Skip to main content
SpringerLink
Log in

Beneficial effects of metformin treatment on memory impairment

  • Review
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Memory issues are a prevalent symptom in different neurodegenerative diseases and can also manifest in certain psychiatric conditions. Despite limited medications approved for treating memory problems, research suggests a lack of sufficient options in the market. Studies indicate that a significant percentage of elderly individuals experience various forms of memory disorders. Metformin, commonly prescribed for type 2 diabetes, has shown neuroprotective properties through diverse mechanisms. This study explores the potential of metformin in addressing memory impairments. The current research gathered its data by conducting an extensive search across electronic databases including PubMed, Web of Science, Scopus, and Google Scholar. Previous research suggests that metformin enhances brain cell survival and memory function in both animal and clinical models by reducing oxidative stress, inflammation, and cell death while increasing beneficial neurotrophic factors. The findings of the research revealed that metformin is an effective medication for enhancing various types of memory problems in numerous studies. Given the rising incidence of memory disorders, it is plausible to utilize metformin, which is an affordable and accessible drug. It is often recommended as a treatment to boost memory.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

No data associated in the manuscript.

Abbreviations

MDD:

Major depressive disorder

SCZ:

Schizophrenia

T2DM:

Type 2 diabetes mellitus

Cmax:

Acid dissociation constant value

pKa:

Peak plasma concentrations

OCTs:

Organic cation transporters

AMPK:

AMP-activated protein kinase

GLUT4:

Glucose transporter 4

NO:

Nitric oxide

Aβ:

β-Amyloid

Nrf2:

Erythroid 2-related factor 2

BDNF:

Brain-derived neurotrophic factor

mTOR:

Mammalian target of rapamycin

NF-κB:

Nuclear factor kappa B

hNSCs:

Human neural stem cells

Bcl-2:

B-cell lymphoma-2

CREB:

CAMP-responsive element binding protein

aPKC-CBP:

Atypical protein kinase C-mediated Ser436 phosphorylation of camp response element-binding protein

ApoE:

Apolipoprotein E

APP:

Amyloid precursor protein

RAGE:

Receptor for advanced glycation end products

AGEs:

Advanced glycation end products

NRF1:

Nitrogen response factor 1

Tfam:

Transcription factor A mitochondrial

NOS:

Nitric oxide synthase

ROS:

Reactive oxygen species

RNS:

Reactive nitrogen species

PI3K:

Phosphatidylinositol 3-kinase/AKT protein kinase B

CNS:

Central nervous system

JNKs:

Jun N-terminal kinases

UPR:

Unfolded protein response

ER:

Endoplasmic reticulum

Grp78:

Glucose-regulated protein 78/BiP

AChE:

Acetylcholinesterase

ChE:

Choline esterase

Bcl-xL:

B-cell lymnhoma extra large

GDNF:

Glial cell line-derived neurotrophic factor

TH:

Tyrosine hydroxylase

NLRP3:

Nucleotide-binding oligomerization domain, Leucine rich repeat and pyrin domain containing

MAPK:

Mitogen-activated protein kinases

eNOS:

Endothelial nitric oxide synthase

LTP:

Long-term potentiation

fEPSP:

Field excitatory postsynaptic potential

References

  1. Corcoran C, Jacobs TF (2018) Metformin

  2. Drzewoski J, Hanefeld M (2021) The current and potential therapeutic use of metformin—the good old drug. Pharmaceuticals 14(2):122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Du M-R et al (2022) Exploring the pharmacological potential of metformin for neurodegenerative diseases. Front Aging Neurosci 14:838173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mohammed I et al (2021) A critical review of the evidence that metformin is a putative anti-aging drug that enhances healthspan and extends lifespan. Front Endocrinol 12:933

    Article  Google Scholar 

  5. Camina E, Güell F (2017) The neuroanatomical, neurophysiological and psychological basis of memory: current models and their origins. Front Pharmacol 8:438

