piperidines and Neurogenic-Inflammation

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Capsaicin; Disease Models, Animal; Dopaminergic Neurons; Humans; Indoles; Mice; Mice, Inbred C57BL; Neurogenic Inflammation; Neuroglia; Neuroprotection; Parkinson Disease; Piperidines; Pyrazoles; Receptor Cross-Talk; Receptors, Cannabinoid; Substantia Nigra; TRPV Cation Channels

Stress occurs in everyday life and persistence of it causes memory loss. Bioflavonoids like quercetin are reported to have poor bioavailability and limited therapeutic potential against stress induced neurological disorders. Therefore, the present study is an attempt to elucidate the therapeutic potency of combination of quercetin with piperine; a bioavailability enhancer against chronic unpredictable stress (CUS)-induced behavioral and biochemical alterations. Laca mice were subjected to a series of stressful events for a period of 28 days. Quercetin (20, 40 and 80 mg/kg, p.o.), piperine (20 mg/kg, p.o.) and their combinations were administered daily 30 min before CUS procedure. Piracetam (100 mg/kg, i.p.) served as a standard control. CUS caused impaired spatial navigation in Morris water maze test and poor retention in elevated plus maze task. Further, there was significant increase in brain oxidative stress markers and neuro-inflammation (TNF-α). This was coupled with marked rise in acetylcholinesterase and serum corticosterone levels. Co-administration of piperine with quercetin significantly elevated their potential to restore these behavioral, biochemical and molecular changes associated with mouse model of CUS. These results suggest that piperine enhances the neuroprotective effects of quercetin against CUS-induced oxidative stress, neuro-inflammation and memory deficits.

Topics: Alkaloids; Animals; Behavior, Animal; Benzodioxoles; Biological Availability; Chronic Disease; Cognitive Dysfunction; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Male; Mice, Inbred Strains; Neurogenic Inflammation; Oxidative Stress; Piperidines; Polyunsaturated Alkamides; Quercetin; Stress, Psychological

Toluene is a representative airborne occupational and domestic pollutant that causes eye and respiratory tract irritation. We investigated whether a single inhalation of toluene elicits microvascular leakage in the rat airway. We also evaluated the effects of CP-99,994, a tachykinin NK(1) receptor antagonist, and ketotifen, a histamine H1 receptor antagonist with mast cell-stabilizing properties, on the airway response. The content of Evans blue dye that extravasated into the tissues was measured as an index of plasma leakage. Toluene (18-450 ppm, 10 min) concentration-dependently induced dye leakage into the trachea and main bronchi of anesthetized and mechanically ventilated rats. Toluene at concentrations of ≥ 50 and ≥ 30 ppm caused significant responses in the trachea and main bronchi, respectively, which both peaked after exposure to 135 ppm toluene for 10 min. This response was abolished by CP-99,994 (5 mg/kg i.v.), but not by ketotifen (1mg/kg i.v.). Nebulized phosphoramidon (1 mM, 1 min), a neutral endopeptidase 24.11 inhibitor, significantly enhanced the response induced by toluene (135 ppm, 10 min) compared with nebulized 0.9% saline (1 min). These results show that toluene can rapidly increase airway plasma leakage that is predominantly mediated by tachykinins endogenously released from airway sensory nerves. However, mast cell activation might not be important in this airway response.

Topics: Animals; Bronchi; Dose-Response Relationship, Drug; Glycopeptides; Inhalation Exposure; Ketotifen; Male; Mast Cells; Microvessels; Neurogenic Inflammation; Piperidines; Rats; Rats, Wistar; Solvents; Tachykinins; Time Factors; Toluene; Trachea

Various volatile organic compounds (VOCs) act as a causative agent of skin inflammation. We investigated the effect of topical application of several VOCs and formalin on microvascular leakage in rat skin. We tested capsaicin, which is a reagent that specifically causes the skin response via endogenously released tachykinins. Evans blue dye extravasation served as an index of the increase in skin vascular permeability. After shaving the abdomen, we applied formalin, m-xylene, toluene, styrene, benzene, ethylbenzene, acetone, diethyl ether, hexane, heptane, cyclohexane and capsaicin to the skin. At 40min after application, skin samples were collected. Among all of the VOCs tested, all of the aromatic compounds significantly produced skin microvascular leakage that was similar to formalin and capsaicin. We also investigated the skin responses seen after the intravenous administration of CP-99,994 (1.5 or 5mg/kg), which is a tachykinin NK1 receptor antagonist, ketotifen (1 or 3mg/kg), which is a histamine H1 receptor antagonist that stabilizes the mast cells, and the topical application of capsazepine (22.5 or 50mM), which is the transient receptor potential vanilloid 1 (TRPV1) antagonist. The response induced by formalin and capsaicin was completely inhibited by CP-99,994. On the other hand, the antagonist partially reduced the response induced by m-xylene, toluene and styrene by 39%, 50% and 46%, respectively. Capsazepine and ketotifen did not alter the response induced by formalin or any of the aromatic compounds. Like capsaicin, formalin and the aromatic compounds at least partially caused skin microvascular leakage, which was due to tachykinin NK1 receptor activation related to the release of tachykinins from the sensory nerve endings. However, it is unlikely that mast cells and TRPV1 play an important role in the skin response.

