Research Article
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Pitavastatinin Ratlarda Termal Plantar ve Dinamik Plantar Testler ile Ağrı Yanıtına Etkinliğinin Değerlendirilmesi

Year 2024, Issue: Early Access
https://doi.org/10.18678/dtfd.1551657

Abstract

Amaç: Pitavastatin (Pita), iyi bilinen bir hipolipidemik ajan olan statin ailesinin bir üyesidir ve bazı statin üyelerinin ağrı tedavisinde etkili olduğu gösterilmiştir. Bu çalışmada sıçanlarda farklı doz ve sürelerde nosisepsiyon ölçülerek Pita'nın antinosiseptif etkilerinin değerlendirilmesi amaçlanmıştır.
Gereç ve Yöntemler: Bu çalışma ilaçsız kontrol olarak salin oral, tek doz 1 mg/kg Pita, tek doz 3 mg/kg Pita, 14 gün boyunca 1 mg/kg Pita, 14 gün boyunca 3 mg/kg Pita ve 14 gün boyunca 20 mg/kg diklofenak olmak üzere altı gruptan oluşmaktadır. Ağrı eşiği değişikliklerini gözlemlemek için termal plantar ve mekanik plantar testler kullanıldı. Pita dozları, süreleri ve davranışsal ağrı tepkileri arasındaki korelasyonlar değerlendirildi. Siyatik sinirler histopatolojik olarak değerlendirildi.
Bulgular: Pita, 14 gün boyunca uygulanan 1 mg/kg dozunda mekanik eşiği 25,43±4,79 g'dan 32,28±2,27 g'a çıkararak (p=0,041) ve 14 gün boyunca uygulanan 3 mg/kg dozunda ise mekanik eşiği 27,41±2,36 g'dan 34,35±2,58 g'a çıkararak (p=0,039) dinamik plantar testte anlamlı bir antinosiseptif etki gösterdi. Ayrıca Pita, termal plantar testte 3 mg/kg tek dozda termal latansı 8,95±1,28 sn'den 11,71±1,49 sn'ye çıkardı (p=0,004). Dinamik plantar ve termal plantar testlerde Pita'nın antinosiseptif etkileri kanıtlanmış olmakla birlikte, bu bulgular histopatolojik değerlendirmede anlamlı bir düzeye ulaşmadı.
Sonuç: Bu sonuçlar Pita'nın antinosiseptif etkiye sahip olduğunu ve uygun doz ve zamanlama ile kullanıldığında ağrı tedavisinde tercih edilebileceğini düşündürmektedir.