    Article  PubMed  PubMed Central  Google Scholar 

  6. Chen Z-X et al (2015) Specific marker of feigned memory impairment: the activation of left superior frontal gyrus. J Forensic Leg Med 36:164–171

    Article  PubMed  Google Scholar 

  7. Anderson ND, Murphy KJ, Troyer AK (2024) Living with mild cognitive impairment: a guide to maximizing brain health and reducing the risk of dementia. Oxford University Press, Oxford

    Google Scholar 

  8. Gellersen HM et al (2024) Demands on perceptual and mnemonic fidelity are a key determinant of age-related cognitive decline throughout the lifespan. J Exp Psychol Gen 153(1):200

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ishikawa KM et al (2022) The prevalence of mild cognitive impairment by aspects of social isolation. PLoS ONE 17(6):e0269795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Burt DB, Zembar MJ, Niederehe G (1995) Depression and memory impairment: a meta-analysis of the association, its pattern, and specificity. Psychol Bull 117(2):285

    Article  CAS  PubMed  Google Scholar 

  11. Roux CM, Leger M, Freret T (2021) Memory disorders related to hippocampal function: the interest of 5-HT4Rs targeting. Int J Mol Sci 22(21):12082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schneider LS et al (2014) Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014. J Intern Med 275(3):251–283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Alhowail A, Chigurupati S (2022) Research advances on how metformin improves memory impairment in “chemobrain.” Neural Regen Res 17(1):15

    Article  CAS  PubMed  Google Scholar 

  14. Beheshti F et al (2021) Beneficial effects of angiotensin converting enzyme inhibition on scopolamine-induced learning and memory impairment in rats, the roles of brain-derived neurotrophic factor, nitric oxide and neuroinflammation. Clin Exp Hypertens 43(6):505–515

    Article  CAS  PubMed  Google Scholar 

  15. Moscovitch M, Winocur G (1992) The neuropsychology of memory and aging. Handb Aging Cogn 315:372

    Google Scholar 

  16. Detoledo-Morrell L, Geinisman Y, Morrell F (1988) Age-dependent alterations in hippocampal synaptic plasticity: relation to memory disorders. Neurobiol Aging 9:581–590

    Article  CAS  PubMed  Google Scholar 

  17. Tang G et al (2017) Metformin ameliorates sepsis-induced brain injury by inhibiting apoptosis, oxidative stress and neuroinflammation via the PI3K/Akt signaling pathway. Oncotarget 8(58):97977

    Article  PubMed  PubMed Central  Google Scholar 

  18. Correia S et al (2008) Metformin protects the brain against the oxidative imbalance promoted by type 2 diabetes. Med Chem 4(4):358–364

    Article  CAS  PubMed  Google Scholar 

  19. Bailey CJ, Day C (2004) Metformin: its botanical background. Pract Diabet Int 21(3):115–117

    Article  Google Scholar 

  20. Watanabe C (1918) Studies in the metabolism changes induced by administration of guanidine bases: i. influence of injected guanidine hydrochloride upon blood sugar content. J Biol Chem 33(2):253–265

    Article  CAS  Google Scholar 

  21. Adak T et al (2018) A reappraisal on metformin. Regul Toxicol Pharmacol 92:324–332

    Article  CAS  PubMed  Google Scholar 

  22. Aksoz E et al (2019) The protective effect of metformin in scopolamine-induced learning and memory impairment in rats. Pharmacol Rep 71(5):818–825

    Article  CAS  PubMed  Google Scholar 

  23. Ou Z et al (2018) Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice. Brain Behav Immun 69:351–363

    Article  CAS  PubMed  Google Scholar 

  24. Campbell JM et al (2018) Metformin use associated with reduced risk of dementia in patients with diabetes: a systematic review and meta-analysis. J Alzheimers Dis 65(4):1225–1236

    Article  PubMed  PubMed Central  Google Scholar 

  25. Baghcheghi Y et al (2021) Brain-derived neurotrophic factor and nitric oxide contribute to protective effects of rosiglitazone on learning and memory in hypothyroid rats. Acta Neurobiol Exp (Wars) 81(3):218–232

