Effects of metformin on cognitive dysfunction in preeclampsia rats

doi:10.12307/2022.850

Abstract

Abstract: BACKGROUND: Preeclampsia is a unique syndrome of pregnancy involving multiple organ systems, with no final conclusion in its pathogenesis. Endothelial dysfunction is a mechanism that has been widely used in basic research. Therefore, NG-nitro-L-arginine methyl ester was used in this study for preeclampsia modeling, followed by treatment with metformin.
OBJECTIVE: To establish the model of preeclampsia in rats by intraperitoneal injection of NG-nitro-L-arginine methyl ester, and to explore the effects of metformin on preeclampsia and cognitive function in rats.
METHODS: Pregnant rats were randomly divided into control group, model group, and metformin group. The model group was intraperitoneally injected with NG-nitro-L-arginine methyl ester in the middle and late pregnancy, and the metformin group was intraperitoneally injected with the same dose of NG-nitro-L-arginine methyl ester and metformin in the middle and late pregnancy. Body mass of each pregnant rat was recorded and corresponding drug dose was calculated every day. Caudal artery blood pressure was measured, and soluble endothelin and placental growth factor levels were quantified on day 19 of gestation and on days 10 and 30 after delivery. On the 19th day of gestation, urine was collected for 24 hours for urinary albumin and creatinine quantification. The Morris water maze test was conducted on the 10th and 30th days after delivery to obtain the escape latency, number of platform crossings and the average time spent in the target site where the platform was located.
RESULTS AND CONCLUSION: Intraperitoneal injection of NG-nitro-L-arginine methyl ester could successfully establish the preeclampsia model in rats, resulting in hypertension, proteinuria and intrauterine growth restriction and endothelial dysfunction. Metformin could improve the preeclampsia-like performance induced by NG-nitro-L-arginine methyl ester. NG-nitro-L-arginine methyl ester-induced preeclampsia rats presented with impaired cognitive function 10 and 30 days after delivery, and metformin treatment could improve the above performance to a certain extent. Therefore, metformin has certain potential in the treatment and prevention of preeclampsia, and its mechanism of action needs to be further studied.

Key words: preeclampsia, metformin, NG-nitro-L-arginine methyl ester, endothelial dysfunction, cognitive function, rat

CLC Number:

Zhao Junguo, Chen Xin, Jiang Ruohan, Guo Ying, Gao Bo. Effects of metformin on cognitive dysfunction in preeclampsia rats[J]. Chinese Journal of Tissue Engineering Research, 2022, 26(29): 4651-4657.