References

  • Muley MM, Krustev E, McDougall JJ. Preclinical assessment of inflammatory pain. CNS Neurosci Ther. 2016;22(2):88-101.
  • Max MB, Stewart WF. The molecular epidemiology of pain: a new discipline for drug discovery. Nat Rev Drug Discov. 2008;7(8):647-58.
  • Jain KK. Gene therapy for pain. Expert Opin Biol Ther. 2008;8(12):1855-66.
  • Meert TF, Vermeirsch HA. A preclinical comparison between different opioids: antinociceptive versus adverse effects. Pharmacol Biochem Behav. 2005;80(2):309-26.
  • Lennernäs H, Fager G. Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Similarities and differences. Clin Pharmacokinet. 1997;32(5):403-25.
  • Wasim R, Ansari TM, Ahsan F, Siddiqui MH, Singh A, Shariq M, et al. Pleiotropic benefits of statins in cardiovascular diseases. Drug Res (Stuttg). 2022;72(9):477-86.
  • Sirtori CR. The pharmacology of statins. Pharmacol Res. 2014;88:3-11.
  • Mantell G. Lipid lowering drugs in atherosclerosis--the HMG-CoA reductase inhibitors. Clin Exp Hypertens A. 1989;11(5-6):927-41.
  • Chen XY, Li K, Light AR, Fu KY. Simvastatin attenuates formalin-induced nociceptive behaviors by inhibiting microglial RhoA and p38 MAPK activation. J Pain. 2013;14(11):1310-9.
  • Grundy SM. Statin trials and goals of cholesterol-lowering therapy. Circulation. 1998;21;97(15):1436-9.
  • Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme reductase inhibitors. Arterioscler Thromb Vasc Biol. 2001;21(11):1712-9.
  • Bhalla S, Singh N, Jaggi AS. Statins: do they aggravate or ameliorate neuropathic pain? J Pain. 2014;15(11):1069-80.
  • Hoy SM. Pitavastatin: A review in hypercholesterolemia. Am J Cardiovasc Drugs. 2017;17(2):157-68.
  • Duggan ST. Pitavastatin: a review of its use in the management of hypercholesterolaemia or mixed dyslipidaemia. Drugs. 2012;72(4):565-84.
  • Shi XQ, Lim TKY, Lee S, Zhao YQ, Zhang J. Statins alleviate experimental nerve injury-induced neuropathic pain. Pain. 2011;152(5):1033-43.
  • Bhalla S, Singh N, Jaggi AS. Dose-related neuropathic and anti-neuropathic effects of simvastatin in vincristine-induced neuropathic pain in rats. Food Chem Toxicol. 2015;80:32-40.
  • Cameron N, Cotter M, Inkster M, Nangle M. Looking to the future: diabetic neuropathy and effects of rosuvastatin on neurovascular function in diabetes models. Diabetes Res Clin Pract. 2003;61(Suppl 1):S35-9.
  • Pathak NN, Balaganur V, Lingaraju MC, More AS, Kant V, Kumar D, et al. Antihyperalgesic and anti-inflammatory effects of atorvastatin in chronic constriction injury-induced neuropathic pain in rats. Inflammation. 2013;36(6):1468-78.
  • Pan HC, Yang DY, Ou YC, Ho SP, Cheng FC, Chen CJ. Neuroprotective effect of atorvastatin in an experimental model of nerve crush injury. Neurosurgery. 2010;67(2):376-89.
  • Iqbal R, Akhtar MS, Hassan MQ, Jairajpuri Z, Akhtar M, Najmi AK. Pitavastatin ameliorates myocardial damage by preventing inflammation and collagen deposition via reduced free radical generation in isoproterenol-induced cardiomyopathy. Clin Exp Hypertens. 2019;41(5):434-43.
  • Hu G, Ito O, Rong R, Sakuyama A, Miura T, Ito D, et al. Pitavastatin upregulates nitric oxide synthases in the kidney of spontaneously hypertensive rats and Wistar-Kyoto rats. Am J Hypertens. 2018;31(10):1139-46.
  • Altintas Aykan D, Yaman S. Evaluation of the effects of tadalafil on pain response in thermal plantar and dynamic plantar tests in rats. Ann Med Res. 2020;27(3):749-54.
  • Mert T, Metin TO, Sahin E, Yaman S, Sahin M. Neuroprotective and anti-neuropathic actions of pulsed magnetic fields with low frequencies in rats with chronic peripheral neuropathic pain. Brain Res Bull. 2021;177:273-81.
  • Mert T, Metin TO, Sahin M, Yaman S. Antiinflammatory properties of antiLy6G antibody disappear during magnetic field exposure in rats with carrageenan induced acute paw inflammation. Naunyn Schmiedebergs Arch Pharmacol. 2020;393(11):2107-15.
  • Balaha M, Kandeel S, Kabel A. Phloretin either alone or in combination with duloxetine alleviates the STZ-induced diabetic neuropathy in rats. Biomed Pharmacother. 2018;101:821-32.
  • Bostan H, Cabalar M, Altinay S, Kalkan Y, Tumkaya L, Kanat A, et al. Sciatic nerve injury following analgesic drug injection in rats: A histopathological examination. North Clin Istanb. 2018;5(3):176-85.
  • Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005;19(1):117-25.
  • Jung KH, Chu K, Jeong SW, Han SY, Lee ST, Kim JY, et al. HMG-CoA reductase inhibitor, atorvastatin, promotes sensorimotor recovery, suppressing acute inflammatory reaction after experimental intracerebral hemorrhage. Stroke. 2004;35(7):1744-9.
  • Chu LW, Chen JY, Yu KL, Cheng KI, Wu PC, Wu BN. Neuroprotective and anti-inflammatory activities of atorvastatin in a rat chronic constriction injury model. Int J Immunopathol Pharmacol. 2012;25(1):219-30.
  • Viana F. Nociceptors: thermal allodynia and thermal pain. Handb Clin Neurol. 2018;156:103-19.
  • Weber MS, Prod'homme T, Steinman L, Zamvil SS. Drug insight: using statins to treat neuroinflammatory disease. Nat Clin Pract Neurol. 2005;1(2):106-12.
  • Skaper SD, Facci L, Zusso M, Giusti P. An inflammation-centric view of neurological disease: beyond the neuron. Front Cell Neurosci 2018;12:72.
  • Corso CR, Martins DF, Borges SC, Beltrame OC, Telles JEQ, Buttow NC, et al. Effect of simvastatin on sensorial, motor, and morphological parameters in sciatic nerve crush induced-neuropathic pain in rats. Inflammopharmacology. 2018;26(3):793-804.
  • Goel R, Kumar N, Kumar Saxena P, Pratap Singh A, Bana S. Pitavastatin attenuates neuropathic pain induced by partial sciatic nerve in Wistar rats. J Pharm Pharmacol. 2023;75(1):66-75.
  • Pathak NN, Balaganur V, Lingaraju MC, Kant V, Latief N, More AS, et al. Atorvastatin attenuates neuropathic pain in rat neuropathy model by down-regulating oxidative damage at peripheral, spinal and supraspinal levels. Neurochem Int. 2014;68:1-9.
  • Jung KH, Chu K, Jeong SW, Han SY, Lee ST, Kim JY, et al. HMG-CoA reductase inhibitor, atorvastatin, promotes sensorimotor recovery, suppressing acute inflammatory reaction after experimental intracerebral hemorrhage. Stroke. 2004;35(7):1744-9.
  • Chen XY, Li K, Light AR, Fu KY. Simvastatin attenuates formalin-induced nociceptive behaviors by inhibiting microglial RhoA and p38 MAPK activation. J Pain. 2013;14(11):1310-9.
  • Tatsumi S, Mabuchi T, Katano T, Matsumura S, Abe T, Hidaka H, et al. Involvement of Rho-kinase in inflammatory and neuropathic pain through phosphorylation of myristoylated alanine-rich C-kinase substrate (MARCKS). Neuroscience. 2005;131(2):491-8.
  • Gillon JT, Smith SE, Lowden MR. Atorvastatin as novel treatment for neuropathic pain: a case report. Clin J Pain. 2013;29(12):e46-8.
  • Nohria A, Prsic A, Liu PY, Okamoto R, Creager MA, Selwyn A, et al. Statins inhibit Rho kinase activity in patients with atherosclerosis. Atherosclerosis. 2009;205(2):517-21.