    Article  PubMed  Google Scholar 

  26. Salmani H et al (2020) Losartan modulates brain inflammation and improves mood disorders and memory impairment induced by innate immune activation: the role of PPAR-γ activation. Cytokine 125:154860

    Article  CAS  PubMed  Google Scholar 

  27. Baradaran Z et al (2021) Metformin improved memory impairment caused by chronic ethanol consumption during adolescent to adult period of rats: role of oxidative stress and neuroinflammation. Behav Brain Res 411:113399

    Article  CAS  PubMed  Google Scholar 

  28. Oliveira WH et al (2016) Effects of metformin on inflammation and short-term memory in streptozotocin-induced diabetic mice. Brain Res 1644:149–160

    Article  PubMed  Google Scholar 

  29. Sanchis A et al (2019) Metformin treatment reduces motor and neuropsychiatric phenotypes in the zQ175 mouse model of Huntington disease. Exp Mol Med 51(6):1–16

    Article  CAS  PubMed  Google Scholar 

  30. Sartoretto JL et al (2005) Metformin treatment restores the altered microvascular reactivity in neonatal streptozotocin-induced diabetic rats increasing NOS activity, but not NOS expression. Life Sci 77(21):2676–2689

    Article  CAS  PubMed  Google Scholar 

  31. Markowicz-Piasecka M et al (2017) Metformin—a future therapy for neurodegenerative diseases: theme: drug discovery, development and delivery in Alzheimer’s disease guest editor: Davide Brambilla. Pharm Res 34:2614–2627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li N, Zhou T, Fei E (2022) Actions of metformin in the brain: a new perspective of metformin treatments in related neurological disorders. Int J Mol Sci 23(15):8281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sharma S et al (2023) Permeability of metformin across an in vitro blood-brain barrier model during normoxia and oxygen-glucose deprivation conditions: role of organic cation transporters (Octs). Pharmaceutics 15(5):1357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ameen O, Samaka RM, Abo-Elsoud RA (2022) Metformin alleviates neurocognitive impairment in aging via activation of AMPK/BDNF/PI3K pathway. Sci Rep 12(1):17084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cao G et al (2022) Mechanism of metformin regulation in central nervous system: progression and future perspectives. Biomed Pharmacother 156:113686

    Article  CAS  PubMed  Google Scholar 

  36. Picone P et al (2016) Biological and biophysics aspects of metformin-induced effects: cortex mitochondrial dysfunction and promotion of toxic amyloid pre-fibrillar aggregates. Aging 8(8):1718 (Albany NY)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kim A et al (2014) Effects of proton pump inhibitors on metformin pharmacokinetics and pharmacodynamics. Drug Metab Dispos 42(7):1174–1179

    Article  PubMed  Google Scholar 

  38. Graham GG et al (2011) Clinical pharmacokinetics of metformin. Clin Pharmacokinet 50:81–98

    Article  CAS  PubMed  Google Scholar 

  39. Song R (2016) Mechanism of metformin: a tale of two sites. Diabetes Care 39(2):187–189

    Article  CAS  PubMed  Google Scholar 

  40. Müller J et al (2005) Drug specificity and intestinal membrane localization of human organic cation transporters (OCT). Biochem Pharmacol 70(12):1851–1860

    Article  PubMed  Google Scholar 

  41. Shaw RJ et al (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310(5754):1642–1646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chiang M-C et al (2016) Metformin activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against amyloid-beta-induced mitochondrial dysfunction. Exp Cell Res 347(2):322–331

    Article  CAS  PubMed  Google Scholar 

  43. Sanders MJ et al (2007) Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem J 403(1):139–148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gong L et al (2012) Metformin pathways: pharmacokinetics and pharmacodynamics. Pharmacogenet Genom 22(11):820

    Article  CAS  Google Scholar 

  45. Moore EM et al (2013) Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care 36(10):2981–2987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Tanokashira D et al (2018) Metformin treatment ameliorates diabetes-associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1. FEBS Open Bio 8(7):1104–1118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Alhowail A et al (2019) Ameliorative effect of metformin on cyclophosphamide-induced memory impairment in mice. Eur Rev Med Pharmacol Sci 23(21):9660–9666

