PharmInVivo Ltd

Pécs, Hungary

PharmInVivo Ltd

Pécs, Hungary

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Tekus V.,University of Pécs | Hajna Z.,University of Pécs | Borbely E.,University of Pécs | Markovics A.,University of Pécs | And 9 more authors.
Pain | Year: 2014

The aetiology of complex regional pain syndrome (CRPS), a highly painful, usually post-traumatic condition affecting the limbs, is unknown, but recent results have suggested an autoimmune contribution. To confirm a role for pathogenic autoantibodies, we established a passive-transfer trauma model. Prior to undergoing incision of hind limb plantar skin and muscle, mice were injected either with serum IgG obtained from chronic CRPS patients or matched healthy volunteers, or with saline. Unilateral hind limb plantar skin and muscle incision was performed to induce typical, mild tissue injury. Mechanical hyperalgesia, paw swelling, heat and cold sensitivity, weight-bearing ability, locomotor activity, motor coordination, paw temperature, and body weight were investigated for 8 days. After sacrifice, proinflammatory sensory neuropeptides and cytokines were measured in paw tissues. CRPS patient IgG treatment significantly increased hind limb mechanical hyperalgesia and oedema in the incised paw compared with IgG from healthy subjects or saline. Plantar incision induced a remarkable elevation of substance P immunoreactivity on day 8, which was significantly increased by CRPS-IgG. In this IgG-transfer-trauma model for CRPS, serum IgG from chronic CRPS patients induced clinical and laboratory features resembling the human disease. These results support the hypothesis that autoantibodies may contribute to the pathophysiology of CRPS, and that autoantibody-removing therapies may be effective treatments for long-standing CRPS. © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Szitter I.,University of Pécs | Szitter I.,Janos Szentagothai Research Center | Pinter E.,University of Pécs | Pinter E.,Janos Szentagothai Research Center | And 18 more authors.
Inflammation Research | Year: 2014

Objective and design: The function of the neurokinin 1 (NK1) receptor was investigated in the DSS-induced mouse colitis model using NK1 receptor-deficient mice and the selective antagonist netupitant. Subjects: Colitis was induced by oral administration of 20 mg/ml DSS solution for 7 days in C57BL/6 and Tacr1 KO animals (n = 5-7). Treatment: During the induction, one-half of the C57BL/6 and Tacr1 KO group received one daily dose of 6 mg/kg netupitant, administered intraperitoneally, the other half of the group received saline, respectively. Methods: Disease activity index (DAI), on the basis of stool consistency, blood and weight loss, was determined over 7 days. Histological evaluation, myeloperoxidase (MPO) measurement, cytokine concentrations and receptor expression analysis were performed on the colon samples. Results: NK1 receptors are up-regulated in the colon in response to DSS treatment. DSS increased DAI, histopathological scores, BLC, sICAM-1, IFN-γ, IL-16 and JE in wildtype mice, which were significantly reduced in NK1 receptor-deficient ones. NK1 receptor antagonism with netupitant significantly diminished DAI, inflammatory histopathological alterations, BLC, IFN-γ, IL-13 and IL-16 in wildtype mice, but not in the NK1-deficient ones. MPO was similarly elevated and netupitant significantly decreased its activity in both groups. Conclusions: NK1 receptor antagonism could be beneficial for colitis via inhibiting different inflammatory mechanisms. © 2014 Springer.

Helyes Z.,University of Pécs | Helyes Z.,PharmInVivo Ltd. | Kun J.,University of Pécs | Dobrosi N.,Debrecen University | And 14 more authors.
Journal of Investigative Dermatology | Year: 2015