Topics: Administration, Topical; Animals; Antipruritics; Capillary Leak Syndrome; Capsaicin; Cell Degranulation; Disinfectants; Dose-Response Relationship, Drug; Formaldehyde; Hydrocarbons, Aromatic; Ketotifen; Male; Mast Cells; Neurogenic Inflammation; Neurokinin-1 Receptor Antagonists; Piperidines; Rats; Rats, Wistar; Regional Blood Flow; Skin

Activation of protease-activated receptors (PAR) can induce vasodilation (VD) and increase of vascular permeability either directly by stimulating endothelial cells or indirectly via activation of nociceptors and subsequent release of neuropeptides (neurogenic inflammation). We aimed to estimate the relative contribution of the two pathways for stimulation with endogenous activators of PAR-2 (trypsin) and of PAR-1, 3 and 4 (thrombin) using in vivo dermal microdialysis in rats. Protein extravasation (PE) was assessed by increase of protein concentration in the dialysate, and VD was quantified by laser Doppler scanning. Both trypsin (10(-8)-10(-4) M) and thrombin (10(-6), 10(-5.5) and 10(-5) M) provoked PE and local VD in a dose-dependent manner. Trypsin (10(-4) M)-induced PE was inhibited by 87.2 +/- 21% due to the substance P (SP) NK1 receptor antagonist SR140333. VD was blocked by 58.15 +/- 10.1% in response to the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP(8-37). By contrast, CGRP(8-37) did not affect thrombin-induced VD, while blockade of SP receptors prevented the PE elicited only by low doses of thrombin (10(-6) M), being ineffective at higher thrombin concentrations. In conclusion, intradermal trypsin elicits a neurogenic inflammation in rat, probably mediated via PAR-2 activation on nociceptors and subsequent SP and CGRP release. Thrombin-induced PE and VD are mediated mainly by a non-neurogenic mechanism.

Topics: Animals; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Capillary Permeability; Inflammation; Male; Neurogenic Inflammation; Neurokinin-1 Receptor Antagonists; Peptide Fragments; Piperidines; Quinuclidines; Rats; Rats, Wistar; Receptors, Proteinase-Activated; Skin; Thrombin; Trypsin; Vasodilation

Although neurogenic inflammation via the activation of C fibers in the airway must have an important role in the pathogenesis of asthma, their regulatory mechanism remains uncertain.. The pharmacological profiles of endogenous cannabinoid receptor agonists on the activation of C fibers in airway tissues were investigated and the mechanisms how cannabinoids regulate airway inflammatory reactions were clarified.. The effects of endogenous cannabinoid receptor agonists on electrical field stimulation-induced bronchial smooth muscle contraction, capsaicin-induced bronchoconstriction and capsaicin-induced substance P release in guinea pig airway tissues were investigated. The influences of cannabinoid receptor antagonists and K+ channel blockers to the effects of cannabinoid receptor agonists on these respiratory reactions were examined.. Both endogenous cannabinoid receptor agonists, anandamide and palmitoylethanolamide, inhibited electrical field stimulation-induced guinea pig bronchial smooth muscle contraction, but not neurokinin A-induced contraction. A cannabinoid CB2 antagonist, SR 144528, reduced the inhibitory effect of endogenous agonists, but not a cannabinoid CB1 antagonist, SR 141716A. Inhibitory effects of agonists were also reduced by the pretreatment of large conductance Ca2+ -activated K+ channel (maxi-K+ channel) blockers, iberiotoxin and charybdotoxin, but not by other K+ channel blockers, dendrotoxin or glibenclamide. Anandamide and palmitoylethanolamide blocked the capsaicin-induced release of substance P-like immunoreactivity from guinea pig airway tissues. Additionally, intravenous injection of palmitoylethanolamide dose-dependently inhibited capsaicin-induced guinea pig bronchoconstriction, but not neurokinin A-induced reaction. However, anandamide did not reduce capsaicin-induced guinea pig bronchoconstriction.. These findings suggest that endogenous cannabinoid receptor agonists inhibit the activation of C fibers via cannabinoid CB2 receptors and maxi-K+ channels in guinea pig airways.

