently found a potential protective effect of beta-blockers on oropharyngeal dysphagia (OD). The action mechanism by which beta-blockers could wield this protective effect is unknown, but the neurotransmitter substance P (SP) could play a key role. The aim of this study was to analyze serum and saliva SP levels in patients taking beta-blockers (TBB), and to explore its relationship with OD. METHODS: Adult (>50 year) patients TBB were randomly recruited from the primary care setting and 1:1 matched by age, sex, and Barthel Index (BI) with patients not taking beta-blockers (NTBB). Serum and saliva samples were taken and analyzed for their SP levels using an enzyme-linked immunosorbent assay (ELISA). Socio-demographic and clinical variables were collected. Dysphagia was evaluated in all patients using the clinical volume-viscosity swallow test (V-VST). KEY RESULTS: We studied 28 patients TBB (64.96 ± 7.31 years, 57.1% women, BI 99.6 ± 1.31, carvedilol-equivalent dose 24.11 ± 18.12 mg) and 28 patients NTBB (65.61 ± 6.43 years, 57.1% women, BI 99.6 ± 1.31). SP serum levels were significantly higher in patients TBB (260.68 ± 144.27 vs 175.46 ± 108.36 pg/mL, P = .009) as were SP saliva levels (170.34 ± 146.48 vs 102.73 ± 52.28 pg/mL, P < .001) compared with patients NTBB. The prevalence of OD was 32.1% in patients TBB and 67.9% in patients NTBB (P = .015). Moreover, patients with OD had significantly lower SP saliva levels in comparison with patients without clinical signs of OD (98.39 ± 43.25 vs 174.69 ± 147.21 pg/mL) P < .001. CONCLUSIONS & INFERENCES: We have found that serum and saliva SP levels are greater in patients TBB. This increase in SP levels could be the action mechanism by which beta-blockers protect patients from OD.


Subject(s)
Adrenergic beta-Antagonists/therapeutic use , Deglutition Disorders/epidemiology , Substance P/drug effects , Substance P/metabolism , Aged , Case-Control Studies , Female , Humans , Male , Middle Aged , Substance P/analysis
14.
J Neuroimmunol ; 320: 80-86, 2018 07 15.
Article in English | MEDLINE | ID: mdl-29759144

ABSTRACT

Tropisetron, an antagonist of serotonin type 3 receptors (5-HT3Rs), has been investigated in colonic inflammatory process. Since substance P/neurokinin 1 receptor (SP/NK1R) signaling pathway plays a key role in several sensory neuronal inflammatory. We evaluated the anti-inflammatory activity of tropisetron in mice cerebral cortex, and discovered that it was a potential inhibitor in LPS-mediated neuron inflammation through SP/NK1R signaling pathway. We found that tropisetron significantly reduced the increased number of iba-1 positive microglia, down-regulated the gene transcription and protein expression of IL-1ß,IL-6 and TNF-α in LPS stimulated cerebral cortex. To characterize the inhibitory mechanism of tropisetron at the SP response in inflammation, we further examined the effect of tropisetron on NF-κB and SP/NK1R signaling pathway in the process of mice cerebral cortex inflammation. We found that tropisetron inhibited the gene transcription and protein expression of NF-κB, SP, NK1R via inhibiting 5-HT3R activity. These findings might provide new insights into the anti-inflammatory activities of 5-HT3R inhibitor tropisetron, which would be the interaction of serotonin receptor signaling and SP/NK1R pathway. These might highlight their potential to design novel therapeutic strategies to manage inflammatory diseases.