Although pituitary adenylate cyclase-Activating polypeptide (PACAP) was described as a key vasoregulator in human skin, little is known about its expression in mouse skin. As it is important to investigate PACAP signaling in translational mouse dermatitis models, we determined its presence, regulation, and role in neurogenic and non-neurogenic cutaneous inflammatory mechanisms. The mRNA of PACAP and its specific receptor PAC1 was detected with real-Time PCR in several skin regions at comparable levels. PACAP-38-immunoreactivity measured with radioimmunoassay was similar in plantar and dorsal paw skin and the ear but significantly smaller in the back skin. PACAP and PAC1 mRNA, as well as PACAP-38 and PAC1 protein expression, significantly increased in the plantar skin after intraplantar administration of capsaicin (50 μl, 100 μg ml -1), an agonist of the transient receptor potential vanilloid 1 (TRPV1) receptor, evoking chiefly neurogenic inflammation without inflammatory cell accumulation. Intraplantar complete Freund's adjuvant (CFA; 50 μl, 1 mg ml -1) also increased PACAP/PAC1 mRNA but not the PACAP peptide. Capsaicin-induced neurogenic paw edema, but not CFA-evoked non-neurogenic swelling, was significantly smaller in PACAP-deficient mice throughout a 24-hour period. To our knowledge, we provide previously unreported evidence for PACAP and PAC1 expression upregulation during skin inflammation of different mechanisms and for its pro-inflammatory function in neurogenic edema formation. © 2015 The Society for Investigative Dermatology.

Hajna Z.,University of Pécs | Borbely E.,University of Pécs | Kemeny A.,University of Pécs | Botz B.,University of Pécs | And 10 more authors.
Peptides | Year: 2015

Objective Hemokinin-1, the newest tachykinin encoded by the preprotachykinin C (Tac4) gene, is predominatly produced by immune cells. Similarly to substance P, it has the greatest affinity to the tachykinin NK1 receptor, but has different binding site and signaling mechanisms. Furthermore, several recent data indicate the existence of a not yet identified own receptor and divergent non-NK1-mediated actions. Since there is no information on its functions in the airways, we investigated its role in endotoxin-induced pulmonary inflammation. Methods Acute pneumonitis was induced in Tac4 gene-deleted (Tac4-/-) mice compared to C57Bl/6 wildtypes by intranasal E. coli lipopolysaccharide (LPS). Airway responsiveness to inhaled carbachol was measured with unrestrained whole body plethysmography 24 h later. Semiquantitative histopathological scoring was performed; reactive oxygen species (ROS) production was measured with luminol bioluminescence, myeloperoxidase activity with spectrophotometry, and inflammatory cytokines with Luminex. Results All inflammatory parameters, such as histopathological alterations (perivascular edema, neutrophil/macrophage accumulation, goblet cell hyperplasia), myeloperoxidase activity, ROS production, as well as interleukin-1beta, interleukin-6, tumor necrosis factor alpha, monocyte chemoattractant protein-1 and keratinocyte chemoattractant concentrations were significantly diminished in the lung of Tac4-/- mice. However, bronchial hyperreactivity similarly developed in both groups. Interestingly, in LPS-treated Tac4-/- mouse lungs, bronchus-associated, large, follicle-like lymphoid structures developed. Conclusions We provide the first evidence that hemokinin-1 plays a crucial pro-inflammatory role in the lung by increasing inflammatory cell activities, and might also be a specific regulator of lymphocyte functions. © 2014 Elsevier Inc. All rights reserved.

Tekus V.,University of Pécs | Horvath A.,University of Pécs | Hajna Z.,University of Pécs | Borbely E.,University of Pécs | And 9 more authors.
Life Sciences | Year: 2016

Aims To investigate the roles of TRPV1 and TRPA1 channels in baseline and allyl isothiocyanate (AITC)-evoked nociceptive responses by comparing wild-type and gene-deficient mice. Main methods In contrast to conventional methods of thermonociception measuring reflex latencies, we used our novel methods to determine the noxious heat threshold. Key findings It was revealed that the heat threshold of the tail measured by an increasing-temperature water bath is significantly higher in TRPV1-/-, but not TRPA1-/-, mice compared to respective wild-types. There was no difference between the noxious heat thresholds of the hind paw as measured by an increasing-temperature hot plate in TRPV1-/-, TRPA1-/- and the corresponding wild-type mice. The withdrawal latency of the tail from 0 °C water was prolonged in TRPA1-/-, but not TRPV1-/-, mice compared to respective wild-types. In wild-type animals, dipping the tail or paw into 1% AITC induced an 8-14 °C drop of the noxious heat threshold (heat allodynia) of both the tail and paw, and 40-50% drop of the mechanonociceptive threshold (mechanical allodynia) of the paw measured by dynamic plantar esthesiometry. These AITC-evoked responses were diminished in TRPV1-/-, but not TRPA1-/-, mice. Tail withdrawal latency to 1% AITC was significantly prolonged in both gene-deleted strains. Significance Different heat sensors determine the noxious heat threshold in distinct areas: a pivotal role for TRPV1 on the tail is contrasted with no involvement of either TRPV1 or TRPA1 on the hind paw. Noxious heat threshold measurement appears appropriate for preclinical screening of TRP channel ligands as novel analgesics. © 2016 Elsevier Inc. All rights reserved.

