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Investigation of the Anti-Inflammatory Activity of Hydroxyzine Hihydrochloride in Mammalian Macrophages on the PI3K and P38 Pathway

Year 2022, Volume: 12 Issue: 3, 560 - 565, 29.09.2022
https://doi.org/10.31832/smj.1144968

Abstract

Objective: Depression is a common mental disorder that affects patients' health-related quality of life. Hydroxyzine hydrochloride (HHCL), which is among the antihistamines, is generally used in allergic treatments. Also, HHCL, has been routinely used in the treatment of anxiety, mental distress and stress in recent years. Although there are many studies on hydroxyzine chloride, there is not enough information in the literature about the effects of this drug on the immune system.
Materials and Methods: Previous studies suggest that some antidepressants are anti-inflammatory and anti-analgesic. Therefore, the immunomodulatory activities of one of these drugs, Hydroxyzine hydrochloride, on mammalian macrophages were analyzed in flow cytometry to determine the possible intracellular mechanisms of action of the phosphorylated (active) p38 MAPK and PI3K proteins.
Results: It has been found that Hydroxyzine hydrochloride applied to macrophage cells causes a significant decrease in the levels of p38 MAPK and PI3K proteins.
Conclusion: According to these data, Hydroxyzine hydrochloride (HHCL), had different effects on macrophages. While HHCL triggers a mild inflammatory response in non-activated macrophages; it had anti-inflammatory effects on already activated macrophages. Intracellular mechanisms of action of HHCL were partially via the p38 MAPK and PI3K pathways.