Subject(s)
Gene Expression/drug effects , Inflammation/physiopathology , Serotonin 5-HT3 Receptor Antagonists/pharmacology , Signal Transduction/drug effects , Tropisetron/pharmacology , Animals , Gene Expression Regulation/drug effects , Inflammation/chemically induced , Lipopolysaccharides/toxicity , Mice , NF-kappa B/drug effects , NF-kappa B/metabolism , Receptors, Neurokinin-1/drug effects , Receptors, Neurokinin-1/metabolism , Substance P/drug effects , Substance P/metabolism
15.
Curr Opin Support Palliat Care ; 10(2): 180-8, 2016 06.
Article in English | MEDLINE | ID: mdl-27028050

ABSTRACT

PURPOSE OF THE REVIEW: The purpose of review is to critically present the evidence supporting the use of olanzapine, an atypical antipsychotic, as an antiemetic for cancer and chemotherapy-induced nausea and vomiting (CINV). RECENT FINDINGS: Two phase III clinical studies demonstrated superior efficacy of olanzapine in comparison with the neurokinin-1 receptor antagonists (NK1RA) for substance P (aprepitant, fosaprepitant) in the prevention of nausea after highly emetogenic chemotherapy. Olanzapine is inexpensive and the replacement of NK1RA with olanzapine can reduce the costs of the prevention of CINV. The addition of olanzapine to aprepitant-containing combination regimens for the prevention of CINV was also investigated, and has the potential to further improve the prevention of CINV after highly emetogenic chemotherapy or moderately emetogenic chemotherapy, without substantial increase in costs. In the treatment of uncontrolled ('breakthrough') CINV, olanzapine was more effective than metoclopramide. Existing clinical data also support the use of olanzapine to relieve a cluster of gastrointestinal symptoms in patients with advanced cancer (chronic nausea, vomiting, and anorexia). When used in cancer patients, olanzapine is well tolerated, with sedation being the major dose-limiting side effect. SUMMARY: Existing data from clinical trials justify further research of the role of olanzapine in the prevention of CINV. Olanzapine may be used instead of or in addition to NK1RA in the preventive antiemetic regimens. Olanzapine-containing preventive regimens may provide better nausea control after chemotherapy. When used instead of NK1RA it may also provide substantial reduction in costs of CINV prevention. In patients with advanced cancer, olanzapine was effective against a cluster of gastrointestinal symptoms (nausea, vomiting, and anorexia). The use of olanzapine as an antiemetic for CINV, or to relieve nausea, vomiting, and anorexia in palliative care is currently off-label.


Subject(s)
Antiemetics/therapeutic use , Antineoplastic Agents/adverse effects , Benzodiazepines/therapeutic use , Nausea/drug therapy , Vomiting/drug therapy , Antiemetics/administration & dosage , Antiemetics/adverse effects , Antineoplastic Agents/therapeutic use , Benzodiazepines/administration & dosage , Benzodiazepines/adverse effects , Clinical Trials, Phase III as Topic , Drug Therapy, Combination , Humans , Nausea/chemically induced , Neoplasms/drug therapy , Neurokinin-1 Receptor Antagonists/therapeutic use , Olanzapine , Substance P/drug effects , Vomiting/chemically induced
16.
Spine J ; 16(3): 420-31, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26610672