    CAS  PubMed  Google Scholar 

  48. Zhao M et al (2019) Metformin administration prevents memory impairment induced by hypobaric hypoxia in rats. Behav Brain Res 363:30–37

    Article  CAS  PubMed  Google Scholar 

  49. Jinpiao Z et al (2020) Metformin attenuates sevoflurane-induced neurocognitive impairment through AMPK-ULK1-dependent autophagy in aged mice. Brain Res Bull 157:18–25

    Article  PubMed  Google Scholar 

  50. Saffari PM et al (2020) Metformin loaded phosphatidylserine nanoliposomes improve memory deficit and reduce neuroinflammation in streptozotocin-induced Alzheimer’s disease model. Life Sci 255:117861

    Article  CAS  PubMed  Google Scholar 

  51. Kotagale N et al (2021) Possible involvement of agmatine in neuropharmacological actions of metformin in diabetic mice. Eur J Pharmacol 907:174255

    Article  CAS  PubMed  Google Scholar 

  52. Said ES et al (2021) Evaluation of nootropic activity of telmisartan and metformin on diazepam-induced cognitive dysfunction in mice through AMPK pathway and amelioration of hippocampal morphological alterations. Eur J Pharmacol 912:174511

    Article  CAS  PubMed  Google Scholar 

  53. Sritawan N et al (2021) Effect of metformin treatment on memory and hippocampal neurogenesis decline correlated with oxidative stress induced by methotrexate in rats. Biomed Pharmacother 144:112280

    Article  CAS  PubMed  Google Scholar 

  54. Oliveira WH et al (2021) Metformin prevents p-tau and amyloid plaque deposition and memory impairment in diabetic mice. Exp Brain Res 239:2821–2839

    Article  CAS  PubMed  Google Scholar 

  55. Gwinn DM, Shaw RJ (2010) AMPK control of mTOR signaling and growth. In: The enzymes. Elsevier, Amsterdam, pp 49–75

    Google Scholar 

  56. Wang Y, Engel T, Teng X (2024) Post-translational regulation of the mTORC1 pathway: a switch that regulates metabolism-related gene expression. Biochim Biophys Acta-Gene Regul Mech. https://doi.org/10.1016/j.bbagrm.2024.195005

    Article  PubMed  Google Scholar 

  57. Garza-Lombó C et al (2018) mTOR/AMPK signaling in the brain: cell metabolism, proteostasis and survival. Curr Opin Toxicol 8:102–110

    Article  PubMed  PubMed Central  Google Scholar 

  58. Ping F, Jiang N, Li Y (2020) Association between metformin and neurodegenerative diseases of observational studies: systematic review and meta-analysis. BMJ Open Diabet Res Care 8(1):e001370

    Article  Google Scholar 

  59. Ha J et al (2021) Association of metformin use with Alzheimer’s disease in patients with newly diagnosed type 2 diabetes: a population-based nested case–control study. Sci Rep 11(1):24069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Liu KW, Dai LK, Jean W (2006) Metformin-related vitamin B12 deficiency. Age Ageing 35(2):200–201

    Article  CAS  PubMed  Google Scholar 

  61. Marinangeli C, Didier S, Vingtdeux V (2016) AMPK in neurodegenerative diseases: implications and therapeutic perspectives. Curr Drug Targets 17(8):890–907

    Article  CAS  PubMed  Google Scholar 

  62. Arendt T et al (1995) Paired helical filament-like phosphorylation of tau, deposition of β/A4-amyloid and memory impairment in rat induced by chronic inhibition of phosphatase 1 and 2A. Neuroscience 69(3):691–698

    Article  CAS  PubMed  Google Scholar 

  63. Joshi YB, Chu J, Praticò D (2012) Stress hormone leads to memory deficits and altered tau phosphorylation in a model of Alzheimer’s disease. J Alzheimers Dis 31(1):167–176

