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Prof. Dr. Zsuzsanna Helyes
Department of Pharmacology and Pharmacotherapy, Medical School & Szentagothai Research Centre, University of Pecs, Pecs, Hungary

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0 Arthritis
0 Inflammation
0 Migraine
0 Neuropharmacology
0 Pain

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Migraine

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Journal article
Published: 29 June 2021 in Biomedicines
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SZV 1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime) is a novel multi-target candidate under preclinical development for neuropathic pain. It inhibits amine oxidase copper containing 3, transient receptor potential ankyrin 1 and vanilloid 1 (TRPV1) receptors. Mainly under acidic conditions, it is transformed to the cyclooxygenase inhibitor oxaprozin, which is ineffective for neuropathy. Therefore, an enterosolvent capsule is suggested for oral formulation, which we investigated for nociception, basic kinetics, and thermoregulatory safety in mice. The antihyperalgesic effect of SZV 1287 (10, 20, 50, and 200 mg/kg, p.o.) was determined in partial sciatic nerve ligation-induced traumatic neuropathy by aesthesiometry, brain and plasma concentrations by HPLC, and deep body temperature by thermometry. Its effect on proton-induced TRPV1 activation involved in thermoregulation was assessed by microfluorimetry in cultured trigeminal neurons. The three higher SZV 1287 doses significantly, but not dose-dependently, reduced neuropathic hyperalgesia by 50% of its maximal effect. It was quickly absorbed; plasma concentration was stable for 2 h, and it entered into the brain. Although SZV 1287 significantly decreased the proton-induced TRPV1-mediated calcium-influx potentially leading to hyperthermia, it did not alter deep body temperature. Oral SZV 1287 inhibited neuropathic hyperalgesia and, despite TRPV1 antagonistic action and brain penetration, it did not influence thermoregulation, which makes it a promising analgesic candidate.

ACS Style

Ádám Horváth; Nikolett Szentes; Valéria Tékus; Maja Payrits; Éva Szőke; Emőke Oláh; András Garami; Eszter Fliszár-Nyúl; Miklós Poór; Cecília Sár; Tamás Kálai; Szilárd Pál; Krisztina Percze; Éva Scholz; Tamás Mészáros; Blanka Tóth; Péter Mátyus; Zsuzsanna Helyes. Proof-of-Concept for the Analgesic Effect and Thermoregulatory Safety of Orally Administered Multi-Target Compound SZV 1287 in Mice: A Novel Drug Candidate for Neuropathic Pain. Biomedicines 2021, 9, 749 .

AMA Style

Ádám Horváth, Nikolett Szentes, Valéria Tékus, Maja Payrits, Éva Szőke, Emőke Oláh, András Garami, Eszter Fliszár-Nyúl, Miklós Poór, Cecília Sár, Tamás Kálai, Szilárd Pál, Krisztina Percze, Éva Scholz, Tamás Mészáros, Blanka Tóth, Péter Mátyus, Zsuzsanna Helyes. Proof-of-Concept for the Analgesic Effect and Thermoregulatory Safety of Orally Administered Multi-Target Compound SZV 1287 in Mice: A Novel Drug Candidate for Neuropathic Pain. Biomedicines. 2021; 9 (7):749.

Chicago/Turabian Style

Ádám Horváth; Nikolett Szentes; Valéria Tékus; Maja Payrits; Éva Szőke; Emőke Oláh; András Garami; Eszter Fliszár-Nyúl; Miklós Poór; Cecília Sár; Tamás Kálai; Szilárd Pál; Krisztina Percze; Éva Scholz; Tamás Mészáros; Blanka Tóth; Péter Mátyus; Zsuzsanna Helyes. 2021. "Proof-of-Concept for the Analgesic Effect and Thermoregulatory Safety of Orally Administered Multi-Target Compound SZV 1287 in Mice: A Novel Drug Candidate for Neuropathic Pain." Biomedicines 9, no. 7: 749.

Journal article
Published: 04 April 2021 in International Journal of Molecular Sciences
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Somatostatin receptor subtype 4 (SST4) has been shown to mediate analgesic, antidepressant and anti-inflammatory functions without endocrine actions; therefore, it is proposed to be a novel target for drug development. To overcome the species differences of SST4 receptor expression and function between humans and mice, we generated an SST4 humanized mouse line to serve as a translational animal model for preclinical research. A transposon vector containing the hSSTR4 and reporter gene construct driven by the hSSTR4 regulatory elements were created. The vector was randomly inserted in Sstr4-deficient mice. hSSTR4 expression was detected by bioluminescent in vivo imaging of the luciferase reporter predominantly in the brain. RT-qPCR confirmed the expression of the human gene in the brain and various peripheral tissues consistent with the in vivo imaging. RNAscope in situ hybridization revealed the presence of hSSTR4 transcripts in glutamatergic excitatory neurons in the CA1 and CA2 regions of the hippocampus; in the GABAergic interneurons in the granular layer of the olfactory bulb and in both types of neurons in the primary somatosensory cortex, piriform cortex, prelimbic cortex and amygdala. This novel SST4 humanized mouse line might enable us to investigate the differences of human and mouse SST4 receptor expression and function and assess the effects of SST4 receptor agonist drug candidates.

ACS Style

Balázs Nemes; Kata Bölcskei; Angéla Kecskés; Viktória Kormos; Balázs Gaszner; Timea Aczél; Dániel Hegedüs; Erika Pintér; Zsuzsanna Helyes; Zoltán Sándor. Human Somatostatin SST4 Receptor Transgenic Mice: Construction and Brain Expression Pattern Characterization. International Journal of Molecular Sciences 2021, 22, 3758 .

AMA Style

Balázs Nemes, Kata Bölcskei, Angéla Kecskés, Viktória Kormos, Balázs Gaszner, Timea Aczél, Dániel Hegedüs, Erika Pintér, Zsuzsanna Helyes, Zoltán Sándor. Human Somatostatin SST4 Receptor Transgenic Mice: Construction and Brain Expression Pattern Characterization. International Journal of Molecular Sciences. 2021; 22 (7):3758.

Chicago/Turabian Style

Balázs Nemes; Kata Bölcskei; Angéla Kecskés; Viktória Kormos; Balázs Gaszner; Timea Aczél; Dániel Hegedüs; Erika Pintér; Zsuzsanna Helyes; Zoltán Sándor. 2021. "Human Somatostatin SST4 Receptor Transgenic Mice: Construction and Brain Expression Pattern Characterization." International Journal of Molecular Sciences 22, no. 7: 3758.

Journal article
Published: 12 March 2021 in International Journal of Molecular Sciences
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Acute myocardial infarction (MI) is one of the most common causes of death worldwide. Pituitary adenylate cyclase activating polypeptide (PACAP) is a cardioprotective neuropeptide expressing its receptors in the cardiovascular system. The aim of our study was to examine tissue PACAP-38 in a translational porcine MI model and plasma PACAP-38 levels in patients with ST-segment elevation myocardial infarction (STEMI). Significantly lower PACAP-38 levels were detected in the non-ischemic region of the left ventricle (LV) in MI heart compared to the ischemic region of MI-LV and also to the Sham-operated LV in porcine MI model. In STEMI patients, plasma PACAP-38 level was significantly higher before percutaneous coronary intervention (PCI) compared to controls, and decreased after PCI. Significant negative correlation was found between plasma PACAP-38 and troponin levels. Furthermore, a significant effect was revealed between plasma PACAP-38, hypertension and HbA1c levels. This was the first study showing significant changes in cardiac tissue PACAP levels in a porcine MI model and plasma PACAP levels in STEMI patients. These results suggest that PACAP, due to its cardioprotective effects, may play a regulatory role in MI and could be a potential biomarker or drug target in MI.

