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Metforminin Tek Başına veya Valproik asit ile Beraber Farelerde Pentilentetrazol ile İndüklenen Nöbetler Üzerine Koruyucu Etkisi

Yıl 2022, Cilt: 17 Sayı: 3, 15 - 21, 02.11.2022
https://doi.org/10.17517/ksutfd.914271

Öz

Özet
Amaç: Bu çalışmanın amacı, metforminin pentilentetrazol (PTZ) ile indüklenen nöbet davranışı üzerindeki etkilerini ve nöronal hasar üzerindeki nöroprotektif etkisini araştırmaktır.
Gereç ve Yöntemler: 35-38 gram ağırlığındaki otuz beş (35) erkek BALB-c Albino fare rastgele beş gruba ayrıldı: Kontrol grubu (1), Salin+PTZ grubu (2), Valproik Asit (VPA 200 mg/kg i.p.)+PTZ grubu (3), Metformin (200 mg/kg i.p.)+PTZ grubu (4) ve VPA+Metformin+PTZ grubu (5). PTZ (60 mg/kg, intraperitoneal-
i.p.), nöbetleri indüklemek için ilaç enjeksiyonundan 30 dakika sonra enjekte edildi ve nöbet aşamaları ve davranışsal skorlama değerlendirildi. İşlem tamamlandıktan sonra beyin dokuları çıkarıldı ve biyokimyasal ve histopatolojik prosedürlerle analiz edildi. Hipokampal Cornu Ammonis (CA)1, CA2, CA3
ve DG (dentat girus) bölgeleri histopatolojik olarak değerlendirildi ve oksidatif stres belirteçleri (toplam antioksidan durum (TAS), toplam oksidan durum (TOS)) ölçüldü.
Bulgular: Salin+PTZ grubuyla karşılaştırıldığında, Metformin tek başına ilk miyoklonik jerk (FMJ) başlangıç süresini etkilemedi, ancak VPA ve metformin kombinasyonun FMJ başlangıç süresini anlamlı derecede artırdığı izlendi (p<0.05). Ek olarak, VPA ile beraber ve/veya VPA olmadan metformin tedavisi beyin
oksidatif stresini önemli ölçüde azalttı (p<0.05). Ayrıca, histopatolojik değerlendirme ile metformin uygulamasının ve VPA+metformin kombinasyonunun hipokampal CA1, CA2, CA3 ve DG alanlarındaki dark nöron oluşumunu azalttığı saptandı (p<0.05).
Sonuç: Metforminin, epileptik nöbetleri ve beyin oksidatif stresini azalttığı ve PTZ ile indüklenen nöbet sonrası nöral hasarı önlediği tespit edilmiştir.

