Effect of various doses of metformin on map-kinase and apoptosis in penicillin-induced secondary rat cortical astrocytes-can metformin be antiepileptic?

Öz

Purpose: Astrocytes in the brain and spinal cord perform many functions and it express plasma membrane carriers for various neurotransmitters. Often sclerotic areas in the hippocampus are known as the cause of epilepsy. In reality, astrocytes initiate glutamate release in sclerotic tissue. In experimental epilepsy, penicillin is widely used to initiate this neuronal stress and establish the epilepsy model. The aim of this study is to demonstrate the protective effect of metformin, which has been proven to be effective in neurodegenerative diseases, on penicillin-induced astrocyte degeneration on the primary astrocyte cell line. This study is thought of as the first study about the effect of metformin on penicillin-induced astrocyte death.
Materials and methods: For this purpose, secondary astrocyte cell culture which was previously obtained from the newborn rat brain was used.
Results: The viability of penicillin-induced astrocyte cells was statistically significantly decreased (p=0.01), While cell viability increased statistically significantly in the metformin group at all metformin doses (p=0.01).
Conclusions: We conclude that metformin has protective effects on damage caused by the penicillin secondary astrocyte cell line. These results suggest that penicillin reduces astrocyte cell viability, but metformin protects astrocytes against the lethal effect of penicillin.

Anahtar Kelimeler

• Astrocyte
• penicillin
• insulin
• rat
• cell culture

Destekleyen Kurum

Pamukkale Üniversitesi

Proje Numarası

2019TIPF018

Etik Beyan

PAUHADYEK-2019/35 09.10.2019 tarih ve 2019/07 toplantı

Teşekkür

Pamukkale Üniversitesi Bilimsel Araştırmalar Proje başkanlığına teşekkür

Penisilinle indüklenen sekonder sıçan kortikal astrositlerinde çeşitli metformin dozlarının map-kinaz ve apoptoz üzerine etkisi- metformin antiepileptik olabilir mi?

Öz

Amaç: Beyin ve omurilikteki astrositler birçok işlevi yerine getirir ve çeşitli nörotransmiterler için plazma membran taşıyıcıları ifade eder. Hipokampustaki sklerotik alanlar sıklıkla epilepsinin nedeni olarak bilinir. Gerçekte, astrositler sklerotik dokuda glutamat salınımını başlatır. Deneysel epilepside, bu nöronal stresi başlatmak ve epilepsi modelini oluşturmak için penisilin yaygın olarak kullanılır. Bu çalışmanın amacı, nörodejeneratif hastalıklarda etkili olduğu kanıtlanmış olan metforminin, birincil astrosit hücre hattında penisilin kaynaklı astrosit dejenerasyonuna karşı koruyucu etkisini göstermektir. Bu çalışma, metforminin penisilin kaynaklı astrosit ölümüne etkisi hakkında yapılan ilk çalışma olarak kabul edilmektedir.
Gereç ve yöntem: Bu amaçla, daha önce yeni doğmuş sıçan beyninden elde edilen ikincil astrosit hücre kültürü kullanılmıştır.

Bulgular: Penisilin kaynaklı astrosit hücrelerinin canlılığı istatistiksel olarak anlamlı derecede azalmıştır (p=0,01). Metformin grubunda ise tüm metformin dozlarında hücre canlılığı istatistiksel olarak anlamlı derecede artmıştır (p=0,01).
Sonuç: Metforminin, penisilin kaynaklı ikincil astrosit hücre hattı hasarına karşı koruyucu etkileri olduğu sonucuna vardık. Bu sonuçlar, penisilinin astrosit hücre canlılığını azalttığını, ancak metforminin astrositleri penisilinin öldürücü etkisine karşı koruduğunu göstermektedir.