Topics: Amides; Animals; Arachidonic Acids; Bronchi; Bronchoconstriction; Calcium Channel Blockers; Camphanes; Cannabinoid Receptor Agonists; Capsaicin; Electric Stimulation; Endocannabinoids; Ethanolamines; Guinea Pigs; Male; Muscle Contraction; Muscle, Smooth; Nerve Fibers, Unmyelinated; Neurogenic Inflammation; Organ Culture Techniques; Palmitic Acids; Piperidines; Polyunsaturated Alkamides; Potassium Channel Blockers; Pyrazoles; Receptors, Cannabinoid; Rimonabant; Substance P

The tricyclic compound (R)-1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidine carboxylic acid (ReN 1869) is a novel, selective histamine H(1) receptor antagonist. It is orally available, well tolerated, easily enters the central nervous system (CNS) but no adverse effects are seen in mice at 300 mg/kg. ReN 1869 at 0.01-10 mg/kg is antinociceptive in tests of chemical nociception in rodents (formalin, capsaicin, phenyl quinone writhing) but not in thermal tests (hot plate and tail flick). ReN 1869 amplifies the analgesic action of morphine but does not show tolerance after chronic dosing. Moreover, the compound is effective against inflammation of neurogenic origin (antidromic nerve stimulation, histamine-evoked edema) but not in carrageenan-induced inflammation. We suggest that ReN 1869, via H(1) blockade, counteracts the effect of histamine liberated from activated mast cells and inhibits pain transmission in the dorsal spinal cord. ReN 1869 represents a new class of antihistamines with pain-relieving properties that probably is mediated centrally through histamine H(1) receptors but alternative mechanisms of action cannot be excluded.

Topics: Animals; Benzoquinones; Binding Sites; Calcitonin Gene-Related Peptide; Calcium; Calcium Channels; Capsaicin; Carrageenan; Central Nervous System; CHO Cells; Cricetinae; Disease Models, Animal; Edema; Extravasation of Diagnostic and Therapeutic Materials; Gene Expression; Guinea Pigs; Histamine; Histamine H1 Antagonists; In Vitro Techniques; Mice; Neurogenic Inflammation; Pain; Pain Measurement; Piperidines; Proto-Oncogene Proteins c-fos; Pyrilamine; Rats; Rats, Sprague-Dawley; Receptors, Histamine H1; Species Specificity; Spinal Cord; Transfection; Tritium

The leukocyte migration induced by Phoneutria nigriventer spider venom (PNV) has been investigated in rats using the pleurisy model. Intrapleural injection of PNV (10-100 microg/cavity) caused a dose- and time-dependent leukocyte accumulation. The bradykinin B(2) receptor antagonist Hoe 140 (0.5 mg/kg) substantially inhibited PNV-induced cell accumulation, whereas the angiotensin-converting enzyme inhibitor captopril (2 mg/kg) potentiated by 80% this effect. The non-specific kallikrein inhibitor aprotinin and the plasma kallikrein inhibitor soybean trypsin inhibitor greatly reduced PNV-induced leukocyte migration, whereas the selective tissue kallikrein inhibitor P(ac)-F-S-R-EDDnp failed to affect PNV-induced responses. Treatment of rats with capsaicin (50 mg/kg) at the neonatal stage resulted in 67% inhibition of the PNV-induced cell migration. The neurokinin NK(1) receptor antagonist SR140333, but not the NK(2) receptor antagonist SR48968, reduced by 55% venom-induced cell accumulation. We conclude that bradykinin generation is involved in the PNV-induced pleural leukocyte migration in rats, where it can directly activate sensory nerves contributing to a neurogenic inflammatory mechanism.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aprotinin; Benzamides; Bradykinin; Bradykinin Receptor Antagonists; Capsaicin; Chemotaxis, Leukocyte; Dose-Response Relationship, Drug; Leukocytes; Male; Neurogenic Inflammation; Neurokinin-1 Receptor Antagonists; Neurons, Afferent; Piperidines; Pleura; Pleurisy; Quinuclidines; Rats; Rats, Wistar; Receptors, Bradykinin; Receptors, Neurokinin-1; Soybean Proteins; Spider Venoms; Trypsin Inhibitors

