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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.
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 StyleBalázs 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 StyleBalázs 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.
Pharmacotherapy of neuropathic pain is still challenging. Our earlier work indicated an analgesic effect of dimethyl trisulfide (DMTS), which was mediated by somatostatin released from nociceptor nerve endings acting on SST4 receptors. Somatostatin release occurred due to TRPA1 ion channel activation. In the present study, we investigated the effect of DMTS in neuropathic pain evoked by partial ligation of the sciatic nerve in mice. Expression of the mRNA of Trpa1 in murine dorsal-root-ganglion neurons was detected by RNAscope. Involvement of TRPA1 ion channels and SST4 receptors was tested with gene-deleted animals. Macrophage activity at the site of the nerve lesion was determined by lucigenin bioluminescence. Density and activation of microglia in the spinal cord dorsal horn was verified by immunohistochemistry and image analysis. Trpa1 mRNA is expressed in peptidergic and non-peptidergic neurons in the dorsal root ganglion. DMTS ameliorated neuropathic pain in Trpa1 and Sstr4 WT mice, but not in KO ones. DMTS had no effect on macrophage activity around the damaged nerve. Microglial density in the dorsal horn was reduced by DMTS independently from TRPA1. No effect on microglial activation was detected. DMTS might offer a novel therapeutic opportunity in the complementary treatment of neuropathic pain.
Ágnes Dombi; Csenge Sánta; István Bátai; Viktória Kormos; Angéla Kecskés; Valéria Tékus; Krisztina Pohóczky; Kata Bölcskei; Erika Pintér; Gábor Pozsgai. Dimethyl Trisulfide Diminishes Traumatic Neuropathic Pain Acting on TRPA1 Receptors in Mice. International Journal of Molecular Sciences 2021, 22, 3363 .
AMA StyleÁgnes Dombi, Csenge Sánta, István Bátai, Viktória Kormos, Angéla Kecskés, Valéria Tékus, Krisztina Pohóczky, Kata Bölcskei, Erika Pintér, Gábor Pozsgai. Dimethyl Trisulfide Diminishes Traumatic Neuropathic Pain Acting on TRPA1 Receptors in Mice. International Journal of Molecular Sciences. 2021; 22 (7):3363.
Chicago/Turabian StyleÁgnes Dombi; Csenge Sánta; István Bátai; Viktória Kormos; Angéla Kecskés; Valéria Tékus; Krisztina Pohóczky; Kata Bölcskei; Erika Pintér; Gábor Pozsgai. 2021. "Dimethyl Trisulfide Diminishes Traumatic Neuropathic Pain Acting on TRPA1 Receptors in Mice." International Journal of Molecular Sciences 22, no. 7: 3363.
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.
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 StyleBálint 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 StyleBálint 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.
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.
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 StyleTimea 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 StyleTimea 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.
Transient receptor potential ankyrin 1 (TRPA1) receptors are non-selective cation channels responsive to a variety of exogenous irritants and endogenous stimuli including products of oxidative stress. It is mainly expressed by primary sensory neurons; however, expression of TRPA1 by astrocytes and oligodendrocytes has recently been detected in the mouse brain. Genetic deletion of TRPA1 was shown to attenuate cuprizone-induced oligodendrocyte apoptosis and myelin loss in mice. In the present study we aimed at investigating mGFAP-Cre conditional TRPA1 knockout mice in the cuprizone model. These animals were generated by crossbreeding GFAP-Cre+/− and floxed TRPA1 (TRPA1Fl/Fl) mice. Cuprizone was administered for 6 weeks and demyelination was followed by magnetic resonance imaging (MRI). At the end of the treatment, demyelination and glial activation was also investigated by histological methods. The results of the MRI showed that demyelination was milder at weeks 3 and 4 in both homozygous (GFAP-Cre+/− TRPA1Fl/Fl) and heterozygous (GFAP-Cre+/− TRPA1Fl/−) conditional knockout animals compared to Cre−/− control mice. However, by week 6 of the treatment the difference was not detectable by either MRI or histological methods. In conclusion, TRPA1 receptors on astrocytes may transiently contribute to the demyelination induced by cuprizone, however, expression and function of TRPA1 receptors by other cells in the brain (oligodendrocytes, microglia, neurons) warrant further investigation.