References

  • Referans 1 GBD 2015 Disease and Injury Incidence and Prevalence Collaborators (2016). Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the global burden of disease study. Lancet 2016; 388:1545–602.
  • Referans 2 Jinghui W, Xiaohang W, Weiyi L, Erping L, Xiayin Z, Wangting Li, YZ, Chuan C, Xiaojian Z, Zhenzhen L, Dongni W, Haotian Lin. Prevalence of depression and depressive symptoms among outpatients: a systematic review and meta-analysis. BMJ Open 2017; 7(8): 17173-17184.
  • Referans 3 Kuo DC, Tran M, Shah AA, et al. World Health Organization. The World Health Report 2002: Reducing Risks, Promoting Healthy Life. 2002. Depression and the suicidal patient. Emerg Med Clin North Am 2015; 33:765–78.
  • Referans 4 Hranov LG. Comorbid anxiety and depression: Illumination of a controversy. Int J Psychiatry Clin Pract. 2007;11:171–189.
  • Referans 5. Starr LR, Hammen C, Connolly NP, Brennan PA. Does relational dysfunction mediate the association between anxiety disorders and later depression? Testing an interpersonal model of comorbidity. Depress Anxiety 2014; 31:77–86.
  • Referans 6. Baldwin DS, Pallanti S, Zwanzger P. Developing a European research network to address unmet needs in anxiety disorders. Neurosci Biobehav Rev. 2013; 37:2312–2317.
  • Referans 7. Baxter AJ, Scott KM, Vos T, Whiteford HA. Global prevalence of anxiety disorders: A systematic review and meta-regression. Psychol Med. 2013; 43:897–910.
  • Referans 8. Norman TR, Olver JS. Duloxetine in the treatment of generalized anxiety disorder. Neuropsychiatr Dis Treat. 2008; 4:1169–1180.
  • Referans 9. Sonam P, Pravin PK, Veeranjaneyulu A, Amrita, S and Jay S. Effect of a combination of duloxetine with hydroxyzine on experimental models of anxiety in mice, Indian J Pharmacol. 2015; 47(2): 173–176.
  • Referans 10. Ghosh S, Majumder S, Pal R, Chakraborty M, Biswas A. Gupta B. Formulation and evaluation of hydroxyzine hydrochloride sustained release microspheres by ionotropic gelation technique using Carbopol 934P, Asian J. Pharm. 2014; 8 (4) 230–236.
  • Referans 11. Dalia FA. El-Telbany A, Rania FA. El-Telban, SZ, Kawkab AA, Yasmin A. Formulation and assessment of hydroxyzine HCL solid lipid nanoparticles by dual emulsification technique for transdermal delivery. Biomedicine & Pharmacotherapy 2021;143:11-13.
  • Referans 12. Global Antidepressants Market Report 2021: COVID-19 Causes a Surge in Demand for Antidepressant Drugs as Mental Health Problems Rise - ResearchAndMarkets.com. Antidepressants Global Market Report 2021: COVID-19 Implications and Growth to 2030. Research and Markets 2021; ID:5314992 https://www.businesswire.com/news/home/20210426005303/en/Global-Antidepressants-Market-Report-2021-COVID-19-Causes-a-Surge-in-Demand-for-Antidepressant-Drugs-as-Mental-Health-Problems-Rise---ResearchAndMarkets
  • Referans 13. Herlaar E, Brown Z. p38 MAPK signalling cascades in inflammatory disease. Mol Med Today.1999; 5(10):439-447. doi: 10.1016/s1357-4310(99)01544-0. PMID: 10498912. Referans 14. Stark AK, Sriskantharajah S, Hessel EM, Okkenhaug K. PI3K inhibitors in inflammation, autoimmunity and cancer. Current opinion in pharmacology 2015;23:82–91. https://doi.org/10.1016/j.coph.2015.05.017
  • Referans 15. Cianciulli A, Calvello R, Porro C, Trotta T, Salvatore R, Panaro MA. PI3k/Akt signalling pathway plays a crucial role in the anti-inflammatory effects of curcumin in LPS-activated microglia. Int Immun opharmacol 2016; 36:282-290. doi: 10.1016/j.intimp.2016.05.007. Epub 2016 May 18. PMID: 27208432.
  • Referans 16. Ayaz F, Demir D, Bölgen N. Injectable chitosan cryogel microspheres with biocompatible properties on mammalian macrophages in vitro. J Mater Sci. 2021; 56: 17268–17277. https://doi.org/10.1007/s10853-021-06399-8
  • Referans 17. Yüzer A., Ayaz F, Ince M. Immunomodulatory activities of zinc(II)phthalocyanine on the mammalian macrophages through p38 pathway: Potential ex vivo immunomodulatory PDT reagents. Bioorg Chem. 2019; 92:103249. doi: 10.1016/j.bioorg.2019.103249. Epub 2019 Sep 12. PMID: 31539741.
  • Referans 18. Rajagopalan M, Saraswat A, Godse K, Shankar DS., Kandhari S, Shenoi SD., Tahiliani S, Zawar, VV. Diagnosis and management of chronic pruritus: an expert consensus review. Indian J Dermatol 2017; 62(1):7–17
  • Referans 19. Schneider G, Stumpf A, Burgmer M, Broecker P, Volmering L, Ständer S. Are patients with chronic pruritus more susceptible to social stress than healthy controls? An experimental case-control study. Br J Dermatol. 2018; 179(5):1174–1176
  • Referans 20. Jayakar T, Dattatray GS, Hemangi RJ, Narsimha RGN, Dhanalakshmi UR, Rashid S, et al. Real-World, Non-Interventional, Observational Study of Hydroxyzine Hydrochloride in Chronic Pruritus: a Prospective, Non-Comparative Study. Dermatol Ther (Heidelb) 2019; 9(2): 299–308.
  • Referans 21. Khopkar U, Pande S. Etiopathogenesis of pruritus due to systemic causes: implications for treatment. Indian J Dermatol Venereol Leprol. 2007; 73(4):215–217
  • Referans 22. Bernstein JA., Lang DM, Khan DA, Craig T, Dreyfus D, Hsieh F, Sheikh J, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol. 2014; 133(5):1270–1277.
  • Referans 23. Weisshaar E, Szepietowski JC, Darsow U, Misery L, Wallengren J, Mettang T, et al. European guideline on chronic pruritus. Acta Derm Venereol. 2012; 92(5):563–581.
  • Referans 24. Asero R. Chronic unremitting urticaria: is the use of antihistamines above the licensed dose effective? A preliminary study of cetirizine at licensed and above-licensed doses. Clin Exp Dermatol. 2007; 32(1):34–38.
  • Referans 25. Schindler JF, Monahan JB, Smith WG. p38 Pathway kinases as anti-inflammatory drug targets. J. Dent. Res. 2007; 86:800– 811.
  • Referans 26. González-Terán B, Cortés JR, Manieri E, Matesanz N, Verdugo Á, Rodríguez ME et all. p38γ/δ MAPKs control TNFα translation in acute hepatitis Exp Clin Endocrinol Diabetes 2012; 120 - A8 DOI: 10.1055/s-0032-1330802 Referans 27. Risco A, del Fresno C, Mambol A, Alsina-Beauchamp D, MacKenzie KF, Yang HT, et all. p38γ and p38δ Kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation. Proc. Natl. Acad. Sci. 2012; 109:11200– 11205
  • Referans 28. Cho YW, Kim EJ, Nyiramana MM, Shin EJ, Jin H, Ryu JH, Kang D. Paroxetine induces apoptosis of human breast cancer MCF-7 cells through Ca2+-and p38 MAP kinase-dependent ROS generation. Cancers 2019; 11: (1) 1-22
  • Referans 29. Sheppard K, Kinross KM, Solomon B, Pearson RB, Phillips WA. Targeting PI3 kinase/AKT/mTOR signaling in cancer. Critical Reviews™ in Oncogenesis 2012;17(1):69-75
  • Referans 30. Aksamitiene E, Kiyatkin A, Kholodenko BN. Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: a fine balance. Biochemical Society Transactions 2012; 40(1):139-146.

