eISSN: 1509-572x
ISSN: 1641-4640
Folia Neuropathologica
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SCImago Journal & Country Rank
4/2018
vol. 56
 
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abstract:
Original paper

Metformin limits apoptosis in primary rat cortical astrocytes subjected to oxygen and glucose deprivation

Bożena Gabryel, Sebastian Liber

Folia Neuropathol 2018; 56 (4): 328-336
Online publish date: 2018/12/31
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Metformin, a type 2 anti-diabetic drug and an activator of AMP-activated protein kinase (AMPK), has been shown to reduce infarct size and pathological changes affecting astroglia in animal models of ischemic stroke. In this study, we evaluated how metformin affects cell viability, apoptosis and determined the role of AMPK, as well as JNK p46/p54 and p38 kinases, in the observed phenomena in the culture of primary rat cortical astrocytes subjected to 12 h of oxygen and glucose deprivation (OGD). Metformin improved cell viability, reduced the fraction of apoptotic nuclei, and inhibited the activation of the executive caspase-3. Decreased activation of JNK p54 and p38 was associated with increased Bcl-XL expression and decreased mitochondrial leakage of cytochrome c. However, only cell viability and partially the fraction of apoptotic nuclei varied concomitantly with changes in AMPK activity, suggesting that AMPK is critical for metformin-mediated effects and regulates programmed cell death in a caspase-independent manner. Experiments with the inhibitors of JNK and p38 supports the role of these kinases in the drug-related inhibition of mitochondrial and extrinsic pathway of apoptosis.
keywords:

metformin, apoptosis, astrocytes, oxygen-glucose deprivation

references:
Ashabi G, Khalaj L, Khodagholi F, Goudarzvand M, Sarkaki A. Pre-treatment with metformin activates Nrf2 antioxidant pathways and inhibits inflammatory responses through induction of AMPK after transient global cerebral ischemia. Metab Brain Dis 2014; 30: 747-754.
Barreto G, White RE, Ouyang Y, Xu L, Giffard RG. Astrocytes: targets for neuroprotection in stroke. Cent Nerv Syst Agents Med Chem 2011; 11: 164-173.
Bradford MM. A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein dye binding. Anal Biochem 1976; 72: 248-251.
Broughton BR, Reutens DC, Sobey CG. Apoptotic mechanisms after cerebral ischemia. Stroke 2009; 40: e331-9.
Chai TF, Hong SY, He H, Zheng L, Hagen T, Luo Y, Yu FX. A potential mechanism of metformin-mediated regulation of glucose homeostasis: inhibition of Thioredoxin-interacting protein (Txnip) gene expression. Cell Signal 2012; 24: 1700-1705.
Chen EC, Liang X, Yee SW, Geier EG, Stocker SL, Chen L, Giacomini KM. Targeted disruption of organic cation transporter 3 attenuates the pharmacologic response to metformin. Mol Pharmacol 2015; 88: 75-83.
Cheng YY, Leu HB, Chen TJ, Chen CL, Kuo CH, Lee SD, Kao CL. Metformin-inclusive therapy reduces the risk of stroke in patients with diabetes: a 4-year follow-up study. J Stroke Cerebrovasc Dis 2014; 23: e99-105.
Conde de la Rosa L, Vrenken TE, Buist-Homan M, Faber KN. Moshage H. Metformin protects primary rat hepatocytes against oxidative stress-induced apoptosis. Pharmacol Res Perspect 2015; 3: e00125.
Dai YL, Huang SL, Leng Y. AICAR and metformin exert AMPK-dependent effects on INS-1E pancreatic -cell apoptosis via differential downstream mechanisms. Int J Biol Sci 2015; 11: 1272-1280.
Gabryel B, Chalimoniuk M, Małecki A, Strosznajder JB. Effect of aniracetam on phosphatidylinositol transfer protein alpha in cytosolic and plasma membrane fractions of astrocytes subjected to simulated ischemia in vitro. Pharmacol Rep 2005; 57: 664-669.
Gabryel B, Kost A, Kasprowska D, Liber S, Machnik G, Wiader­kiewicz R, Łabuzek K. AMP- activated protein kinase is involved in induction of protective autophagy in astrocytes exposed to oxygen-glucose deprivation. Cell Biol Int 2014; 38: 1086-1097.
Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, Furlong TJ, Greenfield JR, Greenup LC, Kirkpatrick CM, Ray JE, Timmins P, Williams KM. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 2011; 50: 81-98.
Harada S, Fujita-Hamabe W, Tokuyama S. The importance of regulation of blood glucose levels through activation of peripheral 5’-AMP-activated protein kinase on ischemic neuronal damage. Brain Res 2010; 1351: 254-263.
Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 2012; 13: 251-262.
Horsdal HT, Mehnert F, Rungby J, Johnsen SP. Type of preadmission antidiabetic treatment and outcome among patients with ischemic stroke: a nationwide follow-up study. J Stroke Cerebrovasc Dis 2012; 21: 717-725.
Jiang T, Yu JT, Zhu XC, Wang HF, Tan MS, Cao L, Zhang QQ, Gao L, Shi JQ, Zhang YD, Tan L. Acute metformin preconditioning confers neuroprotection against focal cerebral ischaemia by pre-activation of AMPK-dependent autophagy. Br J Pharmacol 2014; 171: 3146-3157.
Juurlink BH, Hertz L: Plasticity of astrocytes in primary cultures: an experimental tool and a reason for methodological caution. Dev Neurosci 1985; 7: 263-277.
Kim J, Guan KL. Regulation of the autophagy initiating kinase ULK1 by nutrients: roles of mTORC1 and AMPK. Cell Cycle 2011; 10: 1337-1338.
Kim JS, Park ZY, Yoo YJ, Yu SS, Chun JS. p38 kinase mediates nitric oxide-induced apoptosis of chondrocytes through the inhibition of protein kinase C zeta by blocking autophosphorylation. Cell Death Differ 2015; 12: 201-212.
Li J, Benashski SE, Venna VR, McCullough LD. Effects of metformin in experimental stroke. Stroke 2010; 41: 2645-2652.
Liu H, Nishitoh H, Ichijo H, Kyriakis JM. Activation of apoptosis signal-regulating kinase 1 (ASK1) by tumor necrosis factor receptor-associated factor 2 requires prior dissociation of the ASK1 inhibitor thioredoxin. Mol Cell Biol 2000; 20: 2198-2208.
McCullough LD, Zeng Z, Li H, Landree LE, McFadden J, Ronnett GV. Pharmacological inhibition of AMP activated protein kinase provides neuroprotection in stroke. J Biol Chem 2005; 280: 20493-20502.
Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays.J Immunol Methods 1983; 65: 55-63.
Łabuzek 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.
Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000; 348: 607-614.
Perdan-Pirkmajer K, Pirkmajer S, Černe K, Kržan M. Molecular and kinetic characterization of histamine transport into adult rat cultured astrocytes. Neurochem Int 2012; 61: 415-422.
Shao D, Oka S, Liu T, Zhai P, Ago T, Sciarretta S, Li H, Sadoshima J. A redox-dependent mechanism for regulation of AMPK activation by Thioredoxin1 during energy starvation. Cell Metab 2014; 19: 232-245.
Son YO, Wang X, Hitron JA, Zhang Z, Cheng S, Budhraja A, Ding S, Lee JC, Shi X. Cadmium induces autophagy through ROS-dependent activation of the LKB1-AMPK signaling in skin epidermal cells. Toxicol Appl Pharmacol 2011; 255: 287-296.
Tobiume K, Matsuzawa A, Takahashi T, Nishitoh H, Morita K, Takeda K, Minowa O, Miyazono K, Noda T, Ichijo H. ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Rep 2001; 2: 222-228.
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854-865.
Venna VR, Li J, Hammond MD, Mancini NS, McCullough LD. Chronic metformin treatment improves post-stroke angiogenesis and recovery after experimental stroke. Eur J Neurosci 2014; 39: 2129-2138.
Wang J, Deng X, Zhang F, Chen D, Ding W. ZnO nanoparticle-induced oxidative stress triggers apoptosis by activating JNK signaling pathway in cultured primary astrocytes. Nanoscale Res Lett 2014; 9: 117.
Westhaus A, Blumrich EM, Dringen R. The Antidiabetic Drug Metformin Stimulates Glycolytic Lactate Production in Cultured Primary Rat Astrocytes. Neurochem Res 2017; 42: 294-305.
Yao XM, Ye SD, Xiao CC, Gu JF, Yang D, Wang S. Metformin alleviates high glucose-mediated oxidative stress in rat glomerular mesangial cells by modulation of p38 mitogen-activated protein kinase expression in vitro. Mol Med Rep 2015; 12: 520-526.
Yoshikawa T, Naganuma F, Iida T, Nakamura T, Harada R, Mohsen AS, Kasajima A, Sasano H, Yanai K. Molecular mechanism of histamine clearance by primary human astrocytes. Glia 2013; 61: 905-916.
Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2011; 108: 1167-1174.
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