Gábor Kriszta; Balázs Nemes; Zoltán Sándor; Péter Ács; Sámuel Komoly; Zoltán Berente; Kata Bölcskei; Erika Pintér. Investigation of Cuprizone-Induced Demyelination in mGFAP-Driven Conditional Transient Receptor Potential Ankyrin 1 (TRPA1) Receptor Knockout Mice. Cells 2019, 9, 81 .
AMA StyleGábor Kriszta, Balázs Nemes, Zoltán Sándor, Péter Ács, Sámuel Komoly, Zoltán Berente, Kata Bölcskei, Erika Pintér. Investigation of Cuprizone-Induced Demyelination in mGFAP-Driven Conditional Transient Receptor Potential Ankyrin 1 (TRPA1) Receptor Knockout Mice. Cells. 2019; 9 (1):81.
Chicago/Turabian StyleGábor Kriszta; Balázs Nemes; Zoltán Sándor; Péter Ács; Sámuel Komoly; Zoltán Berente; Kata Bölcskei; Erika Pintér. 2019. "Investigation of Cuprizone-Induced Demyelination in mGFAP-Driven Conditional Transient Receptor Potential Ankyrin 1 (TRPA1) Receptor Knockout Mice." Cells 9, no. 1: 81.
There is a growing interest to use non-invasive optical imaging methods to study central nervous system diseases. The application of a myelin-binding fluorescent dye, 3,3-diethylthiatricarbocyanine iodide (DBT) was recently described for in vivo optical imaging of demyelination in the mouse. In the present study we aimed at adapting the method to our optical imaging systems, the IVIS Lumina II to measure epifluorescence and the fluorescent molecular tomograph (FMT) for 3-dimensional quantification of the fluorophore. Epifluorescent imaging was performed 5−30 min after DBT injection which was followed by FMT imaging at 40 min. Two mice also underwent micro-CT imaging in the FMT cassette for the purpose of FMT-CT co-registration. Ex vivo imaging of the brain and other tissues of the head and neck was carried out 1 h after injection. Both the FMT-CT co-registration and the ex vivo imaging of organs proved that DBT poorly crossed the blood-brain barrier. The dye did not accumulate in the myelin sheath of the sciatic nerve. In contrast, there was an intense accumulation in the pituitary and salivary glands. The FMT-CT co-registration unequivocally demonstrated that the signal localized to the head did not originate from beyond the blood-brain barrier. No myelin binding was demonstrated by the ex vivo imaging either. In conclusion, DBT is unsuitable for in vivo imaging of myelination due to its poor BBB penetration, accumulation in other structures of the head and neck region and lack of selective binding towards myelin in vivo.
Bálint Botz; István Zoárd Bátai; Tamás Kiss; Erika Pintér; Zsuzsanna Helyes; Kata Bölcskei. The fluorescent dye 3,3′-diethylthiatricarbocyanine iodide is unsuitable for in vivo imaging of myelination in the mouse. Brain Research Bulletin 2019, 156, 10 -14.
AMA StyleBálint Botz, István Zoárd Bátai, Tamás Kiss, Erika Pintér, Zsuzsanna Helyes, Kata Bölcskei. The fluorescent dye 3,3′-diethylthiatricarbocyanine iodide is unsuitable for in vivo imaging of myelination in the mouse. Brain Research Bulletin. 2019; 156 ():10-14.
Chicago/Turabian StyleBálint Botz; István Zoárd Bátai; Tamás Kiss; Erika Pintér; Zsuzsanna Helyes; Kata Bölcskei. 2019. "The fluorescent dye 3,3′-diethylthiatricarbocyanine iodide is unsuitable for in vivo imaging of myelination in the mouse." Brain Research Bulletin 156, no. : 10-14.
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.
Ivica Matak; Kata Bölcskei; Lidija Bach-Rojecky; Zsuzsanna Helyes. Mechanisms of Botulinum Toxin Type A Action on Pain. Toxins 2019, 11, 459 .
AMA StyleIvica Matak, Kata Bölcskei, Lidija Bach-Rojecky, Zsuzsanna Helyes. Mechanisms of Botulinum Toxin Type A Action on Pain. Toxins. 2019; 11 (8):459.
Chicago/Turabian StyleIvica Matak; Kata Bölcskei; Lidija Bach-Rojecky; Zsuzsanna Helyes. 2019. "Mechanisms of Botulinum Toxin Type A Action on Pain." Toxins 11, no. 8: 459.