ACS Style

Dora Szabo; Zsolt Sarszegi; Beata Polgar; Eva Saghy; Adam Nemeth; Dora Reglodi; Andras Makkos; Aniko Gorbe; Zsuzsanna Helyes; Peter Ferdinandy; Robert Herczeg; Attila Gyenesei; Attila Cziraki; Andrea Tamas. PACAP-38 in Acute ST-Segment Elevation Myocardial Infarction in Humans and Pigs: A Translational Study. International Journal of Molecular Sciences 2021, 22, 2883 .

AMA Style

Dora Szabo, Zsolt Sarszegi, Beata Polgar, Eva Saghy, Adam Nemeth, Dora Reglodi, Andras Makkos, Aniko Gorbe, Zsuzsanna Helyes, Peter Ferdinandy, Robert Herczeg, Attila Gyenesei, Attila Cziraki, Andrea Tamas. PACAP-38 in Acute ST-Segment Elevation Myocardial Infarction in Humans and Pigs: A Translational Study. International Journal of Molecular Sciences. 2021; 22 (6):2883.

Chicago/Turabian Style

Dora Szabo; Zsolt Sarszegi; Beata Polgar; Eva Saghy; Adam Nemeth; Dora Reglodi; Andras Makkos; Aniko Gorbe; Zsuzsanna Helyes; Peter Ferdinandy; Robert Herczeg; Attila Gyenesei; Attila Cziraki; Andrea Tamas. 2021. "PACAP-38 in Acute ST-Segment Elevation Myocardial Infarction in Humans and Pigs: A Translational Study." International Journal of Molecular Sciences 22, no. 6: 2883.

Journal article
Published: 08 February 2021 in International Journal of Molecular Sciences
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Capsaicin-sensitive peptidergic sensory nerves play complex, mainly protective regulatory roles in the inflammatory cascade of the joints via neuropeptide mediators, but the mechanisms of the hyperacute arthritis phase has not been investigated. Therefore, we studied the involvement of these afferents in the early, “black box” period of a rheumatoid arthritis (RA) mouse model. Capsaicin-sensitive fibres were defunctionalized by pretreatment with the ultrapotent capsaicin analog resiniferatoxin and arthritis was induced by K/BxN arthritogenic serum. Disease severity was assessed by clinical scoring, reactive oxygen species (ROS) burst by chemiluminescent, vascular permeability by fluorescent in vivo imaging. Contrast-enhanced magnetic resonance imaging was used to correlate the functional and morphological changes. After sensory desensitization, both early phase ROS-burst and vascular leakage were significantly enhanced, which was later followed by the increased clinical severity scores. Furthermore, the early vascular leakage and ROS-burst were found to be good predictors of later arthritis severity. We conclude that the anti-inflammatory role of peptidergic afferents depends on their activity in the hyperacute phase, characterized by decreased cellular and vascular inflammatory components presumably via anti-inflammatory neuropeptide release. Therefore, these fibres might serve as important gatekeepers in RA.

ACS Style

Bálint Botz; Gábor Kriszta; Kata Bölcskei; Ádám Horváth; Attila Mócsai; Zsuzsanna Helyes. Capsaicin-Sensitive Peptidergic Sensory Nerves Are Anti-Inflammatory Gatekeepers in the Hyperacute Phase of a Mouse Rheumatoid Arthritis Model. International Journal of Molecular Sciences 2021, 22, 1682 .

AMA Style

Bálint Botz, Gábor Kriszta, Kata Bölcskei, Ádám Horváth, Attila Mócsai, Zsuzsanna Helyes. Capsaicin-Sensitive Peptidergic Sensory Nerves Are Anti-Inflammatory Gatekeepers in the Hyperacute Phase of a Mouse Rheumatoid Arthritis Model. International Journal of Molecular Sciences. 2021; 22 (4):1682.

Chicago/Turabian Style

Bálint Botz; Gábor Kriszta; Kata Bölcskei; Ádám Horváth; Attila Mócsai; Zsuzsanna Helyes. 2021. "Capsaicin-Sensitive Peptidergic Sensory Nerves Are Anti-Inflammatory Gatekeepers in the Hyperacute Phase of a Mouse Rheumatoid Arthritis Model." International Journal of Molecular Sciences 22, no. 4: 1682.

Original research article
Published: 27 January 2021 in Frontiers in Pharmacology
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Background: Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via its receptor subtype 4 (SST4) without influencing endocrine functions. Therefore, SST4 is considered to be a novel target for drug development in pain, especially chronic neuropathy which is a great unmet medical need.Purpose and Experimental Approach: Here, we examined the in silico binding, SST4-linked G protein activation and β-arrestin activation on stable SST4 expressing cells and the effects of our novel pyrrolo-pyrimidine molecules (20, 100, 500, 1,000, 2,000 µg·kg−1) on partial sciatic nerve ligation-induced traumatic mononeuropathic pain model in mice.Key Results: The novel compounds bind to the high affinity binding site of SST4 the receptor and activate the G protein. However, unlike the reference SST4 agonists NNC 26-9100 and J-2156, they do not induce β-arrestin activation responsible for receptor desensitization and internalization upon chronic use. They exert 65–80% maximal anti-hyperalgesic effects in the neuropathy model 1 h after a single oral administration of 100–500 µg·kg−1 doses.Conclusion and Implications: The novel orally active compounds show potent and effective SST4 receptor agonism in vitro and in vivo. All four novel ligands proved to be full agonists based on G protein activation, but failed to recruit β-arrestin. Based on their potent antinociceptive effect in the neuropathic pain model following a single oral administration, they are promising candidates for drug development.

ACS Style

Boglárka Kántás; Éva Szőke; Rita Börzsei; Péter Bánhegyi; Junaid Asghar; Lina Hudhud; Anita Steib; Ágnes Hunyady; Ádám Horváth; Angéla Kecskés; Éva Borbély; Csaba Hetényi; Gábor Pethő; Erika Pintér; Zsuzsanna Helyes. In Silico, In Vitro and In Vivo Pharmacodynamic Characterization of Novel Analgesic Drug Candidate Somatostatin SST4 Receptor Agonists. Frontiers in Pharmacology 2021, 11, 1 .

AMA Style

Boglárka Kántás, Éva Szőke, Rita Börzsei, Péter Bánhegyi, Junaid Asghar, Lina Hudhud, Anita Steib, Ágnes Hunyady, Ádám Horváth, Angéla Kecskés, Éva Borbély, Csaba Hetényi, Gábor Pethő, Erika Pintér, Zsuzsanna Helyes. In Silico, In Vitro and In Vivo Pharmacodynamic Characterization of Novel Analgesic Drug Candidate Somatostatin SST4 Receptor Agonists. Frontiers in Pharmacology. 2021; 11 ():1.