Respiratory syncytial virus (RSV) infection in adult rats causes exaggerated inflammation after sensory nerve stimulation in the extrapulmonary, but not in the intrapulmonary airways. The goal of this study was to analyze neurogenic inflammation in weanling F-344 rats infected with RSV 18 +/- 2 d after birth. Five days after RSV inoculation, the extravasation of Evans blue-labeled albumin after nerve stimulation was significantly greater in the intrapulmonary airways of RSV-infected weanling rats than in pathogen-free control rats. In contrast, no difference was found in the extrapulmonary airways. The level of messenger RNA (mRNA) encoding the substance P (SP) receptor (neurokinin 1 [NK1]) increased fourfold in RSV-infected lungs, whereas mRNA encoding the VIPR1 receptor for the antiinflammatory vasoactive intestinal peptide (VIP) increased to a much lesser degree. mRNAs encoding the other neurokinin (NK2) and VIP (VIPR2) receptors were not affected by the virus. Selective inhibition of the NK1 receptor abolished neurogenic inflammation in RSV-infected intrapulmonary airways. Also, neurogenic inflammation and NK1 receptor upregulation in infected lungs were inhibited by prophylaxis with a monoclonal antibody against RSV. These data suggest that RSV lower respiratory tract infection makes the intrapulmonary airways of young rats abnormally susceptible to the proinflammatory effects of SP by selectively upregulating the expression of NK1 receptors.

Topics: Animals; Antibodies, Monoclonal; Body Weight; Cell Line; DNA Primers; Humans; Immunoenzyme Techniques; Lung; Neurogenic Inflammation; Neuropeptides; Piperidines; Rats; Rats, Inbred F344; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Receptors, Vasoactive Intestinal Peptide; Respiratory Syncytial Virus Infections; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Substance P; Up-Regulation

Target-derived nerve growth factor provides trophic support for adult primary afferent neurons containing calcitonin gene-related peptide and tachykinins. Noxious chemical or thermal stimuli cause the release of these mediators from peripheral afferent nerve endings. However, little is known of the extent to which these mediators, in turn, influence nerve growth factor expression in the innervated tissue. The aim of this study was therefore to investigate the possible effect of exogenous substance P, or neurogenic inflammation on the nerve growth factor concentration in the skin of the rat hindpaw. Our results show that substance P as well as topical application of mustard oil cause a significant increase in detectable nerve growth factor, an effect that was prevented by treatment of rats with the tachykinin NK(1) receptor antagonist SR140333. We did not observe a significant inhibitory effect of SR140333 on the nerve growth factor content in non-treated skin, or the nerve growth factor increase caused by carrageenan or allergic inflammation. The results provide evidence that substance P as well as neurogenic inflammation cause a rapid increase in detectable nerve growth factor in the paw skin and suggest the involvement of NK(1) receptors in this effect. We obtained no evidence for the participation of a NK(1) receptor-mediated nerve growth factor increase in models of inflammation induced by non-neurogenic stimuli.

Topics: Animals; Hindlimb; Injections; Male; Nerve Growth Factor; Neurogenic Inflammation; Piperidines; Quinuclidines; Rats; Rats, Sprague-Dawley; Receptors, Tachykinin; Skin; Substance P

Stimulation of the saphenous nerve in the anaesthetised rat results in cutaneous neurogenic oedema formation. We have examined the effect of a tachykinin NK1 and a bradykinin B2 antagonist, and a mu-opioid agonist on plasma extravasation observed in response to two differing nerve stimulating parameters (10 V, 1 ms, 2 Hz and 25 V, 2 ms, 10 Hz). The NK1 antagonist SR140333 abolished oedema, supporting the theory that an NK1 agonist is a primary mediator of neurogenic oedema. The B2 antagonist HOE 140 had no effect, indicating a lack of involvement of B2 receptors in this response. The pre-junctionally acting mu-opioid agonist DAMGO significantly inhibited oedema formation at the 10 V, 1 ms, 2 Hz (P < 0.001), but not the 25 V, 2 ms, 10 Hz stimulation parameters. Thus a post-junctionally acting NK1 antagonist inhibited neurogenic oedema formation induced by both stimulation parameters, whilst a pre-junctionally acting mu-opioid agonist acted only at 10 V, 1 ms, 2 Hz parameters. These findings could be of interest with respect to therapeutic approaches of pathophysiological conditions which involve a neurogenic component.

Topics: Animals; Bradykinin; Bradykinin Receptor Antagonists; Edema; Electric Stimulation; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Extravasation of Diagnostic and Therapeutic Materials; Male; Neurogenic Inflammation; Neurokinin-1 Receptor Antagonists; Neurons, Afferent; Peptide Fragments; Piperidines; Quinuclidines; Rats; Rats, Wistar; Receptor, Bradykinin B2; Receptors, Neurokinin-1; Receptors, Opioid, mu; Substance P; Time Factors