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.
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 StyleTakuya 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 StyleTakuya 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.
The regulatory role of capsaicin-sensitive peptidergic sensory nerves has been shown in acute inflammation, but little is known about their involvement in T/B-cell driven autoimmune arthritis. This study integratively characterized the function of these nerve endings in the proteoglycan-induced chronic arthritis (PGIA), a translational model of rheumatoid arthritis. Peptidergic afferents were defunctionalized by resiniferatoxin (RTX) pretreatment in BALB/c mice, PGIA was induced by repeated antigen challenges. Hind paw volume, arthritis severity, grasping ability and the mechanonociceptive threshold were monitored during the 17-week experiment. Myeloperoxidase activity, vascular leakage and bone turnover were evaluated by in vivo optical imaging. Bone morphology was assessed using micro-CT, the intertarsal small joints were processed for histopathological analysis. Following desensitization of the capsaicin-sensitive afferents, ankle edema, arthritis severity and mechanical hyperalgesia were markedly diminished. Myeloperoxidase activity was lower in the early, but increased in the late phase, whilst plasma leakage and bone turnover were not altered. Desensitized mice displayed similar bone spurs and erosions, but increased trabecular thickness of the tibia and bony ankylosis of the spine. Intertarsal cartilage thickness was not altered in the model, but desensitization increased this parameter in both the non-arthritic and arthritic groups. This is the first integrative in vivo functional and morphological characterization of the PGIA mouse model, wherein peptidergic afferents have an important regulatory function. Their overall effect is proinflammatory by increasing acute inflammation, immune cell activity and pain. Meanwhile, their activation decreases spinal ankylosis, arthritis-induced altered trabecularity, and cartilage thickness in small joints.
Ádám Horváth; Éva Borbély; Kata Bölcskei; Nikolett Szentes; Tamás Kiss; Mátyás Belák; Tibor Rauch; Tibor Glant; Róza Zákány; Tamás Juhász; Edina Karanyicz; Ferenc Boldizsár; Zsuzsanna Helyes; Bálint Botz. Regulatory role of capsaicin-sensitive peptidergic sensory nerves in the proteoglycan-induced autoimmune arthritis model of the mouse. Journal of Neuroinflammation 2018, 15, 1 -12.
AMA StyleÁdám Horváth, Éva Borbély, Kata Bölcskei, Nikolett Szentes, Tamás Kiss, Mátyás Belák, Tibor Rauch, Tibor Glant, Róza Zákány, Tamás Juhász, Edina Karanyicz, Ferenc Boldizsár, Zsuzsanna Helyes, Bálint Botz. Regulatory role of capsaicin-sensitive peptidergic sensory nerves in the proteoglycan-induced autoimmune arthritis model of the mouse. Journal of Neuroinflammation. 2018; 15 (1):1-12.
Chicago/Turabian StyleÁdám Horváth; Éva Borbély; Kata Bölcskei; Nikolett Szentes; Tamás Kiss; Mátyás Belák; Tibor Rauch; Tibor Glant; Róza Zákány; Tamás Juhász; Edina Karanyicz; Ferenc Boldizsár; Zsuzsanna Helyes; Bálint Botz. 2018. "Regulatory role of capsaicin-sensitive peptidergic sensory nerves in the proteoglycan-induced autoimmune arthritis model of the mouse." Journal of Neuroinflammation 15, no. 1: 1-12.
We have recently reported that the Transient Receptor Potential Ankyrin 1 (TRPA1) receptor deficiency significantly attenuated cuprizone-induced demyelination by reducing the apoptosis of mature oligodendrocytes. The aim of the present study was to gather additional data on the role of TRPA1 by investigating the time course of behavioural alterations and morphological changes in cuprizone-treated TRPA1 receptor gene-deficient mice. Demyelination was induced by feeding male wild-type (WT) and TRPA1 gene-deleted (TRPA1 KO) mice with 0.2% cuprizone for 6 weeks. Behavioural tests were performed once per week to follow cuprizone-induced functional changes. Mechanonociceptive thresholds were investigated by a dynamic plantar aesthesiometer and von Frey filaments. Motor performance was assessed by accelerating RotaRod and horizontal grid tests. For the study of spontaneous activity, the open field test was used. The time course of corpus callosum demyelination was also followed weekly by magnetic resonance imaging (MRI). Histological analysis of myelin loss was performed with Luxol Fast Blue (LFB) staining at week 3 and electron microscopy (EM) at week 6. Astrocyte and microglia accumulation at week 3 was assessed by immunohistochemistry (IHC). Cuprizone treatment induced no changes in mechanonociception or motor performance. In the open arena, cuprizone-treated mice spent more time with locomotion, their mean velocity was significantly higher and the distance they travelled was longer than untreated mice. No statistical difference was detected between WT and TRPA1 KO mice in these parameters. On the other hand, significantly increased rearing behaviour was induced in WT mice compared to TRPA1 KO animals. Morphological changes detected with MRI, LFB, IHC and EM analysis revealed reduced damage of the myelin and attenuated accumulation of astrocytes and microglia in cuprizone-treated TRPA1 KO animals, at each examined time point. Our recent data further suggest that inhibition of TRPA1 receptors could be a promising therapeutic approach to limit central nervous system damage in demyelinating diseases.