Figures/Tables 6

References

[1] MOL BWJ, ROBERTS CT, THANGARATINAM S, et al. Pre-eclampsia. Lancet. 2016;387(10022):999-1011.
[2] WEBSTER K, FISHBURN S, MARESH M, et al. Diagnosis and management of hypertension in pregnancy: summary of updated NICE guidance. BMJ. 2019;366:l5119.
[3] CHAIWORAPONGSA T, CHAEMSAITHONG P, YEO L, et al. Pre-eclampsia part 1: current understanding of its pathophysiology. Nat Rev Nephrol. 2014;10(8):466-480.
[4] KUMASAWA K. Animal Models in Preeclampsia. Preeclampsia. 2018: 141-155.
[5] KOLOVETSIOU-KREINER V, MOERTL MG, PAPOUSEK I, et al. Maternal cardiovascular and endothelial function from first trimester to postpartum. PLoS One. 2018;13(5):e0197748.
[6] BAIJNATH S, SOOBRYAN N, MACKRAJ I, et al. The optimization of a chronic nitric oxide synthase (NOS) inhibition model of pre-eclampsia by evaluating physiological changes. Eur J Obstet Gynecol Reprod Biol. 2014;182:71-75.
[7] ZHU H, ZHU W, HU R, et al. The effect of pre-eclampsia-like syndrome induced by L-NAME on learning and memory and hippocampal glucocorticoid receptor expression: A rat model. Hypertens Pregnancy. 2017;36(1):36-43.
[8] LIU W, QIAO F, LIU H, et al. Low molecular weight heparin improves proteinuria in rats with L-NAME induced preeclampsia by decreasing the expression of nephrin, but not podocin. Hypertens Pregnancy. 2015;34(1):24-35.
[9] IJOMONE OK, SHALLIE PD, NAICKER T. Nꭃ-nitro-l-arginine methyl model of pre-eclampsia elicits differential IBA1 and EAAT1 expressions in brain. J Chem Neuroanat. 2019;100:101660.
[10] ALONSO-VENTURA V, LI Y, PASUPULETI V, et al. Effects of preeclampsia and eclampsia on maternal metabolic and biochemical outcomes in later life: a systematic review and meta-analysis. Metabolism. 2020; 102:154012.
[11] SIA WW, PERTMAN SM, YAN RM, et al. Are Preeclampsia and Adverse Obstetrical Outcomes Predictors of Cardiovascular Disease? A Case-Control Study of Women With Heart Disease. J Obstet Gynaecol Can. 2019;41(12):1760-1767.
[12] HEIDEMA WM, SCHOLTEN RR, VAN DRONGELEN J, et al. Metabolic Syndrome After Preeclamptic Pregnancy: A Longitudinal Cohort Study. J Womens Health (Larchmt). 2019;28(3):357-362.
[13] WIEGMAN MJ, ZEEMAN GG, AUKES AM, et al. Regional distribution of cerebral white matter lesions years after preeclampsia and eclampsia. Obstet Gynecol. 2014;123(4):790-795.
[14] 吴牧熙,沈桂权,高波.先兆子痫对脑结构和功能影响的研究进展[J].磁共振成像,2019,10(12):924-927.
[15] FIELDS JA, GAROVIC VD, MIELKE MM, et al. Preeclampsia and cognitive impairment later in life. Am J Obstet Gynecol. 2017;217(1):74.e1-74.e11.
[16] IJOMONE OK, SHALLIE P, NAICKER T. Changes in the structure and function of the brain years after Pre-eclampsia. Ageing Res Rev. 2018; 47:49-54.
[17] BASIT S, WOHLFAHRT J, BOYD HA. Pre-eclampsia and risk of dementia later in life: nationwide cohort study. BMJ. 2018;363:k4109.
[18] 张阳,杨慧,杨柳,等.二甲双胍在妊娠期高血压疾病中的研究现状和前景展望[J].中华妇产科杂志,2020,55(8):567-571.
[19] IJOMONE OK, SHALLIE PD, NAICKER T. Oligodendrocytes Death Induced Sensorimotor and Cognitive Deficit in N-nitro-L-arginine methyl Rat Model of Pre-eclampsia. Neurochem Res. 2020;45(4):902-914.
[20] HU J, ZHANG J, ZHU B. Protective effect of metformin on a rat model of lipopolysaccharide-induced preeclampsia. Fundam Clin Pharmacol. 2019;33(6):649-658.
[21] ZHANG X, LI Q, JIANG W, et al. LAMA5 promotes human umbilical vein endothelial cells migration, proliferation, and angiogenesis and is decreased in preeclampsia. J Matern Fetal Neonatal Med. 2020;33(7): 1114-1124.
[22] MARTINEZ-FIERRO ML, HERNADEZ-DELGADILLO GP, FLORES-MENDOZA JF, et al. Fibroblast Growth Factor Type 2 (FGF2) Administration Attenuated the Clinical Manifestations of Preeclampsia in a Murine Model Induced by L-NAME. Front Pharmacol. 2021;12:663044.
[23] POSSOMATO-VIEIRA JS, KHALIL RA. Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia. Adv Pharmacol. 2016;77:361-431.