    Article  CAS  PubMed  Google Scholar 

  64. Kickstein E et al (2010) Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proc Natl Acad Sci 107(50):21830–21835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Chen J-L et al (2019) Metformin attenuates diabetes-induced tau hyperphosphorylation in vitro and in vivo by enhancing autophagic clearance. Exp Neurol 311:44–56

    Article  CAS  PubMed  Google Scholar 

  66. Gouveia A et al (2016) The aPKC-CBP pathway regulates adult hippocampal neurogenesis in an age-dependent manner. Stem Cell Rep 7(4):719–734

    Article  CAS  Google Scholar 

  67. Wang J et al (2012) Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell 11(1):23–35

    Article  CAS  PubMed  Google Scholar 

  68. Bertrand P et al (1995) Association of apolipoprotein E genotype with brain levels of apolipoprotein E and apolipoprotein J (clusterin) in Alzheimer disease. Mol Brain Res 33(1):174–178

    Article  CAS  PubMed  Google Scholar 

  69. Jack CR Jr et al (1998) Hippocampal atrophy and apolipoprotein E genotype are independently associated with Alzheimer’s disease. Ann Neurol 43(3):303–310

    Article  PubMed  PubMed Central  Google Scholar 

  70. Kim J, Basak JM, Holtzman DM (2009) The role of apolipoprotein E in Alzheimer’s disease. Neuron 63(3):287–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bu G (2022) APOE targeting strategy in Alzheimer’s disease: lessons learned from protective variants. Mol Neurodegener 17(1):1–4

    Article  Google Scholar 

  72. Huang Y-WA et al (2019) Differential signaling mediated by ApoE2, ApoE3, and ApoE4 in human neurons parallels Alzheimer’s disease risk. J Neurosci 39(37):7408–7427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Zhang J et al (2019) Metformin treatment improves the spatial memory of aged mice in an APOE genotype-dependent manner. FASEB J 33(6):7748–7757

    Article  CAS  PubMed  Google Scholar 

  74. Chen F et al (2016) Antidiabetic drugs restore abnormal transport of amyloid-β across the blood–brain barrier and memory impairment in db/db mice. Neuropharmacology 101:123–136

    Article  CAS  PubMed  Google Scholar 

  75. Chung M-M et al (2015) The neuroprotective role of metformin in advanced glycation end product treated human neural stem cells is AMPK-dependent. Biochim Biophys Acta-Mol Basis Dis. https://doi.org/10.1016/j.bbadis.2015.01.006

    Article  Google Scholar 

  76. Dei R et al (2002) Lipid peroxidation and advanced glycation end products in the brain in normal aging and in Alzheimer’s disease. Acta Neuropathol 104:113–122

    Article  CAS  PubMed  Google Scholar 

  77. D’cunha NM et al (2022) The effects of dietary advanced glycation end-products on neurocognitive and mental disorders. Nutrients 14(12):2421

    Article  PubMed  PubMed Central  Google Scholar 

  78. Lin C-H et al (2017) Activation of AMPK is neuroprotective in the oxidative stress by advanced glycosylation end products in human neural stem cells. Exp Cell Res 359(2):367–373

    Article  CAS  PubMed  Google Scholar 

  79. Carnevale D et al (2012) Hypertension induces brain β-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature. Hypertension 60(1):188–197

    Article  CAS  PubMed  Google Scholar 

  80. Apelt J et al (2004) Aging-related increase in oxidative stress correlates with developmental pattern of beta-secretase activity and beta-amyloid plaque formation in transgenic Tg2576 mice with Alzheimer-like pathology. Int J Dev Neurosci 22(7):475–484

    Article  CAS  PubMed  Google Scholar 

  81. Mousavi SM et al (2015) Beneficial effects of Teucrium polium and metformin on diabetes-induced memory impairments and brain tissue oxidative damage in rats. Int J Alzheimer’s Dis. https://doi.org/10.1155/2015/493729