Kata Bölcskei; Gábor Kriszta; Éva Sághy; Maja Payrits; Éva Sipos; Anett Vranesics; Zoltán Berente; Hajnalka Ábrahám; Péter Ács; Sámuel Komoly; Erika Pintér. Behavioural alterations and morphological changes are attenuated by the lack of TRPA1 receptors in the cuprizone-induced demyelination model in mice. Journal of Neuroimmunology 2018, 320, 1 -10.
AMA StyleKata Bölcskei, Gábor Kriszta, Éva Sághy, Maja Payrits, Éva Sipos, Anett Vranesics, Zoltán Berente, Hajnalka Ábrahám, Péter Ács, Sámuel Komoly, Erika Pintér. Behavioural alterations and morphological changes are attenuated by the lack of TRPA1 receptors in the cuprizone-induced demyelination model in mice. Journal of Neuroimmunology. 2018; 320 ():1-10.
Chicago/Turabian StyleKata Bölcskei; Gábor Kriszta; Éva Sághy; Maja Payrits; Éva Sipos; Anett Vranesics; Zoltán Berente; Hajnalka Ábrahám; Péter Ács; Sámuel Komoly; Erika Pintér. 2018. "Behavioural alterations and morphological changes are attenuated by the lack of TRPA1 receptors in the cuprizone-induced demyelination model in mice." Journal of Neuroimmunology 320, no. : 1-10.
Semicarbazide-sensitive amine oxidase (SSAO) produces tissue irritants by deamination of primary amines, which activate transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors expressed predominantly on nociceptors. Since there are no data about its functions in pain, we studied the effects and mechanisms of action of our novel SSAO inhibitor and dual TRPA1/TRPV1 antagonist multi-target drug SZV 1287 in different pain models. Acute chemonociception was induced by TRPV1 and TRPA1 activation (resiniferatoxin and formalin, respectively), chronic arthritis by K/BxN serum transfer, traumatic mononeuropathy by sciatic nerve ligation. SZV 1287 (20 mg/kg i.p.) was investigated in C57BL/6J wildtype (WT), TRPA1- (TRPA1−/−) and TRPV1-deficient (TRPV1−/−) mice. Paw mechanonociception was measured by aesthesiometry, thermonociception by hot plate, nocifensive behavior by licking duration, volume by plethysmometry, myeloperoxidase activity by luminescence and plasma extravasation by fluorescence imaging, glia activation in pain-related brain regions by immunohistochemistry. SZV 1287 significantly inhibited both TRPA1 and TRPV1 activation-induced acute chemonociception and hyperalgesia. In K/BxN arthritis, daily SZV 1287 injections significantly decreased hyperalgesia, L4-L6 spinal dorsal horn microgliosis, edema and myeloperoxidase activity. SZV 1287-evoked antihyperalgesic and anti-edema effects were absent in TRPV1−/−, and remarkably reduced in TRPA1−/− mice. In contrast, myeloperoxidase-inhibitory effect was absent in TRPA1−/−, but not in TRPV1−/− animals. Acute SZV 1287 administration resulted in approximately 50% significant reduction of neuropathic hyperalgesia 7 days after nerve ligation, which was not observed in either TRPA1−/− or TRPV1−/− mice. SZV 1287 inhibits chronic inflammatory and neuropathic pain via TRPV1 and TRPA1/TRPV1 activation, respectively, highlighting its drug developmental potential.