Hidroksizin Hidroklorürün Memeli Makrofajlarında Anti-inflamatuar Aktivitesinin PI3K ve P38 Yolu Üzerinde Araştırılması

Year 2022, Volume: 12 Issue: 3, 560 - 565, 29.09.2022
https://doi.org/10.31832/smj.1144968

Abstract

Amaç: Depresyon, hastaların sağlıkla ilgili yaşam kalitesini etkileyen yaygın bir ruhsal bozukluktur. Antihistaminikler arasında yer alan hidroksizin hidroklorür (HHCL) genellikle alerjik tedavilerde kullanılmaktadır. Ayrıca HHCL, son yıllarda anksiyete, zihinsel sıkıntı ve stres tedavisinde rutin olarak kullanılmaktadır. Hidroksizin klorür ile ilgili birçok çalışma olmasına rağmen literatürde bu ilacın bağışıklık sistemi üzerindeki etkileri hakkında yeterli bilgi bulunmamaktadır.
Gereç ve Yöntemler: Önceki çalışmalar, bazı antidepresanların anti-inflamatuar ve anti-analjezik olduğunu düşündürmektedir. Bu nedenle, bu ilaçlardan birinin, Hidroksizin hidroklorürün memeli makrofajları üzerindeki immünomodülatör aktiviteleri, fosforile edilmiş (aktif) p38 MAPK ve PI3K proteinlerinin olası hücre içi etki mekanizmalarını belirlemek için akış sitometrisinde analiz edildi.
Bulgular: Makrofaj hücrelerine uygulanan Hidroksizin hidroklorürün, p38 MAPK ve PI3K proteinlerinin düzeylerinde önemli bir azalmaya neden olduğu bulunmuştur.
Sonuç: Bu verilere göre Hidroksizin hidroklorür (HHCL), makrofajlar üzerinde farklı etkilere sahipti. HHCL, aktive olmayan makrofajlarda hafif bir inflamatuar yanıtı tetiklerken; zaten aktive olan makrofajlar üzerinde anti-inflamatuar etkileri vardı. HHCL'nin hücre içi etki mekanizmaları, kısmen p38 MAPK ve PI3K yolları aracılığıyla olmuştur.