Evaluation of The Efficacy of Pitavastatin on Pain Response in Rats with Thermal Plantar and Dynamic Plantar Tests

Year 2024, Issue: Early Access
https://doi.org/10.18678/dtfd.1551657

Abstract

Aim: Pitavastatin (Pita) is a member of the statin family, a well-known hypolipidemic agent, and some statin members are effective in treating pain. This study aimed to evaluate the antinociceptive effects of Pita by measuring nociception in rats with different doses and durations.
Material and Methods: This study consisted of six groups including saline oral as a non-drug control, 1 mg/kg Pita single dose, 3 mg/kg Pita single dose, 1 mg/kg Pita for 14 days, 3 mg/kg Pita for 14 days, and 20 mg/kg diclofenac for 14 days. Thermal plantar and mechanical plantar tests were used to observe pain threshold changes. Correlations between Pita doses, durations, and behavioral pain responses were evaluated. The sciatic nerves were evaluated histopathologically.
Results: Pita showed a significant antinociceptive effect in the dynamic plantar test at doses of 1 mg/kg for 14 days by increasing the mechanical threshold from 25.43±4.79 g to 32.28±2.27 g (p=0.041) and 3 mg/kg for 14 days by increasing the mechanical threshold from 27.41±2.36 g to 34.35±2.58 g (p=0.039). Also, Pita increased the thermal latency from 8.95±1.28 s to 11.71±1.49 s in the thermal plantar test at a single dose of 3 mg/kg (p=0.004). Although the antinociceptive effects of Pita were proven in dynamic plantar and thermal plantar tests, these findings did not reach a significant level at histopathological evaluation.
Conclusion: These results suggest that Pita has an antinociceptive effect and when used in conjunction with the right dosage and timing, might be favored for the treatment of pain.