ABSTRACT

BACKGROUND CONTEXT: Painfulintervertebral disc degeneration is extremely common and costly. Effective treatments are lacking because the nature of discogenic pain is complex with limited capacity to distinguish painful conditions from age-related changes in the spine. Hypothesized sources of discogenic pain include chronic inflammation, neurovascular ingrowth, and structural disruption. PURPOSE: This study aimed to investigate inflammation, pro-neurovascular growth factors, and structural disruption as sources of painful disc degeneration STUDY DESIGN/SETTING: This study used an in vivo study to address these hypothesized mechanisms with anterior intradiscal injections of tumor necrosis factor-alpha (TNFα), pro-neurovascular growth factors: nerve growth factor and vascular endothelial growth factor (NGF and VEGF), and saline with additional sham surgery and naïve controls. Depth of annular puncture was also evaluated for its effects on structural and painful degeneration. METHODS: Rat lumbar discs were punctured (shallow or deeper puncture) and intradiscally injected with saline, TNFα, or NGF and VEGF. Structural disc degeneration was assessed using X-ray, magnetic resonance imaging (MRI), and histology. The rat painful condition was evaluated using Von Frey hyperalgesia measurements, and substance P immunostaining in dorsal root ganglion (DRG) was performed to determine the source of pain. RESULTS: Saline injection increased painful responses with degenerative changes in disc height, MRI intensity, and morphologies of disc structure and cell. TNFα and NGF/VEGF accelerated painful behavior, and TNFα-injected animals had increased substance P in DRGs. Deeper punctures led to more severe disc degeneration. Multiple regression analysis showed that the painful behavior was correlated with disc height loss. CONCLUSIONS: We concluded that rate and severity of structural disc degeneration was associated with the amount of annular disruption and puncture depth. The painful behavior was associated with disc height loss and discal inflammatory state, whereas pro-inflammatory cytokines might play a more important role in the level of pain, which might have resulted from enhanced DRG sensitization. These in vivo painful disc degeneration models with different severities of structural changes may be useful for investigating discogenic pain mechanisms and for screening therapies, although interpretations must note the differences between all surgically induced animal models and the human condition.


Subject(s)
Annulus Fibrosus , Behavior, Animal/drug effects , Hyperalgesia/physiopathology , Intervertebral Disc Degeneration , Nerve Growth Factor/pharmacology , Pain/physiopathology , Tumor Necrosis Factor-alpha/pharmacology , Vascular Endothelial Growth Factor A/pharmacology , Animals , Disease Models, Animal , Ganglia, Spinal/drug effects , Ganglia, Spinal/metabolism , Hyperalgesia/metabolism , Injections , Intervertebral Disc , Lumbar Vertebrae , Male , Pain/metabolism , Punctures , Random Allocation , Rats , Rats, Sprague-Dawley , Substance P/drug effects , Substance P/metabolism
17.
Acta Cir Bras ; 30(8): 523-8, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26352331

ABSTRACT

PURPOSE: To investigate the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) after subcutaneous injection of dexamethasone prior to skin incision in rats. METHODS: Twenty seven Wistar-EPM-1 rats were randomly divided into three groups. The sham group (SG) of rats was injected with 0.9 % saline. The second group (Dexa) was injected with 1.0 mg/kg dexamethasone, and the third group (Dexa+) was injected with 10.0 mg/kg dexamethasone. In all groups, the three subcutaneous injections were performed 30 minutes prior to the surgical skin incision and tissue collection. SP and CGRP (15 kDa pro-CGRP and 5 kDa CGRP) were quantified by Western Blotting. RESULTS: No statistically significant differences (p>0.05) were found in pro-CGRP, CGRP and SP values in all three groups. CONCLUSION: The anti-inflammatory effect of dexamethasone did not occur when the substance P and calcitonin gene-related peptide levels were altered during the neurogenic inflammation process of skin wound healing in rats.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Calcitonin Gene-Related Peptide/drug effects , Dermatitis/drug therapy , Dexamethasone/pharmacology , Neurogenic Inflammation/drug therapy , Substance P/drug effects , Animals , Blotting, Western , Calcitonin Gene-Related Peptide/metabolism , Dermatitis/metabolism , Injections, Subcutaneous , Male , Neurogenic Inflammation/metabolism , Random Allocation , Rats, Wistar , Substance P/metabolism , Time Factors , Wound Healing/drug effects
18.
Acta cir. bras ; 30(8): 523-528, Aug. 2015. ilus
Article in English | LILACS | ID: lil-757990

ABSTRACT

PURPOSE: To investigate the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) after subcutaneous injection of dexamethasone prior to skin incision in rats.METHODS:Twenty seven Wistar-EPM-1 rats were randomly divided into three groups. The sham group (SG) of rats was injected with 0.9 % saline. The second group (Dexa) was injected with 1.0 mg/kg dexamethasone, and the third group (Dexa+) was injected with 10.0 mg/kg dexamethasone. In all groups, the three subcutaneous injections were performed 30 minutes prior to the surgical skin incision and tissue collection. SP and CGRP (15 kDa pro-CGRP and 5 kDa CGRP) were quantified by Western Blotting.RESULTS: No statistically significant differences (p>0.05) were found in pro-CGRP, CGRP and SP values in all three groups.CONCLUSION:The anti-inflammatory effect of dexamethasone did not occur when the substance P and calcitonin gene-related peptide levels were altered during the neurogenic inflammation process of skin wound healing in rats.