Chicago/Turabian Style

Boglárka Kántás; Éva Szőke; Rita Börzsei; Péter Bánhegyi; Junaid Asghar; Lina Hudhud; Anita Steib; Ágnes Hunyady; Ádám Horváth; Angéla Kecskés; Éva Borbély; Csaba Hetényi; Gábor Pethő; Erika Pintér; Zsuzsanna Helyes. 2021. "In Silico, In Vitro and In Vivo Pharmacodynamic Characterization of Novel Analgesic Drug Candidate Somatostatin SST4 Receptor Agonists." Frontiers in Pharmacology 11, no. : 1.

Journal article
Published: 19 January 2021 in Molecules
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Melilotus officinalis is known to contain several types of secondary metabolites. In contrast, the carotenoid composition of this medicinal plant has not been investigated, although it may also contribute to the biological activities of the drug, such as anti-inflammatory effects. Therefore, this study focuses on the isolation and identification of carotenoids from Meliloti herba and on the effect of isolated (all-E)-lutein 5,6-epoxide on primary sensory neurons and macrophages involved in nociception, as well as neurogenic and non-neurogenic inflammatory processes. The composition of the plant extracts was analyzed by high performance liquid chromatography (HPLC). The main carotenoid was isolated by column liquid chromatography (CLC) and identified by MS and NMR. The effect of water-soluble lutein 5,6-epoxide-RAMEB (randomly methylated-β-cyclodextrin) was investigated on Ca2+-influx in rat primary sensory neurons induced by the activation of the transient receptor potential ankyrin 1 receptor agonist to mustard-oil and on endotoxin-induced IL-1β release from isolated mouse peritoneal macrophages. (all-E)-Lutein 5,6-epoxide significantly decreased the percent of responsive primary sensory neurons compared to the vehicle-treated stimulated control. Furthermore, endotoxin-evoked IL-1β release from macrophages was significantly decreased by 100 µM lutein 5,6-epoxide compared to the vehicle-treated control. The water-soluble form of lutein 5,6-epoxide-RAMEB decreases the activation of primary sensory neurons and macrophages, which opens perspectives for its analgesic and anti-inflammatory applications.

ACS Style

Györgyi Horváth; Eszter Csikós; Eichertné Andres; Tímea Bencsik; Anikó Takátsy; Gergely Gulyás-Fekete; Erika Turcsi; József Deli; Éva Szőke; Ágnes Kemény; Maja Payrits; Lajos Szente; Marianna Kocsis; Péter Molnár; Zsuzsanna Helyes. Analyzing the Carotenoid Composition of Melilot (Melilotus officinalis (L.) Pall.) Extracts and the Effects of Isolated (all-E)-lutein-5,6-epoxide on Primary Sensory Neurons and Macrophages. Molecules 2021, 26, 503 .

AMA Style

Györgyi Horváth, Eszter Csikós, Eichertné Andres, Tímea Bencsik, Anikó Takátsy, Gergely Gulyás-Fekete, Erika Turcsi, József Deli, Éva Szőke, Ágnes Kemény, Maja Payrits, Lajos Szente, Marianna Kocsis, Péter Molnár, Zsuzsanna Helyes. Analyzing the Carotenoid Composition of Melilot (Melilotus officinalis (L.) Pall.) Extracts and the Effects of Isolated (all-E)-lutein-5,6-epoxide on Primary Sensory Neurons and Macrophages. Molecules. 2021; 26 (2):503.

Chicago/Turabian Style

Györgyi Horváth; Eszter Csikós; Eichertné Andres; Tímea Bencsik; Anikó Takátsy; Gergely Gulyás-Fekete; Erika Turcsi; József Deli; Éva Szőke; Ágnes Kemény; Maja Payrits; Lajos Szente; Marianna Kocsis; Péter Molnár; Zsuzsanna Helyes. 2021. "Analyzing the Carotenoid Composition of Melilot (Melilotus officinalis (L.) Pall.) Extracts and the Effects of Isolated (all-E)-lutein-5,6-epoxide on Primary Sensory Neurons and Macrophages." Molecules 26, no. 2: 503.

Journal article
Published: 15 December 2020 in Biomedicine & Pharmacotherapy
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Diabetes mellitus is a common metabolic disease leading to hyperglycemia due to insufficient pancreatic insulin production or effect. Amine oxidase copper containing 3 (AOC3) is an enzyme that belongs to the semicarbazide-sensitive amine oxidase family, which may be a novel therapeutic target to treat diabetic complications. We aimed to explore the effects of AOC3 inhibition and to test the actions of our novel AOC3 inhibitor multi-target drug candidate, SZV 1287, compared to a selective reference compound, LJP 1207, in an 8-week long insulin-controlled streptozotocin (STZ)-induced (60 mg/kg i.p.) rat diabetes model. Both AOC3 inhibitors (20 mg/kg, daily s.c. injections) were protective against STZ-induced pancreatic beta cell damage determined by insulin immunohistochemistry and radioimmunoassay, neuropathic cold hypersensitivity measured by paw withdrawal latency decrease from 0 °C water, and retinal dysfunction detected by electroretinography. SZV 1287 showed greater inhibitory effects on beta cell damage, and reduced retinal apoptosis shown by histochemistry. Mechanical hypersensitivity measured by aesthesiometry, cardiac dysfunction and nitrosative stress determined by echocardiography and immunohistochemistry/Western blot, respectively, serum Na+, K+, fructosamine, and urine microalbumin, creatinine, total protein/creatinine ratio alterations did not develop in response to diabetes. None of these parameters were influenced by the treatments except for SZV 1287 reducing serum fructosamine and LJP 1207 increasing urine creatinine. We provide the first evidence for protective effects of AOC3 inhibition on STZ-induced pancreatic beta cell damage, neuropathic cold hypersensitivity and diabetic retinal dysfunction. Long-term treatment with our novel multi-target analgesic candidate, SZV 1287, is safe and effective also under diabetic conditions.

ACS Style

Valéria Tékus; Ádám István Horváth; Kata Csekő; Krisztina Szabadfi; Andrea Kovács-Valasek; Bese Dányádi; László Deres; Róbert Halmosi; Éva Sághy; Zoltán V. Varga; Ernest Adeghate; Tamás Kőszegi; Péter Mátyus; Róbert Gábriel; Péter Ferdinandy; Erika Pintér; Zsuzsanna Helyes. Protective effects of the novel amine-oxidase inhibitor multi-target drug SZV 1287 on streptozotocin-induced beta cell damage and diabetic complications in rats. Biomedicine & Pharmacotherapy 2020, 134, 111105 .

AMA Style

Valéria Tékus, Ádám István Horváth, Kata Csekő, Krisztina Szabadfi, Andrea Kovács-Valasek, Bese Dányádi, László Deres, Róbert Halmosi, Éva Sághy, Zoltán V. Varga, Ernest Adeghate, Tamás Kőszegi, Péter Mátyus, Róbert Gábriel, Péter Ferdinandy, Erika Pintér, Zsuzsanna Helyes. Protective effects of the novel amine-oxidase inhibitor multi-target drug SZV 1287 on streptozotocin-induced beta cell damage and diabetic complications in rats. Biomedicine & Pharmacotherapy. 2020; 134 ():111105.