Kaynakça

  • Maiha BB, Magaji MG, Yaro AH, Hamza AH, Ahmed SJ, Magaj AR. Anticonvulsant studies on Cochlospermum tinctorium and Paullinia pinnata extracts in laboratory animals. Nig J Pharm Sci 2009;8:102-108.
  • Carpio A, Hauser WA. Epilepsy in the developing world. Curr Neurol Neurosci Rep 2009;9:319-326.
  • Curia G, Lucchi C, Vinet J, Gualtieri F, Marinelli C, Torsello A et al. Pathophysiogenesis of mesial temporal lobe epilepsy: is prevention of damage antiepileptogenic? Curr.Med.Chem 2014;21:663-688.
  • Akkaya R, Gümüş E, Akkaya B, Karabulut S, Gülmez K, Karademir M et al. Wi-Fi decreases melatonin protective effect and increases hippocampal neuronal damage in pentylenetetrazole induced model seizures in rats. Pathophysiology 2019;26:375-379.
  • Tastemur Y, Gumus E, Ergul M, Ulu M, Akkaya R, Ozturk A et al. Positive effects of angiotensin-converting enzyme (ACE) inhibitor, captopril, on pentylenetetrazole-induced epileptic seizures in mice. Trop J Pharm Res 2020;19:637-643.
  • Thom M, Zhou J, Martinian L, Sisodiya S. Quantitative post‐mortem study of the hippocampus in chronic epilepsy: Seizures do not inevitably cause neuronal loss. Brain 2005;128:1344–1357.
  • Sato H, Takahashi T, Sumitani K, Takatsu H, Urano S. Glucocorticoid generates ROS to induce oxidative injury in the hippocampus, leading to impairment of cognitive function of rats. J Clin Biochem Nutr 2010;47:224-232.
  • Lim DW, Park J, Jung J, Kim SH, Um MY, Yoon M et al. Dicaffeoylquinic acids alleviate memory loss via reduction of oxidative stress in stress-hormone-induced depressive mice. Pharmacol Res 2020;161:105252.
  • Davidson MB, Peters AL. An overview of metformin in the treatment of type 2 diabetes mellitus. Am J Med 1997;102:99-110.
  • Cheng YY, Leu HB, Chen TJ, Chen CL, Kuo CH, Lee SD et al. Metformin-inclusive therapy reduces the risk of stroke in patients with diabetes: A 4-year follow-up study. J Stroke Cerebrovasc Dis 2014;23:99-105.
  • Thangthaeng N, Rutledge M, Wong JM, Vann PH, Forster MJ, Sumien N. Metformin impairs spatial memory and visual acuity in old male mice. Aging Dis 2017;8:17-30.
  • Labuzek K, Liber S, Gabryel B, Okopień B. Metformin has adenosine-monophosphate activated protein kinase (AMPK)-independent effects on LPS-stimulated rat primary microglial cultures. Pharmacol Rep 2010;62:827-848.
  • Tasci I. Metformin: good or bad for the brain? Ann Transl Med 2014;6:53.
  • Moore EM, Mander AG, Ames D, Kotowicz MA, Carne RP, Brodaty H et al. Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care 2013;36:2981-2987.
  • Imfeld P, Bodmer M, Jick SS, Meier CR. Metformin, other antidiabetic drugs, and risk of Alzheimer's disease: a population-based case-control study. J Am Geriatr Soc 2012;60:916-921.
  • Li J, Deng J, Sheng W, Zuo Z. Metformin attenuates Alzheimer's disease-like neuropathology in obese, leptin-resistant mice. Pharmacol Biochem Behav 2012;101:564-574.
  • Wang J, Gallagher D, DeVito LM, Cancino GI, Tsui D, He L et al. Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell 2012;11:23-35.
  • Labuzek K, Liber S, Gabryel B, Okopień B. Metformin has adenosine-monophosphate activated protein kinase (AMPK)-independent effects on LPS-stimulated rat primary microglial cultures. Pharmacol Rep 2010;62:827-848.
  • El-Mir MY, Detaille D, R-Villanueva G, Delgado-Esteban M, Guigas B, Attia S et al. Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons. J Mol Neurosci 2008;34:77-87.
  • Racine RJ. Modification of seizure activity by electrical stimulation. I. After-discharge threshold. Electroencephalogr Clin Neurophysiol 1972;32:269-279.
  • Uyanikgil Y, Özkeşkek K, Çavuşoğlu T, Solmaz V, Tümer MK, Erbas O. Positive effects of ceftriaxone on pentylenetetrazol-induced convulsion model in rats. Int J Neurosci 2016;126:70-75.
  • Erel O. A novel automated method to measure total antioxidant response against potent free radical reactions. Clin Biochem 2004;37:112-119.
  • Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem 2005;38:1103-1111.
  • Haggag BS, Hasanin AH, Raafat MH, Abdel Kawy HS. Lamotrigine decreased hippocampal damage and improved vascular risk markers in a rat model of pentylenetetrazole induced kindling seizure. Korean J Physiol Pharmacol 2014;18:269-278.
  • Shi Y, Miao W, Teng J, Zhang L. Ginsenoside Rb1 protects the brain from damage induced by epileptic seizure via Nrf2/ARE signaling. Cell Physiol Biochem 2018;45:212-225.
  • Danjo S, Ishihara Y, Watanabe M, Nakamura Y, Itoh K. Pentylentetrazole-induced loss of blood-brain barrier integrity involves excess nitric oxide generation by neuronal nitric oxide synthase. Brain Res 2013;1530:44-53.
  • Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M et al. Metformin improves healthspan and lifespan in mice. Nat Commun 2013;4:2192.
  • Labuzek K, Suchy D, Gabryel B, Bielecka A, Liber S, Okopień B. Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacol Rep 2010;62:956-965.
  • Takata F, Dohgu S, Matsumoto J, Machida T, Kaneshima S, Matsuo M et. al. Metformin induces up-regulation of blood-brain barrier functions by activating AMP-activated protein kinase in rat brain microvascular endothelial cells. Biochem Biophys Res Commun 2013;433:586-590.
  • Zhao RR, Xu XC, Xu F, Zhang WL, Zhang WL, Liu LM et al. Metformin protects against seizures, learning and memory impairments and oxidative damage induced by pentylenetetrazole-induced kindling in mice. Biochem Biophys Res Commun 2014;448:414-417.
  • Zeyghami MA, Hesam E, Khadivar P, Hesam HK, Ahmadnia A, Amini A. Effects of atorvastatin and metformin on development of pentylenetetrazole-induced seizure in mice. Heliyon 2020;6:3761.
  • Ilhan A, Iraz M, Gurel A, Armutcu F, Akyol O. Caffeic acid phenethyl ester exerts a neuroprotective effect on CNS against pentylenetetrazol-induced seizures in mice. Neurochem Res 2004;29:2287-2292.
  • Golechha M, Sarangal V, Bhatia J, Chaudhry U, Saluja D, Arya DS. Naringin ameliorates pentylenetetrazol-induced seizures and associated oxidative stress, inflammation, and cognitive impairment in rats: possible mechanisms of neuroprotection. Epilepsy Behav 2014;41:98-102.
  • Dehkordi AH, Abbaszadeh A, Mir S, Hasanvand A. Metformin and its anti-inflammatory and anti-oxidative effects; new concepts. Journal of Renal Injury Prevention 2019;8:54–61.
  • Tang G, Yang H, Chen J, Shi M, Ge L, Ge X et al. Metformin ameliorates sepsis-induced brain injury by inhibiting apoptosis, oxidative stress and neuroinflammation via the PI3K/Akt signaling pathway. Oncotarget 2017;8:97977-97989.
  • Aguiar CC, Almeida AB, Araújo PV, de Abreu RN, Chaves EM, do Vale OC et al. Oxidative stress, and epilepsy: literature review. Oxid Med Cell Longev 2012;2012:795259.
  • Uttara B, Singh AV, Zamboni P, Mahajan RT. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 2009;7:65-74.
  • Gumus E, Taskiran AS, Toptas HA, Güney Ö, Kutlu R, Gunes H et al. Effect of the cyclooxygenase-2 inhibitor tenoxicam on pentylenetetrazole-induced epileptic seizures in rats. Cumhuriyet Med 2017;39:652-658.
  • Kherani ZS, Auer RN. Pharmacologic analysis of the mechanism of dark neuron production in cerebral cortex. Acta Neuropathol. 2008;116:447-452