Ádám Horváth; Valéria Tékus; Noémi Bencze; Nikolett Szentes; Bálint Scheich; Kata Bölcskei; Éva Szőke; Attila Mócsai; Éva Tóth-Sarudy; Péter Mátyus; Erika Pintér; Zsuzsanna Helyes. Analgesic effects of the novel semicarbazide-sensitive amine oxidase inhibitor SZV 1287 in mouse pain models with neuropathic mechanisms: Involvement of transient receptor potential vanilloid 1 and ankyrin 1 receptors. Pharmacological Research 2018, 131, 231 -243.
AMA StyleÁdám Horváth, Valéria Tékus, Noémi Bencze, Nikolett Szentes, Bálint Scheich, Kata Bölcskei, Éva Szőke, Attila Mócsai, Éva Tóth-Sarudy, Péter Mátyus, Erika Pintér, Zsuzsanna Helyes. Analgesic effects of the novel semicarbazide-sensitive amine oxidase inhibitor SZV 1287 in mouse pain models with neuropathic mechanisms: Involvement of transient receptor potential vanilloid 1 and ankyrin 1 receptors. Pharmacological Research. 2018; 131 ():231-243.
Chicago/Turabian StyleÁdám Horváth; Valéria Tékus; Noémi Bencze; Nikolett Szentes; Bálint Scheich; Kata Bölcskei; Éva Szőke; Attila Mócsai; Éva Tóth-Sarudy; Péter Mátyus; Erika Pintér; Zsuzsanna Helyes. 2018. "Analgesic effects of the novel semicarbazide-sensitive amine oxidase inhibitor SZV 1287 in mouse pain models with neuropathic mechanisms: Involvement of transient receptor potential vanilloid 1 and ankyrin 1 receptors." Pharmacological Research 131, no. : 231-243.
The antinociceptive action of botulinum toxin type A (BoNT/A) has been demonstrated in behavioral animal studies and clinical settings. It was shown that this effect is associated with toxin activity in CNS, however, the mechanism is not fully understood. Substance P (SP) is one of the dominant neurotransmitters in primary afferent neurons transmitting pain and itch. Thus, here we examined association of SP-mediated transmission and BoNT/A antinociceptive action by employing gene knockouts. Antinociceptive activity of intraplantarly (i.pl.)-injected BoNT/A was examined in mice lacking the gene encoding for SP/neurokinin A (tac1(-/-)) or SP-preferred receptor neurokinin 1 (tac1r(-/-)), compared to control C57Bl/6J wild type animals. BoNT/A action was assessed in inflammatory pain induced by formalin and CFA, and neuropathic pain induced by partial sciatic nerve ligation. BoNT/A activity in CNS was examined by c-Fos and BoNT/A-cleaved SNAP-25 immunohistochemistry. In wild type mice, acute (formalin-evoked) and chronic pain (neuropathic and inflammatory) was reduced by peripherally injected BoNT/A. In tac1(-/-) and tac1r(-/-) knockout mice, BoNT/A exerted no analgesic effect. In control animals BoNT/A reduced the formalin-evoked c-Fos expression in lumbar dorsal horn, while in knockout mice the c-Fos expression was not reduced. After peripheral toxin injection, cleaved SNAP-25 occurred in lumbar dorsal horn in all animal genotypes. BoNT/A antinociceptive activity is absent in animals lacking the SP and neurokinin 1 receptor encoding genes, in spite of presence of toxin's enzymatic activity in central sensory regions. Thus, we conclude that the integrity of SP-ergic system is necessary for the antinociceptive activity of BoNT/A.
Ivica Matak; Valéria Tékus; Kata Bölcskei; Zdravko Lacković; Zsuzsanna Helyes. Involvement of substance P in the antinociceptive effect of botulinum toxin type A: Evidence from knockout mice. Neuroscience 2017, 358, 137 -145.
AMA StyleIvica Matak, Valéria Tékus, Kata Bölcskei, Zdravko Lacković, Zsuzsanna Helyes. Involvement of substance P in the antinociceptive effect of botulinum toxin type A: Evidence from knockout mice. Neuroscience. 2017; 358 ():137-145.
Chicago/Turabian StyleIvica Matak; Valéria Tékus; Kata Bölcskei; Zdravko Lacković; Zsuzsanna Helyes. 2017. "Involvement of substance P in the antinociceptive effect of botulinum toxin type A: Evidence from knockout mice." Neuroscience 358, no. : 137-145.