Chicago/Turabian Style

Valéria Tékus; Ádám István Horváth; Kata Csekő; Krisztina Szabadfi; Andrea Kovács-Valasek; Bese Dányádi; László Deres; Róbert Halmosi; Éva Sághy; Zoltán V. Varga; Ernest Adeghate; Tamás Kőszegi; Péter Mátyus; Róbert Gábriel; Péter Ferdinandy; Erika Pintér; Zsuzsanna Helyes. 2020. "Protective effects of the novel amine-oxidase inhibitor multi-target drug SZV 1287 on streptozotocin-induced beta cell damage and diabetic complications in rats." Biomedicine & Pharmacotherapy 134, no. : 111105.

Journal article
Published: 21 October 2020 in International Journal of Molecular Sciences
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Somatostatin is an important mood and pain-regulating neuropeptide, which exerts analgesic, anti-inflammatory, and antidepressant effects via its Gi protein-coupled receptor subtype 4 (SST4) without endocrine actions. SST4 is suggested to be a unique novel drug target for chronic neuropathic pain, and depression, as a common comorbidity. However, its neuronal expression and cellular mechanism are poorly understood. Therefore, our goals were (i) to elucidate the expression pattern of Sstr4/SSTR4 mRNA, (ii) to characterize neurochemically, and (iii) electrophysiologically the Sstr4/SSTR4-expressing neuronal populations in the mouse and human brains. Here, we describe SST4 expression pattern in the nuclei of the mouse nociceptive and anti-nociceptive pathways as well as in human brain regions, and provide neurochemical and electrophysiological characterization of the SST4-expressing neurons. Intense or moderate SST4 expression was demonstrated predominantly in glutamatergic neurons in the major components of the pain matrix mostly also involved in mood regulation. The SST4 agonist J-2156 significantly decreased the firing rate of layer V pyramidal neurons by augmenting the depolarization-activated, non-inactivating K+ current (M-current) leading to remarkable inhibition. These are the first translational results explaining the mechanisms of action of SST4 agonists as novel analgesic and antidepressant candidates.

ACS Style

Angéla Kecskés; Krisztina Pohóczky; Miklós Kecskés; Zoltán V. Varga; Viktória Kormos; Éva Szőke; Nóra Henn-Mike; Máté Fehér; József Kun; Attila Gyenesei; Éva Renner; Miklós Palkovits; Péter Ferdinandy; István M. Ábrahám; Balázs Gaszner; Zsuzsanna Helyes. Characterization of Neurons Expressing the Novel Analgesic Drug Target Somatostatin Receptor 4 in Mouse and Human Brains. International Journal of Molecular Sciences 2020, 21, 7788 .

AMA Style

Angéla Kecskés, Krisztina Pohóczky, Miklós Kecskés, Zoltán V. Varga, Viktória Kormos, Éva Szőke, Nóra Henn-Mike, Máté Fehér, József Kun, Attila Gyenesei, Éva Renner, Miklós Palkovits, Péter Ferdinandy, István M. Ábrahám, Balázs Gaszner, Zsuzsanna Helyes. Characterization of Neurons Expressing the Novel Analgesic Drug Target Somatostatin Receptor 4 in Mouse and Human Brains. International Journal of Molecular Sciences. 2020; 21 (20):7788.

Chicago/Turabian Style

Angéla Kecskés; Krisztina Pohóczky; Miklós Kecskés; Zoltán V. Varga; Viktória Kormos; Éva Szőke; Nóra Henn-Mike; Máté Fehér; József Kun; Attila Gyenesei; Éva Renner; Miklós Palkovits; Péter Ferdinandy; István M. Ábrahám; Balázs Gaszner; Zsuzsanna Helyes. 2020. "Characterization of Neurons Expressing the Novel Analgesic Drug Target Somatostatin Receptor 4 in Mouse and Human Brains." International Journal of Molecular Sciences 21, no. 20: 7788.

Review
Published: 02 September 2020 in International Journal of Molecular Sciences
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Head-and-neck squamous cell carcinomas (HNSCC) remain a leading cause of cancer morbidity and mortality worldwide. This is a largely preventable disease with smoking, alcohol abuse, and human papilloma virus (HPV) being the main risk factors. Yet, many patients are diagnosed with advanced disease, and no survival improvement has been seen for oral SCC in the past decade. Clearly, new diagnostic and prognostic markers are needed for early diagnosis and to guide therapy. Gene expression studies implied the involvement of transient receptor potential (TRP) channels in the pathogenesis of HNSCC. TRPs are expressed in normal epithelium where they play a key role in proliferation and differentiation. There is increasing evidence that the expression of TRP channels may change in HNSCC with important implications for diagnosis, prognosis, and therapy. In this review, we propose that TRP channel expression may afford a novel opportunity for early diagnosis of HNSCC and targeted molecular treatment.

ACS Style

Fruzsina Kiss; Krisztina Pohóczky; Arpad Szállási; Zsuzsanna Helyes. Transient Receptor Potential (TRP) Channels in Head-and-Neck Squamous Cell Carcinomas: Diagnostic, Prognostic, and Therapeutic Potentials. International Journal of Molecular Sciences 2020, 21, 6374 .

AMA Style

Fruzsina Kiss, Krisztina Pohóczky, Arpad Szállási, Zsuzsanna Helyes. Transient Receptor Potential (TRP) Channels in Head-and-Neck Squamous Cell Carcinomas: Diagnostic, Prognostic, and Therapeutic Potentials. International Journal of Molecular Sciences. 2020; 21 (17):6374.

Chicago/Turabian Style

Fruzsina Kiss; Krisztina Pohóczky; Arpad Szállási; Zsuzsanna Helyes. 2020. "Transient Receptor Potential (TRP) Channels in Head-and-Neck Squamous Cell Carcinomas: Diagnostic, Prognostic, and Therapeutic Potentials." International Journal of Molecular Sciences 21, no. 17: 6374.

Journal article
Published: 05 August 2020 in International Journal of Molecular Sciences
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Acute gastritis is often untreatable by acid secretion-inhibiting drugs. Understanding the protective mechanisms including the role of Transient Receptor Potential Ankyrin1 (TRPA1) and Vanilloid1 (TRPV1) channels localized on capsaicin-sensitive afferents and non-neuronal structures might identify novel therapeutic approaches. Therefore, we characterized a translational gastritis model using iodoacetamide (IAA) and investigated TRPA1/V1 expressions. Wistar rats and CD1, C57Bl/6J mice were exposed to IAA-containing (0.05, 0.1, 0.2, 0.3, 0.5%) drinking water for 7 or 14 days. Body weight and water consumption were recorded daily. Macroscopic lesions were scored, qualitative histopathologic investigation was performed, TRPA1/V1 immunopositivity and mRNA expressions were measured. IAA induced a concentration-dependent weight loss and reduced water intake in both species. Hyperemia, submucosal edema, inflammatory infiltration and hemorrhagic erosions developed after 7 days, while ulcers after 14 days in rats. Trpa1 mRNA/protein expressions were upregulated at both timepoints. Meanwhile, TRPV1 immunopositivity was upregulated in the gastric corpus after 0.05% IAA ingestion, but downregulated after 0.2%, whereas Trpv1 mRNA did not change. Interestingly, no macroscopic/microscopic changes were observed in mice. These are the first data for the concentration- and duration-dependent changes in the IAA-induced gastritis in rats accompanied by TRPA1 upregulation, therefore, its therapeutic potential in gastritis should further be investigated.