Protective Effect of Metformin Alone or in Combination with Valproic acid on Pentylenetetrazole-Induced Seizures in Mice

Yıl 2022, Cilt: 17 Sayı: 3, 15 - 21, 02.11.2022
https://doi.org/10.17517/ksutfd.914271

Öz

Abstract
Objective: The aim of this study was to investigate the effects of metformin on pentylenetetrazole (PTZ)-induced seizures and the neuroprotective effect of metformin on neuronal damage after pentylenetetrazole administration.
Material and Methods: Thirty-five (35) Male BALB-c Albino mice weighing 35-38 g were divided randomly into five groups: Control group (1), Saline+PTZ group (2), Valproic Acid (VPA, 200 mg/kg intraperitoneal-i.p.)+PTZ group (3), Metformin (200 mg/kg i.p.)+PTZ group (4), and VPA+Metformin+PTZ
group (5). The PTZ (60 mg/kg, i.p.) was injected 30 min after drugs injection to induce seizures and seizure stages and behavioral scoring were evaluated. After completing procedure, brain tissues were removed and analyzed with biochemical and histopathological procedures. The hippocampal Cornu Ammonis (CA) 1, CA2, CA3 and DG (dentate gyrus) regions were histopathologically evaluated and oxidative stress markers (total antioxidant status (TAS), total oxidant status (TOS)) were measured.
Results: Compare to Saline+PTZ group, metformin administration alone did not affect the onset time of the first myoclonic jerk (FMJ), but combination of VPA and metformin significantly increased FMJ onset time (p<0.05). Additionally, the treatment of metformin with or without VPA reduced the brain oxidative
stress (p<0.05). Furthermore, histopathological assessment demonstrated that metformin administration and the combination of VPA and metformin decreased dark neuron formation in the hippocampal CA1, CA2, CA3, and DG areas (p<0.05).
Conclusion: Metformin was found to be significantly effective in reducing epileptic seizures, brain oxidative stress, and preventing neural damage after PTZ-induced seizure