    Article  Google Scholar 

  82. Khallaghi B et al (2016) Metformin-induced protection against oxidative stress is associated with AKT/mTOR restoration in PC12 cells. Life Sci 148:286–292

    Article  CAS  PubMed  Google Scholar 

  83. Izzo A et al (2017) Metformin restores the mitochondrial network and reverses mitochondrial dysfunction in down syndrome cells. Hum Mol Genet 26(6):1056–1069

    CAS  PubMed  Google Scholar 

  84. Pintana H et al (2012) Effects of metformin on learning and memory behaviors and brain mitochondrial functions in high fat diet induced insulin resistant rats. Life Sci 91(11–12):409–414

    Article  CAS  PubMed  Google Scholar 

  85. Lewerenz J, Maher P (2015) Chronic glutamate toxicity in neurodegenerative diseases—what is the evidence? Front Neurosci 9:469

    Article  PubMed  PubMed Central  Google Scholar 

  86. Zaja-Milatovic S et al (2009) Protection of DFP-induced oxidative damage and neurodegeneration by antioxidants and NMDA receptor antagonist. Toxicol Appl Pharmacol 240(2):124–131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Armada-Moreira A et al (2020) Going the extra (synaptic) mile: excitotoxicity as the road toward neurodegenerative diseases. Front Cell Neurosci 14:90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zhou C et al (2016) Metformin prevents cerebellar granule neurons against glutamate-induced neurotoxicity. Brain Res Bull 121:241–245

    Article  CAS  PubMed  Google Scholar 

  89. Docrat TF et al (2020) The protective effect of metformin on mitochondrial dysfunction and endoplasmic reticulum stress in diabetic mice brain. Eur J Pharmacol 875:173059

    Article  CAS  PubMed  Google Scholar 

  90. Obafemi TO et al (2020) Metformin/donepezil combination modulates brain antioxidant status and hippocampal endoplasmic reticulum stress in type 2 diabetic rats. J Diabet Metab Disord 19:499–510

    Article  CAS  Google Scholar 

  91. Read A, Schröder M (2021) The unfolded protein response: an overview. Biology 10(5):384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Liu CY, Kaufman RJ (2003) The unfolded protein response. J Cell Sci 116(10):1861–1862

    Article  CAS  PubMed  Google Scholar 

  93. Zhang K, Kaufman RJ (2006) The unfolded protein response: a stress signaling pathway critical for health and disease. Neurology 66(1 suppl 1):S102–S109

    CAS  PubMed  Google Scholar 

  94. Natrus LV et al (2022) Effect of propionic acid on diabetes-induced impairment of unfolded protein response signaling and astrocyte/microglia crosstalk in rat ventromedial nucleus of the hypothalamus. Neural Plast. https://doi.org/10.1155/2022/6404964s

    Article  PubMed  PubMed Central  Google Scholar 

  95. Niccoli T et al (2016) Increased glucose transport into neurons rescues Aβ toxicity in Drosophila. Curr Biol 26(17):2291–2300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Talesa VN (2001) Acetylcholinesterase in Alzheimer’s disease. Mech Ageing Dev 122(16):1961–1969

    Article  CAS  PubMed  Google Scholar 

  97. García-Ayllón M-S et al (2011) Revisiting the role of acetylcholinesterase in Alzheimer’s disease: cross-talk with P-tau and β-amyloid. Front Mol Neurosci 4:22

    Article  PubMed  PubMed Central  Google Scholar 

  98. Bhutada P et al (2011) Protection of cholinergic and antioxidant system contributes to the effect of berberine ameliorating memory dysfunction in rat model of streptozotocin-induced diabetes. Behav Brain Res 220(1):30–41

    Article  CAS  PubMed  Google Scholar 

  99. Bredesen DE (1995) Neural apoptosis. Ann Neurol 38(6):839–851

    Article  CAS  PubMed  Google Scholar 

  100. Smale G et al (1995) Evidence for apoptotic cell death in Alzheimer’s disease. Exp Neurol 133(2):225–230

    Article  CAS  PubMed  Google Scholar 

  101. Savory J et al (1999) Age-related hippocampal changes in Bcl-2: bax ratio, oxidative stress, redox-active iron and apoptosis associated with aluminum-induced neurodegeneration: increased susceptibility with aging. Neurotoxicology 20(5):805–817