Horvath,University of Pécs | Tekus V.,University of Pécs | Boros M.,University of Pécs | Pozsgai G.,University of Pécs | And 9 more authors.
Arthritis Research and Therapy | Year: 2016

Background: The transient receptor potential ankyrin 1 (TRPA1) is a calcium-permeable cation channel that is expressed on capsaicin-sensitive sensory neurons, endothelial and inflammatory cells. It is activated by a variety of inflammatory mediators, such as methylglyoxal, formaldehyde and hydrogen sulphide. Since only few data are available about the role of TRPA1 in arthritis and related pain, we investigated its involvement in inflammation models of different mechanisms. Methods: Chronic arthritis was induced by complete Freund's adjuvant (CFA), knee osteoarthritis by monosodium iodoacetate (MIA) in TRPA1 knockout (KO) mice and C57Bl/6 wildtype mice. For comparison, carrageenan- and CFA-evoked acute paw and knee inflammatory changes were investigated. Thermonociception was determined on a hot plate, cold tolerance in icy water, mechanonociception by aesthesiometry, paw volume by plethysmometry, knee diameter by micrometry, weight distribution with incapacitance tester, neutrophil myeloperoxidase activity and vascular leakage by in vivo optical imaging, and histopathological alterations by semiquantitative scoring. Results: CFA-induced chronic mechanical hypersensitivity, tibiotarsal joint swelling and histopathological alterations, as well as myeloperoxidase activity in the early phase (day 2), and vascular leakage in the later stage (day 7), were significantly reduced in TRPA1 KO mice. Heat and cold sensitivities did not change in this model. Although in TRPA1 KO animals MIA-evoked knee swelling and histopathological destruction were not altered, hypersensitivity and impaired weight bearing on the osteoarthritic limb were significantly decreased. In contrast, carrageenan- and CFA-induced acute inflammation and pain behaviours were not modified by TRPA1 deletion. Conclusions: TRPA1 has an important role in chronic arthritis/osteoarthritis and related pain behaviours in the mouse. Therefore, it might be a promising target for novel analgesic/anti-inflammatory drugs. © 2016 Horváth et al.

Suto B.,University of Pécs | Szitter I.,University of Pécs | Bagoly T.,University of Pécs | Pinter E.,University of Pécs | And 12 more authors.
Peptides | Year: 2014

Alterations of somatostatin-like immunoreactivity (SST-LI) in the plasma of 11 systemic inflammatory response syndrome (SIRS) patients were investigated in correlation with cytokines, adhesion molecules and coagulation markers repeatedly during 4 days. The origin and role of SST were studied in the cecum ligation and puncture (CLP) rat SIRS model. Capsaicin-sensitive peptidergic sensory nerves were defunctionalized by resiniferatoxin (RTX) pretreatment 2 weeks earlier, in a separate group animals were treated with the somatostatin receptor antagonist cyclo-somatostatin (C-SOM). Plasma SST-LI significantly elevated in septic patients compared to healthy volunteers during the whole 4-day period. Significantly decreased Horowitz score showed severe lung injury, increased plasma C-reactive protein and procalcitonin confirmed SIRS. Soluble P-selectin, tissue plasminogen activator and the interleukin 8 and monocyte chemotactic protein-1 significantly increased, interleukin 6 and soluble CD40 ligand did not change, and soluble Vascular Adhesion Molecule-1 decreased. SST-LI significantly increased in rats both in the plasma and the lung 6 h after CLP compared to sham-operation. After RTX pretreatment SST-LI was not altered in intact animals, but the SIRS-induced elevation was absent. Lung MPO activity significantly increased 6 h following CLP compared to sham operation, which was significantly higher both after RTX-desensitization and C-SOM-treatment. Most non-pretreated operated rats survived the 6 h, but 60% of the RTX-pretreated ones died showing a significantly worse survival. This is the first comprehensive study in humans and animal experiments providing evidence that SST is released from the activated peptidergic sensory nerves. It gets into the bloodstream and mediates a potent endogenous protective mechanism. © 2014 Elsevier Inc.

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