References

  • Muley MM, Krustev E, McDougall JJ. Preclinical assessment of inflammatory pain. CNS Neurosci Ther. 2016;22(2):88-101.
  • Max MB, Stewart WF. The molecular epidemiology of pain: a new discipline for drug discovery. Nat Rev Drug Discov. 2008;7(8):647-58.
  • Jain KK. Gene therapy for pain. Expert Opin Biol Ther. 2008;8(12):1855-66.
  • Meert TF, Vermeirsch HA. A preclinical comparison between different opioids: antinociceptive versus adverse effects. Pharmacol Biochem Behav. 2005;80(2):309-26.
  • Lennernäs H, Fager G. Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Similarities and differences. Clin Pharmacokinet. 1997;32(5):403-25.
  • Wasim R, Ansari TM, Ahsan F, Siddiqui MH, Singh A, Shariq M, et al. Pleiotropic benefits of statins in cardiovascular diseases. Drug Res (Stuttg). 2022;72(9):477-86.
  • Sirtori CR. The pharmacology of statins. Pharmacol Res. 2014;88:3-11.
  • Mantell G. Lipid lowering drugs in atherosclerosis--the HMG-CoA reductase inhibitors. Clin Exp Hypertens A. 1989;11(5-6):927-41.
  • Chen XY, Li K, Light AR, Fu KY. Simvastatin attenuates formalin-induced nociceptive behaviors by inhibiting microglial RhoA and p38 MAPK activation. J Pain. 2013;14(11):1310-9.
  • Grundy SM. Statin trials and goals of cholesterol-lowering therapy. Circulation. 1998;21;97(15):1436-9.
  • Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme reductase inhibitors. Arterioscler Thromb Vasc Biol. 2001;21(11):1712-9.
  • Bhalla S, Singh N, Jaggi AS. Statins: do they aggravate or ameliorate neuropathic pain? J Pain. 2014;15(11):1069-80.
  • Hoy SM. Pitavastatin: A review in hypercholesterolemia. Am J Cardiovasc Drugs. 2017;17(2):157-68.
  • Duggan ST. Pitavastatin: a review of its use in the management of hypercholesterolaemia or mixed dyslipidaemia. Drugs. 2012;72(4):565-84.
  • Shi XQ, Lim TKY, Lee S, Zhao YQ, Zhang J. Statins alleviate experimental nerve injury-induced neuropathic pain. Pain. 2011;152(5):1033-43.
  • Bhalla S, Singh N, Jaggi AS. Dose-related neuropathic and anti-neuropathic effects of simvastatin in vincristine-induced neuropathic pain in rats. Food Chem Toxicol. 2015;80:32-40.
  • Cameron N, Cotter M, Inkster M, Nangle M. Looking to the future: diabetic neuropathy and effects of rosuvastatin on neurovascular function in diabetes models. Diabetes Res Clin Pract. 2003;61(Suppl 1):S35-9.
  • Pathak NN, Balaganur V, Lingaraju MC, More AS, Kant V, Kumar D, et al. Antihyperalgesic and anti-inflammatory effects of atorvastatin in chronic constriction injury-induced neuropathic pain in rats. Inflammation. 2013;36(6):1468-78.
  • Pan HC, Yang DY, Ou YC, Ho SP, Cheng FC, Chen CJ. Neuroprotective effect of atorvastatin in an experimental model of nerve crush injury. Neurosurgery. 2010;67(2):376-89.
  • Iqbal R, Akhtar MS, Hassan MQ, Jairajpuri Z, Akhtar M, Najmi AK. Pitavastatin ameliorates myocardial damage by preventing inflammation and collagen deposition via reduced free radical generation in isoproterenol-induced cardiomyopathy. Clin Exp Hypertens. 2019;41(5):434-43.
  • Hu G, Ito O, Rong R, Sakuyama A, Miura T, Ito D, et al. Pitavastatin upregulates nitric oxide synthases in the kidney of spontaneously hypertensive rats and Wistar-Kyoto rats. Am J Hypertens. 2018;31(10):1139-46.
  • Altintas Aykan D, Yaman S. Evaluation of the effects of tadalafil on pain response in thermal plantar and dynamic plantar tests in rats. Ann Med Res. 2020;27(3):749-54.