    CAS  PubMed  Google Scholar 

  102. Li LX et al (2019) Metformin inhibits Aβ25-35-induced apoptotic cell death in SH-SY5Y cells. Basic Clin Pharmacol Toxicol 125(5):439–449

    Article  CAS  PubMed  Google Scholar 

  103. Ullah I et al (2012) Neuroprotection with metformin and thymoquinone against ethanol-induced apoptotic neurodegeneration in prenatal rat cortical neurons. BMC Neurosci 13:1–11

    Article  Google Scholar 

  104. Gabryel B et al (2014) AMP-activated protein kinase is involved in induction of protective autophagy in astrocytes exposed to oxygen-glucose deprivation. Cell Biol Int 38(10):1086–1097

    Article  CAS  PubMed  Google Scholar 

  105. Tobiume K et al (2001) ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Rep 2(3):222–228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Gabryel B, Liber S (2018) Metformin limits apoptosis in primary rat cortical astrocytes subjected to oxygen and glucose deprivation. Folia Neuropathol 56(4):328–336

    Article  PubMed  Google Scholar 

  107. Bramham CR, Messaoudi E (2005) BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol 76(2):99–125

    Article  CAS  PubMed  Google Scholar 

  108. Katila N et al (2020) Activation of AMPK/aPKCζ/CREB pathway by metformin is associated with upregulation of GDNF and dopamine. Biochem Pharmacol 180:114193

    Article  CAS  PubMed  Google Scholar 

  109. Fang W et al (2020) Metformin ameliorates stress-induced depression-like behaviors via enhancing the expression of BDNF by activating AMPK/CREB-mediated histone acetylation. J Affect Dis 260:302–313

    Article  CAS  PubMed  Google Scholar 

  110. Liu K et al (2022) Acute administration of metformin protects against neuronal apoptosis induced by cerebral ischemia-reperfusion injury via regulation of the AMPK/CREB/BDNF pathway. Front Pharmacol 13:832611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Eyileten C et al (2017) Antidiabetic effect of brain-derived neurotrophic factor and its association with inflammation in type 2 diabetes mellitus. J Diabet Res. https://doi.org/10.1155/2017/2823671

    Article  Google Scholar 

  112. Yu X et al (2022) Metformin alleviates neuroinflammation following intracerebral hemorrhage in mice by regulating microglia/macrophage phenotype in a gut microbiota-dependent manner. Front Cell Neurosci 15:789471

    Article  PubMed  PubMed Central  Google Scholar 

  113. Saisho Y (2015) Metformin and inflammation: its potential beyond glucose-lowering effect. Endocr Metab Immune Disord Drug Targets. https://doi.org/10.2174/1871530315666150316124019

    Article  PubMed  Google Scholar 

  114. Docrat TF, Nagiah S, Chuturgoon AA (2021) Metformin protects against neuroinflammation through integrated mechanisms of miR-141 and the NF-ĸB-mediated inflammasome pathway in a diabetic mouse model. Eur J Pharmacol 903:174146

    Article  CAS  PubMed  Google Scholar 

  115. Ha J-S et al (2019) Anti-inflammatory effects of metformin on neuro-inflammation and NLRP3 inflammasome activation in BV-2 microglial cells. Biomed Sci Lett 25(1):92–98

    Article  Google Scholar 

  116. Isoda K et al (2006) Metformin inhibits proinflammatory responses and nuclear factor-κB in human vascular wall cells. Arterioscler Thromb Vasc Biol 26(3):611–617

    Article  CAS  PubMed  Google Scholar 

  117. Ladeiras-Lopes R et al (2015) Novel therapeutic targets of metformin: metabolic syndrome and cardiovascular disease. Expert Opin Ther Targets 19(7):869–877