ACS Style

Kata Csekő; Dániel Pécsi; Béla Kajtár; Ivett Hegedűs; Alexander Bollenbach; Dimitrios Tsikas; Imre László Szabó; Sándor Szabó; Zsuzsanna Helyes. Upregulation of the TRPA1 Ion Channel in the Gastric Mucosa after Iodoacetamide-Induced Gastritis in Rats: A Potential New Therapeutic Target. International Journal of Molecular Sciences 2020, 21, 5591 .

AMA Style

Kata Csekő, Dániel Pécsi, Béla Kajtár, Ivett Hegedűs, Alexander Bollenbach, Dimitrios Tsikas, Imre László Szabó, Sándor Szabó, Zsuzsanna Helyes. Upregulation of the TRPA1 Ion Channel in the Gastric Mucosa after Iodoacetamide-Induced Gastritis in Rats: A Potential New Therapeutic Target. International Journal of Molecular Sciences. 2020; 21 (16):5591.

Chicago/Turabian Style

Kata Csekő; Dániel Pécsi; Béla Kajtár; Ivett Hegedűs; Alexander Bollenbach; Dimitrios Tsikas; Imre László Szabó; Sándor Szabó; Zsuzsanna Helyes. 2020. "Upregulation of the TRPA1 Ion Channel in the Gastric Mucosa after Iodoacetamide-Induced Gastritis in Rats: A Potential New Therapeutic Target." International Journal of Molecular Sciences 21, no. 16: 5591.

Journal article
Published: 04 August 2020 in Molecules
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Thyme (TO), cinnamon (CO), and Ceylon type lemongrass (LO) essential oils (EOs) are commonly used for inhalation. However, their effects and mechanisms on inflammatory processes are not well-documented, and the number of in vivo data that would be important to determine their potential benefits or risks is low. Therefore, we analyzed the chemical composition and investigated the activity of TO, CO, and LO on airway functions and inflammatory parameters in an acute pneumonitis mouse model. The components of commercially available EOs were measured by gas chromatography–mass spectrometry. Airway inflammation was induced by intratracheal endotoxin administration in mice. EOs were inhaled during the experiments. Airway function and hyperresponsiveness were determined by unrestrained whole-body plethysmography on conscious animals. Myeloperoxidase (MPO) activity was measured by spectrophotometry from lung tissue homogenates, from which semiquantitative histopathological scores were assessed. The main components of TO, CO, and LO were thymol, cinnamaldehyde, and citronellal, respectively. We provide here the first evidence that TO and CO reduce inflammatory airway hyperresponsiveness and certain cellular inflammatory parameters, so they can potentially be considered as adjuvant treatments in respiratory inflammatory conditions. In contrast, Ceylon type LO inhalation might have an irritant effect (e.g., increased airway hyperresponsiveness and MPO activity) on the inflamed airways, and therefore should be avoided.

ACS Style

Eszter Csikós; Kata Csekő; Amir Reza Ashraf; Ágnes Kemény; László Kereskai; Béla Kocsis; Andrea Böszörményi; Zsuzsanna Helyes; Györgyi Horváth. Effects of Thymus vulgaris L., Cinnamomum verum J.Presl and Cymbopogon nardus (L.) Rendle Essential Oils in the Endotoxin-Induced Acute Airway Inflammation Mouse Model. Molecules 2020, 25, 3553 .

AMA Style

Eszter Csikós, Kata Csekő, Amir Reza Ashraf, Ágnes Kemény, László Kereskai, Béla Kocsis, Andrea Böszörményi, Zsuzsanna Helyes, Györgyi Horváth. Effects of Thymus vulgaris L., Cinnamomum verum J.Presl and Cymbopogon nardus (L.) Rendle Essential Oils in the Endotoxin-Induced Acute Airway Inflammation Mouse Model. Molecules. 2020; 25 (15):3553.

Chicago/Turabian Style

Eszter Csikós; Kata Csekő; Amir Reza Ashraf; Ágnes Kemény; László Kereskai; Béla Kocsis; Andrea Böszörményi; Zsuzsanna Helyes; Györgyi Horváth. 2020. "Effects of Thymus vulgaris L., Cinnamomum verum J.Presl and Cymbopogon nardus (L.) Rendle Essential Oils in the Endotoxin-Induced Acute Airway Inflammation Mouse Model." Molecules 25, no. 15: 3553.

Journal article
Published: 16 July 2020 in International Journal of Molecular Sciences
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Transient Receptor Potential Vanilloid 1 and Ankyrin 1 (TRPV1, TRPA1) cation channels are expressed in nociceptive primary sensory neurons and regulate nociceptor and inflammatory functions. Resolvins are endogenous lipid mediators. Resolvin D1 (RvD1) is described as a selective inhibitor of TRPA1-related postoperative and inflammatory pain in mice acting on the G protein-coupled receptor DRV1/GPR32. Resolvin D2 (RvD2) is a very potent TRPV1 and TRPA1 inhibitor in DRG neurons, and decreases inflammatory pain in mice acting on the GPR18 receptor, via TRPV1/TRPA1-independent mechanisms. We provided evidence that resolvins inhibited neuropeptide release from the stimulated sensory nerve terminals by TRPV1 and TRPA1 activators capsaicin (CAPS) and allyl-isothiocyanate (AITC), respectively. We showed that RvD1 and RvD2 in nanomolar concentrations significantly decreased TRPV1 and TRPA1 activation on sensory neurons by fluorescent calcium imaging and inhibited the CAPS- and AITC-evoked 45Ca-uptake on TRPV1- and TRPA1-expressing CHO cells. Since CHO cells are unlikely to express resolvin receptors, resolvins are suggested to inhibit channel opening through surrounding lipid raft disruption. Here, we proved the ability of resolvins to alter the membrane polarity related to cholesterol composition by fluorescence spectroscopy. It is concluded that targeting lipid raft integrity can open novel peripheral analgesic opportunities by decreasing the activation of nociceptors.

ACS Style

Maja Payrits; Ádám Horváth; Tünde Biró-Sütő; János Erostyák; Géza Makkai; Éva Sághy; Krisztina Pohóczky; Angéla Kecskés; Miklós Kecskés; János Szolcsányi; Zsuzsanna Helyes; Éva Szőke. Resolvin D1 and D2 Inhibit Transient Receptor Potential Vanilloid 1 and Ankyrin 1 Ion Channel Activation on Sensory Neurons via Lipid Raft Modification. International Journal of Molecular Sciences 2020, 21, 5019 .

AMA Style

Maja Payrits, Ádám Horváth, Tünde Biró-Sütő, János Erostyák, Géza Makkai, Éva Sághy, Krisztina Pohóczky, Angéla Kecskés, Miklós Kecskés, János Szolcsányi, Zsuzsanna Helyes, Éva Szőke. Resolvin D1 and D2 Inhibit Transient Receptor Potential Vanilloid 1 and Ankyrin 1 Ion Channel Activation on Sensory Neurons via Lipid Raft Modification. International Journal of Molecular Sciences. 2020; 21 (14):5019.

Chicago/Turabian Style

Maja Payrits; Ádám Horváth; Tünde Biró-Sütő; János Erostyák; Géza Makkai; Éva Sághy; Krisztina Pohóczky; Angéla Kecskés; Miklós Kecskés; János Szolcsányi; Zsuzsanna Helyes; Éva Szőke. 2020. "Resolvin D1 and D2 Inhibit Transient Receptor Potential Vanilloid 1 and Ankyrin 1 Ion Channel Activation on Sensory Neurons via Lipid Raft Modification." International Journal of Molecular Sciences 21, no. 14: 5019.