References

  • Referans 1 GBD 2015 Disease and Injury Incidence and Prevalence Collaborators (2016). Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the global burden of disease study. Lancet 2016; 388:1545–602.
  • Referans 2 Jinghui W, Xiaohang W, Weiyi L, Erping L, Xiayin Z, Wangting Li, YZ, Chuan C, Xiaojian Z, Zhenzhen L, Dongni W, Haotian Lin. Prevalence of depression and depressive symptoms among outpatients: a systematic review and meta-analysis. BMJ Open 2017; 7(8): 17173-17184.
  • Referans 3 Kuo DC, Tran M, Shah AA, et al. World Health Organization. The World Health Report 2002: Reducing Risks, Promoting Healthy Life. 2002. Depression and the suicidal patient. Emerg Med Clin North Am 2015; 33:765–78.
  • Referans 4 Hranov LG. Comorbid anxiety and depression: Illumination of a controversy. Int J Psychiatry Clin Pract. 2007;11:171–189.
  • Referans 5. Starr LR, Hammen C, Connolly NP, Brennan PA. Does relational dysfunction mediate the association between anxiety disorders and later depression? Testing an interpersonal model of comorbidity. Depress Anxiety 2014; 31:77–86.
  • Referans 6. Baldwin DS, Pallanti S, Zwanzger P. Developing a European research network to address unmet needs in anxiety disorders. Neurosci Biobehav Rev. 2013; 37:2312–2317.
  • Referans 7. Baxter AJ, Scott KM, Vos T, Whiteford HA. Global prevalence of anxiety disorders: A systematic review and meta-regression. Psychol Med. 2013; 43:897–910.
  • Referans 8. Norman TR, Olver JS. Duloxetine in the treatment of generalized anxiety disorder. Neuropsychiatr Dis Treat. 2008; 4:1169–1180.
  • Referans 9. Sonam P, Pravin PK, Veeranjaneyulu A, Amrita, S and Jay S. Effect of a combination of duloxetine with hydroxyzine on experimental models of anxiety in mice, Indian J Pharmacol. 2015; 47(2): 173–176.
  • Referans 10. Ghosh S, Majumder S, Pal R, Chakraborty M, Biswas A. Gupta B. Formulation and evaluation of hydroxyzine hydrochloride sustained release microspheres by ionotropic gelation technique using Carbopol 934P, Asian J. Pharm. 2014; 8 (4) 230–236.
  • Referans 11. Dalia FA. El-Telbany A, Rania FA. El-Telban, SZ, Kawkab AA, Yasmin A. Formulation and assessment of hydroxyzine HCL solid lipid nanoparticles by dual emulsification technique for transdermal delivery. Biomedicine & Pharmacotherapy 2021;143:11-13.
  • Referans 12. Global Antidepressants Market Report 2021: COVID-19 Causes a Surge in Demand for Antidepressant Drugs as Mental Health Problems Rise - ResearchAndMarkets.com. Antidepressants Global Market Report 2021: COVID-19 Implications and Growth to 2030. Research and Markets 2021; ID:5314992 https://www.businesswire.com/news/home/20210426005303/en/Global-Antidepressants-Market-Report-2021-COVID-19-Causes-a-Surge-in-Demand-for-Antidepressant-Drugs-as-Mental-Health-Problems-Rise---ResearchAndMarkets
  • Referans 13. Herlaar E, Brown Z. p38 MAPK signalling cascades in inflammatory disease. Mol Med Today.1999; 5(10):439-447. doi: 10.1016/s1357-4310(99)01544-0. PMID: 10498912. Referans 14. Stark AK, Sriskantharajah S, Hessel EM, Okkenhaug K. PI3K inhibitors in inflammation, autoimmunity and cancer. Current opinion in pharmacology 2015;23:82–91. https://doi.org/10.1016/j.coph.2015.05.017
  • Referans 15. Cianciulli A, Calvello R, Porro C, Trotta T, Salvatore R, Panaro MA. PI3k/Akt signalling pathway plays a crucial role in the anti-inflammatory effects of curcumin in LPS-activated microglia. Int Immun opharmacol 2016; 36:282-290. doi: 10.1016/j.intimp.2016.05.007. Epub 2016 May 18. PMID: 27208432.
  • Referans 16. Ayaz F, Demir D, Bölgen N. Injectable chitosan cryogel microspheres with biocompatible properties on mammalian macrophages in vitro. J Mater Sci. 2021; 56: 17268–17277. https://doi.org/10.1007/s10853-021-06399-8