    Article  CAS  PubMed  Google Scholar 

  118. Gantois I et al (2017) Metformin ameliorates core deficits in a mouse model of fragile X syndrome. Nat Med 23(6):674–677

    Article  CAS  PubMed  Google Scholar 

  119. Zhou C et al (2021) Metformin attenuates LPS-induced neuronal injury and cognitive impairments by blocking NF-κB pathway. BMC Neurosci 22:1–12

    Article  Google Scholar 

  120. Wang Y et al (2020) Metformin ameliorates synaptic defects in a mouse model of AD by inhibiting Cdk5 activity. Front Cell Neurosci 14:170

    Article  PubMed  PubMed Central  Google Scholar 

  121. Zhang P et al (2015) S-nitrosylation-dependent proteasomal degradation restrains Cdk5 activity to regulate hippocampal synaptic strength. Nat Commun 6(1):8665

    Article  CAS  PubMed  Google Scholar 

  122. Zhang H et al (2022) Role of Aβ in Alzheimer’s-related synaptic dysfunction. Front Cell Dev Biol 10:964075

    Article  PubMed  PubMed Central  Google Scholar 

  123. Gupta A, Bisht B, Dey CS (2011) Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like changes. Neuropharmacology 60(6):910–920

    Article  CAS  PubMed  Google Scholar 

  124. Asadbegi M et al (2016) Neuroprotective effects of metformin against Aβ-mediated inhibition of long-term potentiation in rats fed a high-fat diet. Brain Res Bull 121:178–185

    Article  CAS  PubMed  Google Scholar 

  125. Zhang W et al (2021) Metformin improves cognitive impairment in diabetic mice induced by a combination of streptozotocin and isoflurane anesthesia. Bioengineered 12(2):10982–10993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

No funding received.

Author information

Authors and Affiliations

  1. Student Research Committee, Jiroft University of Medical Sciences, Jiroft, Iran

    Mohammad Pourfridoni, Mahdiyeh Hedayati-Moghadam, Hedyeh Askarpour, Hadi Shafieemojaz & Yousef Baghcheghi

  2. Department of Physiology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran

    Mahdiyeh Hedayati-Moghadam

  3. Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran

    Shirin Fathi

  4. Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran

    Shiva Fathi

  5. Departrment of Pediatrics, Jiroft University of Medical Sciences, Jiroft, Iran

    Fatemeh Sadat Mirrashidi

  6. Clinical Research Development Center of Imam Khomeini Hospital, Jiroft University of Medical Sciences, Jiroft, Iran

    Mohammad Pourfridoni, Mahdiyeh Hedayati-Moghadam, Shirin Fathi, Shiva Fathi, Fatemeh Sadat Mirrashidi, Hedyeh Askarpour, Hadi Shafieemojaz & Yousef Baghcheghi

  7. Bio Environmental Health Hazards Research Center, Jiroft University of Medical Sciences, Jiroft, Iran

    Yousef Baghcheghi

Authors
  1. Mohammad Pourfridoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mahdiyeh Hedayati-Moghadam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shirin Fathi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shiva Fathi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fatemeh Sadat Mirrashidi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hedyeh Askarpour
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hadi Shafieemojaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yousef Baghcheghi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors (Mohammad Pourfridoni, Mahdiyeh Hedayati-Moghadam, Shirin Fathi, Shiva Fathi, Fatemeh Sadat Mirrashidi, Hedyeh Askarpour, Hadi Shafieemojaz, Yousef Baghcheghi) have accepted responsibility for the entire content of this manuscript and approved its submission.

Corresponding author

Correspondence to Yousef Baghcheghi.

Ethics declarations

Conflict of interest

The authors have not disclosed any competing interests.

Ethical approval

Not applicable (this paper was provided based on researching in global databases).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pourfridoni, M., Hedayati-Moghadam, M., Fathi, S. et al. Beneficial effects of metformin treatment on memory impairment. Mol Biol Rep 51, 640 (2024). https://doi.org/10.1007/s11033-024-09445-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11033-024-09445-1

Keywords

Search

Navigation