Review
Published: 23 June 2020 in International Journal of Molecular Sciences
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Cardiovascular diseases, including coronary artery disease, ischemic heart diseases such as acute myocardial infarction and postischemic heart failure, heart failure of other etiologies, and cardiac arrhythmias, belong to the leading causes of death. Activation of capsaicin-sensitive sensory nerves by the transient receptor potential vanilloid 1 (TRPV1) capsaicin receptor and other receptors, as well as neuropeptide mediators released from them upon stimulation, play important physiological regulatory roles. Capsaicin-sensitive sensory nerves also contribute to the development and progression of some cardiac diseases, as well as to mechanisms of endogenous stress adaptation leading to cardioprotection. In this review, we summarize the role of capsaicin-sensitive afferents and the TRPV1 ion channel in physiological and pathophysiological functions of the heart based mainly on experimental results and show their diagnostic or therapeutic potentials. Although the actions of several other channels or receptors expressed on cardiac sensory afferents and the effects of TRPV1 channel activation on different non-neural cell types in the heart are not precisely known, most data suggest that stimulation of the TRPV1-expressing sensory nerves or stimulation/overexpression of TRPV1 channels have beneficial effects in cardiac diseases.

ACS Style

Tamara Szabados; Kamilla Gömöri; Laura Pálvölgyi; Anikó Görbe; István Baczkó; Zsuzsanna Helyes; Gábor Jancsó; Péter Ferdinandy; Péter Bencsik. Capsaicin-Sensitive Sensory Nerves and the TRPV1 Ion Channel in Cardiac Physiology and Pathologies. International Journal of Molecular Sciences 2020, 21, 4472 .

AMA Style

Tamara Szabados, Kamilla Gömöri, Laura Pálvölgyi, Anikó Görbe, István Baczkó, Zsuzsanna Helyes, Gábor Jancsó, Péter Ferdinandy, Péter Bencsik. Capsaicin-Sensitive Sensory Nerves and the TRPV1 Ion Channel in Cardiac Physiology and Pathologies. International Journal of Molecular Sciences. 2020; 21 (12):4472.

Chicago/Turabian Style

Tamara Szabados; Kamilla Gömöri; Laura Pálvölgyi; Anikó Görbe; István Baczkó; Zsuzsanna Helyes; Gábor Jancsó; Péter Ferdinandy; Péter Bencsik. 2020. "Capsaicin-Sensitive Sensory Nerves and the TRPV1 Ion Channel in Cardiac Physiology and Pathologies." International Journal of Molecular Sciences 21, no. 12: 4472.

Journal article
Published: 09 June 2020 in International Journal of Molecular Sciences
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The Transient Receptor Potential Ankyrin 1 (TRPA1) cation channel expressed on capsaicin-sensitive afferents, immune and endothelial cells is activated by inflammatory mediators and exogenous irritants, e.g., endotoxins, nicotine, crotonaldehyde and acrolein. We investigated its involvement in acute and chronic pulmonary inflammation using Trpa1 gene-deleted (Trpa1−/−) mice. Acute pneumonitis was evoked by intranasal Escherichia coli endotoxin (lipopolysaccharide: LPS) administration, chronic bronchitis by daily cigarette smoke exposure (CSE) for 4 months. Frequency, peak inspiratory/expiratory flows, minute ventilation determined by unrestrained whole-body plethysmography were significantly greater, while tidal volume, inspiratory/expiratory/relaxation times were smaller in Trpa1−/− mice. LPS-induced bronchial hyperreactivity, myeloperoxidase activity, frequency-decrease were significantly greater in Trpa1−/− mice. CSE significantly decreased tidal volume, minute ventilation, peak inspiratory/expiratory flows in wildtypes, but not in Trpa1−/− mice. CSE remarkably increased the mean linear intercept (histopathology), as an emphysema indicator after 2 months in wildtypes, but only after 4 months in Trpa1−/− mice. Semiquantitative histopathological scores were not different between strains in either models. TRPA1 has a complex role in basal airway function regulation and inflammatory mechanisms. It protects against LPS-induced acute pneumonitis and hyperresponsiveness, but is required for CSE-evoked emphysema and respiratory deterioration. Further research is needed to determine TRPA1 as a potential pharmacological target in the lung.

ACS Style

Zsófia Hajna; Kata Csekő; Ágnes Kemény; László Kereskai; Tamás Kiss; Anikó Perkecz; István Szitter; Béla Kocsis; Erika Pintér; Zsuzsanna Helyes. Complex Regulatory Role of the TRPA1 Receptor in Acute and Chronic Airway Inflammation Mouse Models. International Journal of Molecular Sciences 2020, 21, 4109 .

AMA Style

Zsófia Hajna, Kata Csekő, Ágnes Kemény, László Kereskai, Tamás Kiss, Anikó Perkecz, István Szitter, Béla Kocsis, Erika Pintér, Zsuzsanna Helyes. Complex Regulatory Role of the TRPA1 Receptor in Acute and Chronic Airway Inflammation Mouse Models. International Journal of Molecular Sciences. 2020; 21 (11):4109.

Chicago/Turabian Style

Zsófia Hajna; Kata Csekő; Ágnes Kemény; László Kereskai; Tamás Kiss; Anikó Perkecz; István Szitter; Béla Kocsis; Erika Pintér; Zsuzsanna Helyes. 2020. "Complex Regulatory Role of the TRPA1 Receptor in Acute and Chronic Airway Inflammation Mouse Models." International Journal of Molecular Sciences 21, no. 11: 4109.

Journal article
Published: 22 April 2020 in International Journal of Molecular Sciences
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A large percentage of primary sensory neurons in the trigeminal ganglia (TG) contain neuropeptides such as tachykinins or calcitonin gene-related peptide. Neuropeptides released from the central terminals of primary afferents sensitize the secondary nociceptive neurons in the trigeminal nucleus caudalis (TNC), but also activate glial cells contributing to neuroinflammation and consequent sensitization in chronic orofacial pain and migraine. In the present study, we investigated the newest member of the tachykinin family, hemokinin-1 (HK-1) encoded by the Tac4 gene in the trigeminal system. HK-1 had been shown to participate in inflammation and hyperalgesia in various models, but its role has not been investigated in orofacial pain or headache. In the complete Freund’s adjuvant (CFA)-induced inflammatory orofacial pain model, we showed that Tac4 expression increased in the TG in response to inflammation. Duration-dependent Tac4 upregulation was associated with the extent of the facial allodynia. Tac4 was detected in both TG neurons and satellite glial cells (SGC) by the ultrasensitive RNAscope in situ hybridization. We also compared gene expression changes of selected neuronal and glial sensitization and neuroinflammation markers between wild-type and Tac4-deficient (Tac4-/-) mice. Expression of the SGC/astrocyte marker in the TG and TNC was significantly lower in intact and saline/CFA-treated Tac4-/- mice. The procedural stress-related increase of the SGC/astrocyte marker was also strongly attenuated in Tac4-/- mice. Analysis of TG samples with a mouse neuroinflammation panel of 770 genes revealed that regulation of microglia and cytotoxic cell-related genes were significantly different in saline-treated Tac4-/- mice compared to their wild-types. It is concluded that HK-1 may participate in neuron-glia interactions both under physiological and inflammatory conditions and mediate pain in the trigeminal system.