Anahtar Kelimeler

• Astrosit
• penisilin
• insülin
• sıçan
• hücre kültürü

Proje Numarası

2019TIPF018

Kaynakça

1. Taverna E, Götz M, Huttner WB. The cell biology of neurogenesis: toward an understanding of the development and evolution of the neocortex. Ann Rev Cell Dev Biol. 2018;30:465-502. doi:10.1146/annurev-cellbio-101011-155801
2. Vasile F, Dossi E, Rouach N. Human astrocytes: structure and functions in the healthy brain. Brain Struct Funct. 2017;222(5):2017-2029. doi:10.1007/s00429-017-1383-5
3. De Zeeuw CI, Hoogland TM. Reappraisal of Bergmann glial cells as modulators of cerebellar circuit function. Front Cell Neurosci. 2015;9:246. doi:10.3389/fncel.2015.00246
4. Prevot V, Dehouck B, Sharif A, Ciofi P, Giacobini P, Clasadonte J. The versatile tanycyte: a hypothalamic integrator of reproduction and energy metabolism. Endocr Rev. 2018;39(3):333-368. doi:10.1210/er.2017-00235
5. Agulhon C, Fiacco T, McCarthy K. Hippocampal short- and long-term plasticity are not modulated by astrocyte Ca2+ signaling. Science. 2010;327(2326):1250-1222. doi:10.1126/science.1184821
6. Rafalski VA, Brunet A. Energy metabolism in adult neural stem cell fate. Prog Neurobiol. 2011;93(2):133-203. doi:10.1016/j.pneurobio.2010.10.007
7. Santello M, Volterra A. Synaptic modulation by astrocytes via Ca [2+]-dependent glutamate release. Neuroscience. 2009;158(1):253-259. doi:10.1016/j.neuroscience.2008.03.039
8. Siracusa R, Fusco R Cuzzocrea S. Front pharmacol. Astrocytes: Role and functions in brain pathologies. Front Pharmacol. 2019;10:1114. doi:10.3389/fphar.2019.01114