Majority of the work for establishing nitroglycerin (NTG)-induced migraine models in animals was done in rats, though recently some studies in mice were also reported. Different special formulations of NTG were investigated in various studies; however, NTG treated groups were often compared to simple saline treated control groups. The aim of the present studies was to critically assess the utility of a panel of potential outcome measures in mice by revisiting previous findings and investigating endpoints that have not been tested in mice yet. We investigated two NTG formulations, Nitrolingual and Nitro Pohl, at an intraperitoneal dose of 10 mg/kg, in comparison with relevant vehicle controls, and evaluated the following outcome measures: light aversive behaviour, cranial blood perfusion by laser Doppler imaging, number of c-Fos- and neuronal nitrogen monoxide synthase (nNOS)-immunoreactive neurons in the trigeminal nucleus caudalis (TNC) and trigeminal ganglia, thermal hyperalgesia and tactile allodynia of the hind paw and orofacial pain hypersensitivity. We could not confirm previous reports of significant NTG-induced changes in light aversion and cranial blood perfusion of mice but we observed considerable effects elicited by the vehicle of Nitrolingual. In contrast, the vehicle of Nitro Pohl was apparently inert. Increased c-Fos expression in the TNC, thermal hyperalgesia, tactile allodynia and orofacial hypersensitivity were apparently good endpoints in mice that were increased by NTG-administration. The NTG-induced increase in c-Fos expression was prevented by topiramate but not by sumatriptan treatment. However, the NTG-induced orofacial hypersensitivity was dose dependently attenuated by sumatriptan. Our results pointed to utilisable NTG formulations and outcome measures for NTG-induced migraine models in mice. Pending further cross-validation with positive and negative control drugs in these mouse models and in the human NTG models of migraine, these tests might be valuable translational research tools for development of new anti-migraine drugs.
Sándor Farkas; Kata Bölcskei; Adrienn Markovics; Anita Varga; Ágnes Kis-Varga; Viktória Kormos; Balázs Gaszner; Csilla Horváth; Bernadett Tuka; János Tajti; Zsuzsanna Helyes. Utility of different outcome measures for the nitroglycerin model of migraine in mice. Journal of Pharmacological and Toxicological Methods 2015, 77, 33 -44.
AMA StyleSándor Farkas, Kata Bölcskei, Adrienn Markovics, Anita Varga, Ágnes Kis-Varga, Viktória Kormos, Balázs Gaszner, Csilla Horváth, Bernadett Tuka, János Tajti, Zsuzsanna Helyes. Utility of different outcome measures for the nitroglycerin model of migraine in mice. Journal of Pharmacological and Toxicological Methods. 2015; 77 ():33-44.
Chicago/Turabian StyleSándor Farkas; Kata Bölcskei; Adrienn Markovics; Anita Varga; Ágnes Kis-Varga; Viktória Kormos; Balázs Gaszner; Csilla Horváth; Bernadett Tuka; János Tajti; Zsuzsanna Helyes. 2015. "Utility of different outcome measures for the nitroglycerin model of migraine in mice." Journal of Pharmacological and Toxicological Methods 77, no. : 33-44.
Somatostatin regulates stress-related behavior and its expression is altered in mood disorders. However, little is known about the underlying mechanisms, especially about the importance of its receptors (sst1–sst5) in anxiety and depression-like behavior. Here we analyzed the potential role of sst4 receptor in these processes, since sst4 is present in stress-related brain regions, but there are no data about its functional relevance. Genetic deletion of sst4 (Sstr4−/−) and its pharmacological activation with the newly developed selective non-peptide agonist J-2156 were used. Anxiety was examined in the elevated plus maze (EPM) and depression-like behavior in the forced swim (FST) and tail suspension tests (TST). Neuronal activation during the TST was monitored by Fos immunohistochemistry, receptor expression was identified by sst4LacZ immunostaining in several brain regions. Sstr4−/− mice showed increased anxiety in the EPM and enhanced depression-like behavior in the FST. J-2156 (100 μg/kg i.p.) exhibited anxiolytic effect in the EPM and decreased immobility in the TST. J-2156 alone did not influence Fos immunoreactivity in intact mice, but significantly increased the stress-induced Fos response in the dorsal raphe nucleus, central projecting Edinger–Westphal nucleus, periaqueductal gray matter, the magnocellular, but not the parvocellular part of the hypothalamic paraventricular nucleus, lateral septum, bed nucleus of the stria terminalis and the amygdala. Notably, sst4LacZ immunoreactivity occurred in the central and basolateral amygdala. Together, these studies reveal that sst4 mediates anxiolytic and antidepressant-like effects by enhancing the stress-responsiveness of several brain regions with special emphasis on the amygdala.