ACS Style

Timea Aczél; Angéla Kecskés; József Kun; Kálmán Szenthe; Ferenc Bánáti; Susan Szathmary; Róbert Herczeg; Péter Urbán; Attila Gyenesei; Balázs Gaszner; Zsuzsanna Helyes; Kata Bölcskei. Hemokinin-1 Gene Expression Is Upregulated in Trigeminal Ganglia in an Inflammatory Orofacial Pain Model: Potential Role in Peripheral Sensitization. International Journal of Molecular Sciences 2020, 21, 2938 .

AMA Style

Timea Aczél, Angéla Kecskés, József Kun, Kálmán Szenthe, Ferenc Bánáti, Susan Szathmary, Róbert Herczeg, Péter Urbán, Attila Gyenesei, Balázs Gaszner, Zsuzsanna Helyes, Kata Bölcskei. Hemokinin-1 Gene Expression Is Upregulated in Trigeminal Ganglia in an Inflammatory Orofacial Pain Model: Potential Role in Peripheral Sensitization. International Journal of Molecular Sciences. 2020; 21 (8):2938.

Chicago/Turabian Style

Timea Aczél; Angéla Kecskés; József Kun; Kálmán Szenthe; Ferenc Bánáti; Susan Szathmary; Róbert Herczeg; Péter Urbán; Attila Gyenesei; Balázs Gaszner; Zsuzsanna Helyes; Kata Bölcskei. 2020. "Hemokinin-1 Gene Expression Is Upregulated in Trigeminal Ganglia in an Inflammatory Orofacial Pain Model: Potential Role in Peripheral Sensitization." International Journal of Molecular Sciences 21, no. 8: 2938.

Journal article
Published: 11 December 2019 in International Journal of Molecular Sciences
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Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via the somatostatin sst4 receptor without endocrine actions. Therefore, sst4 is considered to be a novel target for drug development in pain including chronic neuropathy, which is an emerging unmet medical need. Here, we examined the in silico binding, the sst4-linked G-protein activation on stable receptor expressing cells (1 nM to 10 μM), and the effects of our novel pyrrolo-pyrimidine molecules in mouse inflammatory and neuropathic pain models. All four of the tested compounds (C1–C4) bind to the same binding site of the sst4 receptor with similar interaction energy to high-affinity reference sst4 agonists, and they all induce G-protein activation. C1 is the more efficacious (γ-GTP-binding: 218.2% ± 36.5%) and most potent (EC50: 37 nM) ligand. In vivo testing of the actions of orally administered C1 and C2 (500 µg/kg) showed that only C1 decreased the resiniferatoxin-induced acute neurogenic inflammatory thermal allodynia and mechanical hyperalgesia significantly. Meanwhile, both of them remarkably reduced partial sciatic nerve ligation-induced chronic neuropathic mechanical hyperalgesia after a single oral administration of the 500 µg/kg dose. These orally active novel sst4 agonists exert potent anti-hyperalgesic effect in a chronic neuropathy model, and therefore, they can open promising drug developmental perspectives.

ACS Style

Boglárka Kántás; Rita Börzsei; Éva Szőke; Péter Bánhegyi; Ádám Horváth; Ágnes Hunyady; Éva Borbély; Csaba Hetényi; Erika Pintér; Zsuzsanna Helyes. Novel Drug-Like Somatostatin Receptor 4 Agonists are Potential Analgesics for Neuropathic Pain. International Journal of Molecular Sciences 2019, 20, 6245 .

AMA Style

Boglárka Kántás, Rita Börzsei, Éva Szőke, Péter Bánhegyi, Ádám Horváth, Ágnes Hunyady, Éva Borbély, Csaba Hetényi, Erika Pintér, Zsuzsanna Helyes. Novel Drug-Like Somatostatin Receptor 4 Agonists are Potential Analgesics for Neuropathic Pain. International Journal of Molecular Sciences. 2019; 20 (24):6245.

Chicago/Turabian Style

Boglárka Kántás; Rita Börzsei; Éva Szőke; Péter Bánhegyi; Ádám Horváth; Ágnes Hunyady; Éva Borbély; Csaba Hetényi; Erika Pintér; Zsuzsanna Helyes. 2019. "Novel Drug-Like Somatostatin Receptor 4 Agonists are Potential Analgesics for Neuropathic Pain." International Journal of Molecular Sciences 20, no. 24: 6245.

Review
Published: 05 August 2019 in Toxins
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Already a well-established treatment for different autonomic and movement disorders, the use of botulinum toxin type A (BoNT/A) in pain conditions is now continuously expanding. Currently, the only approved use of BoNT/A in relation to pain is the treatment of chronic migraines. However, controlled clinical studies show promising results in neuropathic and other chronic pain disorders. In comparison with other conventional and non-conventional analgesic drugs, the greatest advantages of BoNT/A use are its sustained effect after a single application and its safety. Its efficacy in certain therapy-resistant pain conditions is of special importance. Novel results in recent years has led to a better understanding of its actions, although further experimental and clinical research is warranted. Here, we summarize the effects contributing to these advantageous properties of BoNT/A in pain therapy, specific actions along the nociceptive pathway, consequences of its central activities, the molecular mechanisms of actions in neurons, and general pharmacokinetic parameters.

ACS Style

Ivica Matak; Kata Bölcskei; Lidija Bach-Rojecky; Zsuzsanna Helyes. Mechanisms of Botulinum Toxin Type A Action on Pain. Toxins 2019, 11, 459 .

AMA Style

Ivica Matak, Kata Bölcskei, Lidija Bach-Rojecky, Zsuzsanna Helyes. Mechanisms of Botulinum Toxin Type A Action on Pain. Toxins. 2019; 11 (8):459.

Chicago/Turabian Style

Ivica Matak; Kata Bölcskei; Lidija Bach-Rojecky; Zsuzsanna Helyes. 2019. "Mechanisms of Botulinum Toxin Type A Action on Pain." Toxins 11, no. 8: 459.

Journal article
Published: 01 July 2019 in Bulletin of Medical Sciences
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The Transient Receptor Potential Vanilloid 1 (TRPV1) and Ankyrin 1 (TRPA1) are non-selective cation channels predominantly localized on capsaicin-sensitive sensory neurons; however both receptors have been described in non-neuronal tissues. It has been published that both receptors upregulated in peritoneal endometriosis in humans. Our research group demonstrated that TRPA1 and TRPV1 expression is elevated in human deep infiltrating endometriosis (DIE) lesions and the receptors have an estrogen-dependent expression pattern in rat endometrium. Here, we investigated the expression changes of TRPA1/V1 and the role of the capsaicin-sensitive sensory-nerve endings in a rat model of peritoneal endometriosis. Peritoneal endometriosis was surgically induced in 8-week-old female rats (n=7-7) for 2-weeks (acute condition) and 8-weeks (chronic condition). TRPA1/V1 mRNAs were quantified with quantitative polymerase chain reaction (qPCR). The expression levels were compared with the results obtained earlier from human DIE samples. The blockade of the TRPA1/V1 expressing capsaicin-sensitive nerve endings was induced with resiniferatoxin (RTX), followed by the measurement of the weight and size of the endometriosis lesions. We detected TRPV1 and TRPA1 mRNA in normal rat endometrium, their expression was not altered in sham-operated animals. In chronic, but not in acute endometriosis the expression was significantly elevated in the lesions, which results are consistent with our previous findings in human DIE. The elimination of capsaicin-sensitive nerve endings decreased the weight of the endometriosis lesions while the size of the ectopic tissue was not altered. Taken together, our results obtained from the rat endometriosis model are consistent with the previous human results, therefore this model is considered to have translational significance and it is suitable for functional analysis of the ion channels. The local, non-neuronal TRPA1 and TRPV1 might play a role in inflammation and sensory neuronal activation in endometriosis related pain, which is mediated by a broad range of pro-inflammatory molecules.