  • Referans 17. Yüzer A., Ayaz F, Ince M. Immunomodulatory activities of zinc(II)phthalocyanine on the mammalian macrophages through p38 pathway: Potential ex vivo immunomodulatory PDT reagents. Bioorg Chem. 2019; 92:103249. doi: 10.1016/j.bioorg.2019.103249. Epub 2019 Sep 12. PMID: 31539741.
  • Referans 18. Rajagopalan M, Saraswat A, Godse K, Shankar DS., Kandhari S, Shenoi SD., Tahiliani S, Zawar, VV. Diagnosis and management of chronic pruritus: an expert consensus review. Indian J Dermatol 2017; 62(1):7–17
  • Referans 19. Schneider G, Stumpf A, Burgmer M, Broecker P, Volmering L, Ständer S. Are patients with chronic pruritus more susceptible to social stress than healthy controls? An experimental case-control study. Br J Dermatol. 2018; 179(5):1174–1176
  • Referans 20. Jayakar T, Dattatray GS, Hemangi RJ, Narsimha RGN, Dhanalakshmi UR, Rashid S, et al. Real-World, Non-Interventional, Observational Study of Hydroxyzine Hydrochloride in Chronic Pruritus: a Prospective, Non-Comparative Study. Dermatol Ther (Heidelb) 2019; 9(2): 299–308.
  • Referans 21. Khopkar U, Pande S. Etiopathogenesis of pruritus due to systemic causes: implications for treatment. Indian J Dermatol Venereol Leprol. 2007; 73(4):215–217
  • Referans 22. Bernstein JA., Lang DM, Khan DA, Craig T, Dreyfus D, Hsieh F, Sheikh J, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol. 2014; 133(5):1270–1277.
  • Referans 23. Weisshaar E, Szepietowski JC, Darsow U, Misery L, Wallengren J, Mettang T, et al. European guideline on chronic pruritus. Acta Derm Venereol. 2012; 92(5):563–581.
  • Referans 24. Asero R. Chronic unremitting urticaria: is the use of antihistamines above the licensed dose effective? A preliminary study of cetirizine at licensed and above-licensed doses. Clin Exp Dermatol. 2007; 32(1):34–38.
  • Referans 25. Schindler JF, Monahan JB, Smith WG. p38 Pathway kinases as anti-inflammatory drug targets. J. Dent. Res. 2007; 86:800– 811.
  • Referans 26. González-Terán B, Cortés JR, Manieri E, Matesanz N, Verdugo Á, Rodríguez ME et all. p38γ/δ MAPKs control TNFα translation in acute hepatitis Exp Clin Endocrinol Diabetes 2012; 120 - A8 DOI: 10.1055/s-0032-1330802 Referans 27. Risco A, del Fresno C, Mambol A, Alsina-Beauchamp D, MacKenzie KF, Yang HT, et all. p38γ and p38δ Kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation. Proc. Natl. Acad. Sci. 2012; 109:11200– 11205
  • Referans 28. Cho YW, Kim EJ, Nyiramana MM, Shin EJ, Jin H, Ryu JH, Kang D. Paroxetine induces apoptosis of human breast cancer MCF-7 cells through Ca2+-and p38 MAP kinase-dependent ROS generation. Cancers 2019; 11: (1) 1-22
  • Referans 29. Sheppard K, Kinross KM, Solomon B, Pearson RB, Phillips WA. Targeting PI3 kinase/AKT/mTOR signaling in cancer. Critical Reviews™ in Oncogenesis 2012;17(1):69-75
  • Referans 30. Aksamitiene E, Kiyatkin A, Kholodenko BN. Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: a fine balance. Biochemical Society Transactions 2012; 40(1):139-146.
There are 28 citations in total.

Details

Primary Language English
Subjects Health Care Administration
Journal Section Articles
Authors

Derya Yetkin 0000-0002-1452-5655

Publication Date September 29, 2022
Submission Date July 18, 2022
Published in Issue Year 2022 Volume: 12 Issue: 3

Cite

AMA Yetkin D. Investigation of the Anti-Inflammatory Activity of Hydroxyzine Hihydrochloride in Mammalian Macrophages on the PI3K and P38 Pathway. Sakarya Tıp Dergisi. September 2022;12(3):560-565. doi:10.31832/smj.1144968

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