Subject(s)
Animals , Male , Anti-Inflammatory Agents/pharmacology , Calcitonin Gene-Related Peptide/drug effects , Dermatitis/drug therapy , Dexamethasone/pharmacology , Neurogenic Inflammation/drug therapy , Substance P/drug effects , Blotting, Western , Calcitonin Gene-Related Peptide/metabolism , Dermatitis/metabolism , Injections, Subcutaneous , Neurogenic Inflammation/metabolism , Random Allocation , Rats, Wistar , Substance P/metabolism , Time Factors , Wound Healing/drug effects
19.
J Esthet Restor Dent ; 26(5): 353-8, 2014.
Article in English | MEDLINE | ID: mdl-25493305

ABSTRACT

In-office bleaching is an effective method for whitening teeth.Tooth sensitivity associated with in-office whitening is reversible and may range from mild to considerable. The incidence and severity of tooth sensitivity can be reduced by pretreatment with a desensitizer such as potassium nitrate. Histologic studies and clinical studies on long-term pulpal effects are lacking to definitively support the safety of in-office tooth whitening. Future studies on the etiology of tooth sensitivity related to whitening might greatly improve the means of preventing and managing this side effect.


Subject(s)
Dental Pulp/drug effects , Dentin Desensitizing Agents/administration & dosage , Dentin Sensitivity/prevention & control , Hydrogen Peroxide/therapeutic use , Neurotransmitter Agents/analysis , Nitrates/administration & dosage , Oxidants/therapeutic use , Patient Satisfaction , Potassium Compounds/administration & dosage , Sodium Fluoride/administration & dosage , Substance P/drug effects , Tooth Bleaching/adverse effects , Tooth Bleaching/methods , Urea/analogs & derivatives , Humans
20.
Acta Cir Bras ; 29(4): 224-30, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24760022

ABSTRACT

PURPOSE: To investigate the subcutaneous injection of carbon dioxide (CO2) on neuropeptides Calcitonin Gene-Related Peptide (CGRP) and Substance P (SP) secretion in rat skin. METHODS: Fifty-six Wistar-EPM rats were distributed in two groups: one for CGRP analysis, the other for SP analysis. Each group was subdivided into four subgroups: control (Cont), control with needle (ContNd), CO2 injection (CO2Inj) and atmospheric air injection (AirInj) - with seven animals each. Sample analyses of partial skin were conducted by Western Blotting (WB). RESULTS: In SP group, there was a decrease in the amount of neuropeptides in subgroups CO2Inj and AirInj. Similarly, in CGRP group, there was a decrease in the amount of pro-CGRP neuropeptides (15 kDa) in subgroups CO2Inj and AirInj; Nevertheless, there was no decrease in the amount of CGRP (5 kDa) in any subgroups. CONCLUSION: Subcutaneous injection of CO2 and atmospheric air decreased the amount of Substance P and pro-Calcitonin Gene-Related Peptide (15 kDa) neuropeptides in rat skin.


Subject(s)
Calcitonin Gene-Related Peptide/drug effects , Carbon Dioxide/administration & dosage , Skin/drug effects , Substance P/drug effects , Animals , Blotting, Western , Calcitonin Gene-Related Peptide/metabolism , Injections, Subcutaneous , Male , Random Allocation , Rats, Wistar , Reproducibility of Results , Skin/metabolism , Substance P/metabolism , Time Factors
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