ACS Style

Pohóczky Krisztina; Bohonyi Noémi; Maczkó Péter; Kajtár Béla; Helyes Zsuzsanna. Presence and upregulation of Transient Receptor Potential Vanilloid 1 (TRPV1) and Ankyrin 1 (TRPA1) in translational rat endometriosis model. Bulletin of Medical Sciences 2019, 92, 15 -26.

AMA Style

Pohóczky Krisztina, Bohonyi Noémi, Maczkó Péter, Kajtár Béla, Helyes Zsuzsanna. Presence and upregulation of Transient Receptor Potential Vanilloid 1 (TRPV1) and Ankyrin 1 (TRPA1) in translational rat endometriosis model. Bulletin of Medical Sciences. 2019; 92 (1):15-26.

Chicago/Turabian Style

Pohóczky Krisztina; Bohonyi Noémi; Maczkó Péter; Kajtár Béla; Helyes Zsuzsanna. 2019. "Presence and upregulation of Transient Receptor Potential Vanilloid 1 (TRPV1) and Ankyrin 1 (TRPA1) in translational rat endometriosis model." Bulletin of Medical Sciences 92, no. 1: 15-26.

Journal article
Published: 10 April 2019 in International Journal of Molecular Sciences
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Transient receptor potential (TRP) channels have emerged as potential sensors and transducers of inflammatory pain. The aims of this study were to investigate (1) the expression of TRP channels in intervertebral disc (IVD) cells in normal and inflammatory conditions and (2) the function of Transient receptor potential ankyrin 1 (TRPA1) and Transient receptor potential vanilloid 1 (TRPV1) in IVD inflammation and matrix homeostasis. RT-qPCR was used to analyze human fetal, healthy, and degenerated IVD tissues for the gene expression of TRPA1 and TRPV1. The primary IVD cell cultures were stimulated with either interleukin-1 beta (IL-1β) or tumor necrosis factor alpha (TNF-α) alone or in combination with TRPA1/V1 agonist allyl isothiocyanate (AITC, 3 and 10 µM), followed by analysis of calcium flux and the expression of inflammation mediators (RT-qPCR/ELISA) and matrix constituents (RT-qPCR). The matrix structure and composition in caudal motion segments from TRPA1 and TRPV1 wild-type (WT) and knock-out (KO) mice was visualized by FAST staining. Gene expression of other TRP channels (A1, C1, C3, C6, V1, V2, V4, V6, M2, M7, M8) was also tested in cytokine-treated cells. TRPA1 was expressed in fetal IVD cells, 20% of degenerated IVDs, but not in healthy mature IVDs. TRPA1 expression was not detectable in untreated cells and it increased upon cytokine treatment, while TRPV1 was expressed and concomitantly reduced. In inflamed IVD cells, 10 µM AITC activated calcium flux, induced gene expression of IL-8, and reduced disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and collagen 1A1, possibly via upregulated TRPA1. TRPA1 KO in mice was associated with signs of degeneration in the nucleus pulposus and the vertebral growth plate, whereas TRPV1 KO did not show profound changes. Cytokine treatment also affected the gene expression of TRPV2 (increase), TRPV4 (increase), and TRPC6 (decrease). TRPA1 might be expressed in developing IVD, downregulated during its maturation, and upregulated again in degenerative disc disease, participating in matrix homeostasis. However, follow-up studies with larger sample sizes are needed to fully elucidate the role of TRPA1 and other TRP channels in degenerative disc disease.

ACS Style

Takuya Kameda; Joel Zvick; Miriam Vuk; Aleksandra Sadowska; Wai Kit Tam; Victor Y. Leung; Kata Bölcskei; Zsuzsanna Helyes; Lee Ann Applegate; Oliver N. Hausmann; Juergen Klasen; Olga Krupkova; Karin Wuertz-Kozak. Expression and Activity of TRPA1 and TRPV1 in the Intervertebral Disc: Association with Inflammation and Matrix Remodeling. International Journal of Molecular Sciences 2019, 20, 1767 .

AMA Style

Takuya Kameda, Joel Zvick, Miriam Vuk, Aleksandra Sadowska, Wai Kit Tam, Victor Y. Leung, Kata Bölcskei, Zsuzsanna Helyes, Lee Ann Applegate, Oliver N. Hausmann, Juergen Klasen, Olga Krupkova, Karin Wuertz-Kozak. Expression and Activity of TRPA1 and TRPV1 in the Intervertebral Disc: Association with Inflammation and Matrix Remodeling. International Journal of Molecular Sciences. 2019; 20 (7):1767.

Chicago/Turabian Style

Takuya Kameda; Joel Zvick; Miriam Vuk; Aleksandra Sadowska; Wai Kit Tam; Victor Y. Leung; Kata Bölcskei; Zsuzsanna Helyes; Lee Ann Applegate; Oliver N. Hausmann; Juergen Klasen; Olga Krupkova; Karin Wuertz-Kozak. 2019. "Expression and Activity of TRPA1 and TRPV1 in the Intervertebral Disc: Association with Inflammation and Matrix Remodeling." International Journal of Molecular Sciences 20, no. 7: 1767.

Review
Published: 30 March 2019 in Pharmaceuticals
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Inflammatory bowel diseases (IBD) have long been recognized to be accompanied by pain resulting in high morbidity. Transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) ion channels located predominantly on the capsaicin-sensitive sensory neurons play a complex role in hyperalgesia and neurogenic inflammation. This review provides an overview of their expression and role in intestinal inflammation, in particular colitis, that appears to be virtually inconsistent based on the thorough investigations of the last twenty years. However, preclinical results with pharmacological interventions, as well as scarcely available human studies, more convincingly point out the potential therapeutic value of TRPV1 and TRPA1 antagonists in colitis and visceral hypersensitivity providing future therapeutical perspectives through a complex, unique mechanism of action for drug development in IBD.

ACS Style

Kata Csekő; Bram Beckers; Daniel Keszthelyi; Zsuzsanna Helyes. Role of TRPV1 and TRPA1 Ion Channels in Inflammatory Bowel Diseases: Potential Therapeutic Targets? Pharmaceuticals 2019, 12, 48 .

AMA Style

Kata Csekő, Bram Beckers, Daniel Keszthelyi, Zsuzsanna Helyes. Role of TRPV1 and TRPA1 Ion Channels in Inflammatory Bowel Diseases: Potential Therapeutic Targets? Pharmaceuticals. 2019; 12 (2):48.

Chicago/Turabian Style

Kata Csekő; Bram Beckers; Daniel Keszthelyi; Zsuzsanna Helyes. 2019. "Role of TRPV1 and TRPA1 Ion Channels in Inflammatory Bowel Diseases: Potential Therapeutic Targets?" Pharmaceuticals 12, no. 2: 48.