Kaynakça

  • Maiha BB, Magaji MG, Yaro AH, Hamza AH, Ahmed SJ, Magaj AR. Anticonvulsant studies on Cochlospermum tinctorium and Paullinia pinnata extracts in laboratory animals. Nig J Pharm Sci 2009;8:102-108.
  • Carpio A, Hauser WA. Epilepsy in the developing world. Curr Neurol Neurosci Rep 2009;9:319-326.
  • Curia G, Lucchi C, Vinet J, Gualtieri F, Marinelli C, Torsello A et al. Pathophysiogenesis of mesial temporal lobe epilepsy: is prevention of damage antiepileptogenic? Curr.Med.Chem 2014;21:663-688.
  • Akkaya R, Gümüş E, Akkaya B, Karabulut S, Gülmez K, Karademir M et al. Wi-Fi decreases melatonin protective effect and increases hippocampal neuronal damage in pentylenetetrazole induced model seizures in rats. Pathophysiology 2019;26:375-379.
  • Tastemur Y, Gumus E, Ergul M, Ulu M, Akkaya R, Ozturk A et al. Positive effects of angiotensin-converting enzyme (ACE) inhibitor, captopril, on pentylenetetrazole-induced epileptic seizures in mice. Trop J Pharm Res 2020;19:637-643.
  • Thom M, Zhou J, Martinian L, Sisodiya S. Quantitative post‐mortem study of the hippocampus in chronic epilepsy: Seizures do not inevitably cause neuronal loss. Brain 2005;128:1344–1357.
  • Sato H, Takahashi T, Sumitani K, Takatsu H, Urano S. Glucocorticoid generates ROS to induce oxidative injury in the hippocampus, leading to impairment of cognitive function of rats. J Clin Biochem Nutr 2010;47:224-232.
  • Lim DW, Park J, Jung J, Kim SH, Um MY, Yoon M et al. Dicaffeoylquinic acids alleviate memory loss via reduction of oxidative stress in stress-hormone-induced depressive mice. Pharmacol Res 2020;161:105252.
  • Davidson MB, Peters AL. An overview of metformin in the treatment of type 2 diabetes mellitus. Am J Med 1997;102:99-110.
  • Cheng YY, Leu HB, Chen TJ, Chen CL, Kuo CH, Lee SD et al. Metformin-inclusive therapy reduces the risk of stroke in patients with diabetes: A 4-year follow-up study. J Stroke Cerebrovasc Dis 2014;23:99-105.
  • Thangthaeng N, Rutledge M, Wong JM, Vann PH, Forster MJ, Sumien N. Metformin impairs spatial memory and visual acuity in old male mice. Aging Dis 2017;8:17-30.
  • Labuzek K, Liber S, Gabryel B, Okopień B. Metformin has adenosine-monophosphate activated protein kinase (AMPK)-independent effects on LPS-stimulated rat primary microglial cultures. Pharmacol Rep 2010;62:827-848.
  • Tasci I. Metformin: good or bad for the brain? Ann Transl Med 2014;6:53.
  • Moore EM, Mander AG, Ames D, Kotowicz MA, Carne RP, Brodaty H et al. Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care 2013;36:2981-2987.
  • Imfeld P, Bodmer M, Jick SS, Meier CR. Metformin, other antidiabetic drugs, and risk of Alzheimer's disease: a population-based case-control study. J Am Geriatr Soc 2012;60:916-921.
  • Li J, Deng J, Sheng W, Zuo Z. Metformin attenuates Alzheimer's disease-like neuropathology in obese, leptin-resistant mice. Pharmacol Biochem Behav 2012;101:564-574.
  • Wang J, Gallagher D, DeVito LM, Cancino GI, Tsui D, He L et al. Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell 2012;11:23-35.
  • Labuzek K, Liber S, Gabryel B, Okopień B. Metformin has adenosine-monophosphate activated protein kinase (AMPK)-independent effects on LPS-stimulated rat primary microglial cultures. Pharmacol Rep 2010;62:827-848.
  • El-Mir MY, Detaille D, R-Villanueva G, Delgado-Esteban M, Guigas B, Attia S et al. Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons. J Mol Neurosci 2008;34:77-87.
  • Racine RJ. Modification of seizure activity by electrical stimulation. I. After-discharge threshold. Electroencephalogr Clin Neurophysiol 1972;32:269-279.
  • Uyanikgil Y, Özkeşkek K, Çavuşoğlu T, Solmaz V, Tümer MK, Erbas O. Positive effects of ceftriaxone on pentylenetetrazol-induced convulsion model in rats. Int J Neurosci 2016;126:70-75.
  • Erel O. A novel automated method to measure total antioxidant response against potent free radical reactions. Clin Biochem 2004;37:112-119.
  • Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem 2005;38:1103-1111.