[24] NEMA J , SUNDRANI D , JOSHI S . Prenatal vitamin D supplementation reduces blood pressure and improves placental angiogenesis in an animal model of preeclampsia. Food Funct. 2020;11(12):10413-10422.
[25] NAVARATNAM K, ABREU P, CLARKE H, et al. Evaluation of agreement of placental growth factor (PlGF) tests and the soluble FMS-like tyrosine kinase 1 (sFlt-1)/PlGF ratio, comparison of predictive accuracy for pre-eclampsia, and relation to uterine artery Doppler and response to aspirin. J Matern Fetal Neonatal Med. 2019;32(2):179-187.
[26] BENSCHOP L, SCHALEKAMP-TIMMERMANS S, BROERE-BROWN ZA, et al. Placental Growth Factor as an Indicator of Maternal Cardiovascular Risk After Pregnancy. Circulation. 2019;139(14):1698-1709.
[27] POON LC, GALINDO A, SURBEK D, et al. From first-trimester screening to risk stratification of evolving pre-eclampsia in second and third trimesters of pregnancy: comprehensive approach. Ultrasound Obstet Gynecol. 2020;55(1):5-12.
[28] CHEN J, KHALIL RA. Matrix Metalloproteinases in Normal Pregnancy and Preeclampsia. Prog Mol Biol Transl Sci. 2017;148:87-165.
[29] MARKOVIC S, ROUSSEL T, NEEMAN M, et al. Deuterium Magnetic Resonance Imaging and the Discrimination of Fetoplacental Metabolism in Normal and L-NAME-Induced Preeclamptic Mice. Metabolites. 2021;11(6):376.
[30] COATES BJ, BRODERICK TL, BATIA LM, et al. MgSO4 prevents left ventricular dysfunction in an animal model of preeclampsia. Am J Obstet Gynecol. 2006;195(5):1398-1403.
[31] ROBERTS TJ, CHAPMAN AC, CIPOLLA MJ. PPAR-gamma agonist rosiglitazone reverses increased cerebral venous hydraulic conductivity during hypertension. Am J Physiol Heart Circ Physiol. 2009;297(4): H1347-1353.
[32] YANG X, GUO L, SUN X, et al. Protective effects of hydrogen-rich saline in preeclampsia rat model. Placenta. 2011;32(9):681-686.
[33] LI Y, YANG N, WANG B, et al. Effect and mechanism of prophylactic use of tadalafil during pregnancy on l-NAME-induced preeclampsia-like rats. Placenta. 2020;99:35-44.
[34] ZHANG Y, LIU X, YANG L, et al. Current Researches, Rationale, Plausibility, and Evidence Gaps on Metformin for the Management of Hypertensive Disorders of Pregnancy. Front Pharmacol. 2020;11: 596145.
[35] SONG WY, DING H, DUNN T, et al. Low-dose metformin treatment in the subacute phase improves the locomotor function of a mouse model of spinal cord injury. Neural Regen Res. 2021;16(11):2234-2242.
[36] PONIEDZIAŁEK-CZAJKOWSKA E, MIERZYŃSKI R, DŁUSKI D, et al. Prevention of Hypertensive Disorders of Pregnancy-Is There a Place for Metformin? J Clin Med. 2021;10(13):2805.
[37] LIU T, HONG L, YANG Y, et al. Metformin reduces proteinuria in spontaneously hypertensive rats by activating the HIF-2α-VEGF-A pathway. Eur J Pharmacol. 2021;891:173731.
[38] DENG-BRYANT Y, LEUNG LY, CAUDLE K, et al. Cognitive Evaluation Using Morris Water Maze in Neurotrauma. Methods Mol Biol. 2016; 1462:539-551.
[39] WHITING MD, KOKIKO-COCHRAN ON. Assessment of Cognitive Function in the Water Maze Task: Maximizing Data Collection and Analysis in Animal Models of Brain Injury. Methods Mol Biol. 2016; 1462:553-571.
[40] WANG HL, LIU FL, LI RQ, et al. Electroacupuncture improves learning and memory functions in a rat cerebral ischemia/reperfusion injury model through PI3K/Akt signaling pathway activation. Neural Regen Res. 2021;16(6):1011-1016.
[41] LIU X, ZHAO W, LIU H, et al. Developmental and Functional Brain Impairment in Offspring from Preeclampsia-Like Rats. Mol Neurobiol. 2016;53(2):1009-1019.
[42] KUCUK M, UGUR YILMAZ C, ORHAN N, et al. The Effects of Lipopolysaccharide on the Disrupted Blood-Brain Barrier in a Rat Model of Preeclampsia. J Stroke Cerebrovasc Dis. 2018;27(12):3411-3418.
[43] YANG X, DING Y, YANG M, et al. Nestin Improves Preeclampsia-Like Symptoms by Inhibiting Activity of Cyclin-Dependent Kinase 5. Kidney Blood Press Res. 2018;43(2):616-627.