  • Mert T, Metin TO, Sahin E, Yaman S, Sahin M. Neuroprotective and anti-neuropathic actions of pulsed magnetic fields with low frequencies in rats with chronic peripheral neuropathic pain. Brain Res Bull. 2021;177:273-81.
  • Mert T, Metin TO, Sahin M, Yaman S. Antiinflammatory properties of antiLy6G antibody disappear during magnetic field exposure in rats with carrageenan induced acute paw inflammation. Naunyn Schmiedebergs Arch Pharmacol. 2020;393(11):2107-15.
  • Balaha M, Kandeel S, Kabel A. Phloretin either alone or in combination with duloxetine alleviates the STZ-induced diabetic neuropathy in rats. Biomed Pharmacother. 2018;101:821-32.
  • Bostan H, Cabalar M, Altinay S, Kalkan Y, Tumkaya L, Kanat A, et al. Sciatic nerve injury following analgesic drug injection in rats: A histopathological examination. North Clin Istanb. 2018;5(3):176-85.
  • Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005;19(1):117-25.
  • Jung KH, Chu K, Jeong SW, Han SY, Lee ST, Kim JY, et al. HMG-CoA reductase inhibitor, atorvastatin, promotes sensorimotor recovery, suppressing acute inflammatory reaction after experimental intracerebral hemorrhage. Stroke. 2004;35(7):1744-9.
  • Chu LW, Chen JY, Yu KL, Cheng KI, Wu PC, Wu BN. Neuroprotective and anti-inflammatory activities of atorvastatin in a rat chronic constriction injury model. Int J Immunopathol Pharmacol. 2012;25(1):219-30.
  • Viana F. Nociceptors: thermal allodynia and thermal pain. Handb Clin Neurol. 2018;156:103-19.
  • Weber MS, Prod'homme T, Steinman L, Zamvil SS. Drug insight: using statins to treat neuroinflammatory disease. Nat Clin Pract Neurol. 2005;1(2):106-12.
  • Skaper SD, Facci L, Zusso M, Giusti P. An inflammation-centric view of neurological disease: beyond the neuron. Front Cell Neurosci 2018;12:72.
  • Corso CR, Martins DF, Borges SC, Beltrame OC, Telles JEQ, Buttow NC, et al. Effect of simvastatin on sensorial, motor, and morphological parameters in sciatic nerve crush induced-neuropathic pain in rats. Inflammopharmacology. 2018;26(3):793-804.
  • Goel R, Kumar N, Kumar Saxena P, Pratap Singh A, Bana S. Pitavastatin attenuates neuropathic pain induced by partial sciatic nerve in Wistar rats. J Pharm Pharmacol. 2023;75(1):66-75.
  • Pathak NN, Balaganur V, Lingaraju MC, Kant V, Latief N, More AS, et al. Atorvastatin attenuates neuropathic pain in rat neuropathy model by down-regulating oxidative damage at peripheral, spinal and supraspinal levels. Neurochem Int. 2014;68:1-9.
  • Jung KH, Chu K, Jeong SW, Han SY, Lee ST, Kim JY, et al. HMG-CoA reductase inhibitor, atorvastatin, promotes sensorimotor recovery, suppressing acute inflammatory reaction after experimental intracerebral hemorrhage. Stroke. 2004;35(7):1744-9.
  • Chen XY, Li K, Light AR, Fu KY. Simvastatin attenuates formalin-induced nociceptive behaviors by inhibiting microglial RhoA and p38 MAPK activation. J Pain. 2013;14(11):1310-9.
  • Tatsumi S, Mabuchi T, Katano T, Matsumura S, Abe T, Hidaka H, et al. Involvement of Rho-kinase in inflammatory and neuropathic pain through phosphorylation of myristoylated alanine-rich C-kinase substrate (MARCKS). Neuroscience. 2005;131(2):491-8.
  • Gillon JT, Smith SE, Lowden MR. Atorvastatin as novel treatment for neuropathic pain: a case report. Clin J Pain. 2013;29(12):e46-8.
  • Nohria A, Prsic A, Liu PY, Okamoto R, Creager MA, Selwyn A, et al. Statins inhibit Rho kinase activity in patients with atherosclerosis. Atherosclerosis. 2009;205(2):517-21.
There are 40 citations in total.