Bálint Scheich; Balázs Gaszner; Viktória Kormos; Kristóf László; Csaba Ádori; Éva Borbély; Zsófia Hajna; Valéria Tékus; Kata Bölcskei; István Ábrahám; Erika Pintér; János Szolcsányi; Zsuzsanna Helyes. Somatostatin receptor subtype 4 activation is involved in anxiety and depression-like behavior in mouse models. Neuropharmacology 2015, 101, 204 -215.
AMA StyleBálint Scheich, Balázs Gaszner, Viktória Kormos, Kristóf László, Csaba Ádori, Éva Borbély, Zsófia Hajna, Valéria Tékus, Kata Bölcskei, István Ábrahám, Erika Pintér, János Szolcsányi, Zsuzsanna Helyes. Somatostatin receptor subtype 4 activation is involved in anxiety and depression-like behavior in mouse models. Neuropharmacology. 2015; 101 ():204-215.
Chicago/Turabian StyleBálint Scheich; Balázs Gaszner; Viktória Kormos; Kristóf László; Csaba Ádori; Éva Borbély; Zsófia Hajna; Valéria Tékus; Kata Bölcskei; István Ábrahám; Erika Pintér; János Szolcsányi; Zsuzsanna Helyes. 2015. "Somatostatin receptor subtype 4 activation is involved in anxiety and depression-like behavior in mouse models." Neuropharmacology 101, no. : 204-215.
Vascular leakage is an important feature of various disease conditions. In vivo optical imaging provides a great opportunity for the evaluation of this phenomenon. In the present study, we focus on the development and validation of a near-infrared (NIR) imaging formula to allow reliable, cost-efficient evaluation of vascular leakage in diverse species using the existing small-animal fluorescence imaging technology. IR-676, a moderately hydrophobic NIR cyanine dye, was doped into self-assembling aqueous micelles using a widely employed and safe nonionic emulsifier (Kolliphor HS 15), and was tested in several acute and chronic inflammatory disease models in both mice and rats. The imaging formula is stable and exerts no acute toxic effects in vitro. It accumulated specifically in the inflamed regions in all models, which could be demonstrated by both conventional epifluorescence imaging, and fluorescence tomography both as a standalone technique and also by merging it with computed tomography scans. Ex vivo verification of dye accumulation by confocal fluorescence microscopy was also possible. The present formula allows sensitive and specific detection of inflammatory plasma leakage in diverse models. Its potential for imaging larger animals was also demonstrated. IR-676-doped micelles offer an excellent opportunity to image inflammatory vascular leakage in various models and species.
Bálint Botz; Kata Bölcskei; Agnes Kemeny; Zoltán Sándor; Valéria Tékus; Gyorgy Setalo; Janka Csepregi; Attila Mócsai; Erika Pintér; László Kollár; Zsuzsanna Helyes. Hydrophobic cyanine dye-doped micelles for optical in vivo imaging of plasma leakage and vascular disruption. Journal of Biomedical Optics 2015, 20, 016022 .
AMA StyleBálint Botz, Kata Bölcskei, Agnes Kemeny, Zoltán Sándor, Valéria Tékus, Gyorgy Setalo, Janka Csepregi, Attila Mócsai, Erika Pintér, László Kollár, Zsuzsanna Helyes. Hydrophobic cyanine dye-doped micelles for optical in vivo imaging of plasma leakage and vascular disruption. Journal of Biomedical Optics. 2015; 20 (1):016022.
Chicago/Turabian StyleBálint Botz; Kata Bölcskei; Agnes Kemeny; Zoltán Sándor; Valéria Tékus; Gyorgy Setalo; Janka Csepregi; Attila Mócsai; Erika Pintér; László Kollár; Zsuzsanna Helyes. 2015. "Hydrophobic cyanine dye-doped micelles for optical in vivo imaging of plasma leakage and vascular disruption." Journal of Biomedical Optics 20, no. 1: 016022.