9. Akdogan I, Adiguzel E, Yilmaz I, et al. Penicillin-induced epilepsy model in rats: dose-dependant effect on hippocampal volume and neuron number. Brain Res Bull. 2008;77(4):172-177.
10. Twyman RE, Green RM, MacDonald RL. Kinetics of open channel block by penicillin of single GABAA receptor channels from mouse spinal cord neurones in culture. J Physiol. 1992;445:97-127. doi:10.1113/jphysiol.1992.sp018914
11. Bennett M, Contreras J, Bukauskas F, Sáez JC. New roles for astrocytes: gap junction hemichannels have something to communicate. Trends Neurosci. 2003;26(11):610-617. doi:10.1016/j.tins.2003.09.008
12. Klip A, Leiter LA. Cellular mechanism of action of metformin. Diabetes Care. 1990;13(6):696-704. doi:10.2337/diacare.13.6.696
13. Amr Ahmed EL-Arabey and Mohnad Abdalla 2. Metformin and COVID-19: A novel deal of an old drug. J Med Virol. 2020,92(11):2293-2294. doi:10.1002/jmv.25958
14. Rotermund C, Machetanz G, Fitzgerald JC. The therapeutic potential of metformin in neurodegenerative diseases. Front Endocrinol. 2018;9:400. doi:10.3389/fendo.2018.00400
15. Bezzi P, Carmignoto G, Pasti L, et al. Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature. 1998;391(6664):281-285. doi:10.1038/34651
16. Tian GF, Azmi H, Takano T, et al. An astrocytic basis of epilepsy. Nat Med. 2005;11(9):973-981. doi:10.1038/nm1277
17. Fellin T, Gomez Gonzalo M, Gobbo S, Carmignoto G, Haydon PG. Astrocytic glutamate is not necessary for the generation of epileptiform neuronal activity in hippocampal slices. J Neurosci. 2006;26(36):9312-9322. doi:10.1523/JNEUROSCI.2836-06.2006
18. Ounsted C, Glaser GH, Lindsay J, Richards P. Focal epilepsy with mesial temporal sclerosis after acute meningitis. Arch Neurol. 1985;42(11):1058-1060. doi:10.1001/archneur.1985.04060100040017
19. Uesugi H, Shimizu H, Maehara T, Arai N, Nakayama H. Presence of human herpes virus 6 and herpes simplex virus detected by polymerase chain reaction in surgical tissue from temporal lobe epileptic patients. Psychiatry Clin Neurosci. 2000;54(5):589-593. doi:10.1046/j.1440-1819.2000.00758.x
20. Bsibsi M, Ravid R, Gveric D, van Noort JM. Broad expression of Toll-like receptors in the human central nervous system. J Neuropath Exp Neurol. 2002;61(11):1013-1021. doi:10.1093/JNEN/61.11.1013
21. Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol. 2001;1(2):135-145. doi:10.1038/35100529
22. Rotermund C, Machetanz G, Fitzgerald JC. The Therapeutic Potential of Metformin in Neurodegenerative Diseases. Front Endocrinol. 2018;9:400. doi:10.3389/fendo.2018.00400
23. Lindsay RS, Loeken MR. Metformin use in pregnancy: promises and uncertainties. Diabetologia. 2017;60(9):1612-1619. doi:10.1007/s00125-017-4351-y
24. Chen Y, Gu F, Guan JL. Metformin might inhibit virus through increasing insulin sensitivity. Chin Med J. 2018;131(3):376-377. doi:10.4103/0366-6999.223856
25. Mortensen E, Anzueto A. Association of metformin and mortality for patients with diabetes who are hospitalized with pneumonia. ERJ. 2018;17:2639. doi:10.1183/13993003.congress-2018.PA2639
26. Zhao B, Luo J, Yu T, Zhou L, Lv H, Shang P. Anticancer mechanisms of metformin: A review of the current evidence. Life Sci. 2020;254:117717. doi:10.1016/j.lfs.2020.117717
27. Carpentier PA, Begolka WS, Olson JK, Elhofy A, Karpus WJ, Miller SD. Differential activation of astrocytes by innate and adaptive immune stimuli. Glia. 2005;49(3):360-374. doi:10.1002/glia.20117
28. Farr SA, Roesler E, Niehoff ML, Roby DA, McKee A, Morley JE. Metformin Improves Learning and Memory in the SAMP8 Mouse Model of Alzheimer's Disease. J Alzheimers Dis. 2019;68(4):1699-1710. doi:10.3233/JAD-181240
29. Ryu YK, Park HY, Go J, et al. Metformin Inhibits the Development of L-DOPA-Induced Dyskinesia in a Murine Model of Parkinson's Disease. Mol Neurobiol. 2018;55(7):5715-5726. doi:10.1007/s12035-017-0752-7
30. Gantois I, Popic J, Khoutorsky A, Sonenberg N. Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders. Annu Rev Med. 2019;70:167-181. doi:10.1146/annurev-med-081117-041238
31. Conde de la Rosa L, Vrenken TE, Buist Homan M, Faber KN, Moshage H. Metformin protects primary rat hepatocytes against oxidative stress-induced apoptosis. PharmaRes Per. 2015;3(2):e00125. doi:10.1002/prp2.125
32. Hirosumi J, Tuncman G, Chang L. A central role for JNK in obesity and insulin resistance. Nature. 2002;420(6913):333-336. doi:10.1038/nature01137
33. Czaja MJ. The future of GI and liver research: editorial perspectives. III. JNK/AP-1 regulation of hepatocyte death. Am J Physiol Gastrointest Liver Physiol. 2003;284(6):G875-879. doi:10.1152/ajpgi.00549.2002
34. Wu N, Gu C, Gu H, Hu H, Han Y, Li Q. Metformin induces apoptosis of lung cancer cells through activating JNK/p38 MAPK pathway and GADD118. Neoplasma. 2011;58(6):482-490. doi:10.4149/neo_2011_06_482