Details

Primary Language English
Subjects Pain, Peripheral Nervous System
Journal Section Research Article
Authors

Selma Yaman 0000-0002-9301-9119

Duygun Altıntaş Aykan 0000-0001-8224-4006

Tuba Ozcan Metin 0000-0003-0624-026X

Early Pub Date November 30, 2024
Publication Date
Submission Date September 17, 2024
Acceptance Date November 9, 2024
Published in Issue Year 2024 Issue: Early Access

Cite

APA Yaman, S., Altıntaş Aykan, D., & Ozcan Metin, T. (2024). Evaluation of The Efficacy of Pitavastatin on Pain Response in Rats with Thermal Plantar and Dynamic Plantar Tests. Duzce Medical Journal(Early Access). https://doi.org/10.18678/dtfd.1551657
AMA Yaman S, Altıntaş Aykan D, Ozcan Metin T. Evaluation of The Efficacy of Pitavastatin on Pain Response in Rats with Thermal Plantar and Dynamic Plantar Tests. Duzce Med J. November 2024;(Early Access). doi:10.18678/dtfd.1551657
Chicago Yaman, Selma, Duygun Altıntaş Aykan, and Tuba Ozcan Metin. “Evaluation of The Efficacy of Pitavastatin on Pain Response in Rats With Thermal Plantar and Dynamic Plantar Tests”. Duzce Medical Journal, no. Early Access (November 2024). https://doi.org/10.18678/dtfd.1551657.
EndNote Yaman S, Altıntaş Aykan D, Ozcan Metin T (November 1, 2024) Evaluation of The Efficacy of Pitavastatin on Pain Response in Rats with Thermal Plantar and Dynamic Plantar Tests. Duzce Medical Journal Early Access
IEEE S. Yaman, D. Altıntaş Aykan, and T. Ozcan Metin, “Evaluation of The Efficacy of Pitavastatin on Pain Response in Rats with Thermal Plantar and Dynamic Plantar Tests”, Duzce Med J, no. Early Access, November 2024, doi: 10.18678/dtfd.1551657.
ISNAD Yaman, Selma et al. “Evaluation of The Efficacy of Pitavastatin on Pain Response in Rats With Thermal Plantar and Dynamic Plantar Tests”. Duzce Medical Journal Early Access (November 2024). https://doi.org/10.18678/dtfd.1551657.
JAMA Yaman S, Altıntaş Aykan D, Ozcan Metin T. Evaluation of The Efficacy of Pitavastatin on Pain Response in Rats with Thermal Plantar and Dynamic Plantar Tests. Duzce Med J. 2024. doi:10.18678/dtfd.1551657.
MLA Yaman, Selma et al. “Evaluation of The Efficacy of Pitavastatin on Pain Response in Rats With Thermal Plantar and Dynamic Plantar Tests”. Duzce Medical Journal, no. Early Access, 2024, doi:10.18678/dtfd.1551657.
Vancouver Yaman S, Altıntaş Aykan D, Ozcan Metin T. Evaluation of The Efficacy of Pitavastatin on Pain Response in Rats with Thermal Plantar and Dynamic Plantar Tests. Duzce Med J. 2024(Early Access).