  • Haggag BS, Hasanin AH, Raafat MH, Abdel Kawy HS. Lamotrigine decreased hippocampal damage and improved vascular risk markers in a rat model of pentylenetetrazole induced kindling seizure. Korean J Physiol Pharmacol 2014;18:269-278.
  • Shi Y, Miao W, Teng J, Zhang L. Ginsenoside Rb1 protects the brain from damage induced by epileptic seizure via Nrf2/ARE signaling. Cell Physiol Biochem 2018;45:212-225.
  • Danjo S, Ishihara Y, Watanabe M, Nakamura Y, Itoh K. Pentylentetrazole-induced loss of blood-brain barrier integrity involves excess nitric oxide generation by neuronal nitric oxide synthase. Brain Res 2013;1530:44-53.
  • Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M et al. Metformin improves healthspan and lifespan in mice. Nat Commun 2013;4:2192.
  • Labuzek K, Suchy D, Gabryel B, Bielecka A, Liber S, Okopień B. Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacol Rep 2010;62:956-965.
  • Takata F, Dohgu S, Matsumoto J, Machida T, Kaneshima S, Matsuo M et. al. Metformin induces up-regulation of blood-brain barrier functions by activating AMP-activated protein kinase in rat brain microvascular endothelial cells. Biochem Biophys Res Commun 2013;433:586-590.
  • Zhao RR, Xu XC, Xu F, Zhang WL, Zhang WL, Liu LM et al. Metformin protects against seizures, learning and memory impairments and oxidative damage induced by pentylenetetrazole-induced kindling in mice. Biochem Biophys Res Commun 2014;448:414-417.
  • Zeyghami MA, Hesam E, Khadivar P, Hesam HK, Ahmadnia A, Amini A. Effects of atorvastatin and metformin on development of pentylenetetrazole-induced seizure in mice. Heliyon 2020;6:3761.
  • Ilhan A, Iraz M, Gurel A, Armutcu F, Akyol O. Caffeic acid phenethyl ester exerts a neuroprotective effect on CNS against pentylenetetrazol-induced seizures in mice. Neurochem Res 2004;29:2287-2292.
  • Golechha M, Sarangal V, Bhatia J, Chaudhry U, Saluja D, Arya DS. Naringin ameliorates pentylenetetrazol-induced seizures and associated oxidative stress, inflammation, and cognitive impairment in rats: possible mechanisms of neuroprotection. Epilepsy Behav 2014;41:98-102.
  • Dehkordi AH, Abbaszadeh A, Mir S, Hasanvand A. Metformin and its anti-inflammatory and anti-oxidative effects; new concepts. Journal of Renal Injury Prevention 2019;8:54–61.
  • Tang G, Yang H, Chen J, Shi M, Ge L, Ge X et al. Metformin ameliorates sepsis-induced brain injury by inhibiting apoptosis, oxidative stress and neuroinflammation via the PI3K/Akt signaling pathway. Oncotarget 2017;8:97977-97989.
  • Aguiar CC, Almeida AB, Araújo PV, de Abreu RN, Chaves EM, do Vale OC et al. Oxidative stress, and epilepsy: literature review. Oxid Med Cell Longev 2012;2012:795259.
  • Uttara B, Singh AV, Zamboni P, Mahajan RT. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 2009;7:65-74.
  • Gumus E, Taskiran AS, Toptas HA, Güney Ö, Kutlu R, Gunes H et al. Effect of the cyclooxygenase-2 inhibitor tenoxicam on pentylenetetrazole-induced epileptic seizures in rats. Cumhuriyet Med 2017;39:652-658.
  • Kherani ZS, Auer RN. Pharmacologic analysis of the mechanism of dark neuron production in cerebral cortex. Acta Neuropathol. 2008;116:447-452
Toplam 39 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Sağlık Kurumları Yönetimi
Bölüm Araştırma Makaleleri
Yazarlar

Erkan Gümüş 0000-0001-6432-7457

Mustafa Ergül 0000-0003-4303-2996

Kader Gülmez 0000-0001-6648-2397

Mustafa Ulu 0000-0003-4503-3036

Recep Akkaya 0000-0002-3477-7198

Ercan Özdemir 0000-0001-8231-1053

Ahmet Şevki Taşkıran 0000-0002-5810-8415

Erken Görünüm Tarihi 1 Kasım 2022
Yayımlanma Tarihi 2 Kasım 2022
Gönderilme Tarihi 13 Nisan 2021
Kabul Tarihi 20 Mayıs 2021
Yayımlandığı Sayı Yıl 2022 Cilt: 17 Sayı: 3

Kaynak Göster

AMA Gümüş E, Ergül M, Gülmez K, Ulu M, Akkaya R, Özdemir E, Taşkıran AŞ. Protective Effect of Metformin Alone or in Combination with Valproic acid on Pentylenetetrazole-Induced Seizures in Mice. KSÜ Tıp Fak Der. Kasım 2022;17(3):15-21. doi:10.17517/ksutfd.914271