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Is metformin neuroprotective against diabetes mellitus-induced neurodegeneration? An updated graphical review of molecular basis

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Abstract

Diabetes mellitus (DM) is a metabolic disease that activates several molecular pathways involved in neurodegenerative disorders. Metformin, an anti-hyperglycemic drug used for treating DM, has the potential to exert a significant neuroprotective role against the detrimental effects of DM. This review discusses recent clinical and laboratory studies investigating the neuroprotective properties of metformin against DM-induced neurodegeneration and the roles of various molecular pathways, including mitochondrial dysfunction, oxidative stress, inflammation, apoptosis, and its related cascades. A literature search was conducted from January 2000 to December 2022 using multiple databases including Web of Science, Wiley, Springer, PubMed, Elsevier Science Direct, Google Scholar, the Core Collection, Scopus, and the Cochrane Library to collect and evaluate peer-reviewed literature regarding the neuroprotective role of metformin against DM-induced neurodegenerative events. The literature search supports the conclusion that metformin is neuroprotective against DM-induced neuronal cell degeneration in both peripheral and central nervous systems, and this effect is likely mediated via modulation of oxidative stress, inflammation, and cell death pathways.

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Data availability

This manuscript is a review article with no unpublished research data included. All references are available upon request to the corresponding author.

Abbreviations

AChE/Ach:

Acetylcholinesterase/acetylcholine

AD:

Alzheimer disease

AGE:

Advanced glycation end products

ALS:

Amyotrophic lateral sclerosis

AMPK:

Adenosine monophosphate-activated protein kinase

AMPK/Tet2:

Adenosine monophosphate-activated protein kinase/Ten-eleven translocation-2

APP:

Amyloid precursor protein

AOPPs:

Advanced oxidation protein products

Bcl-2:

B-cell lymphoma 2

BDNF:

Brain derived neurotropic factor

BiP:

Binding immunoglobulin protein

CAT:

Catalase

CCL 2 and 20:

C–C Motif chemokine ligand 2 and 20

Cdk5:

Cyclin-dependent kinase 5

CHOP:

CCAAT-enhancer-binding protein homologous protein

ChREBP:

Carbohydrate-responsive element-binding protein

CMA:

Chaperone-mediated autophagy

CNS:

Central nervous system

CoA-SH:

Coenzyme A

COX-PG:

Cyclooxygenase-prostaglandin

cPLA2:

Cytosolic phospholipases A2

CREB:

CAMP response element-binding protein

CRP:

C-reactive protein

CXCL 5 or 7 or 12:

C-X-C motif chemokine ligand 5 or 7 or 5

DAP12:

12-Kilodalton DNAX activating protein (also known as TYROBP and KARAP)

DM:

Diabetes mellitus

eIF2α:

Eukaryotic initiation factor-2α

eNOS:

Endothelial nitric oxide synthase

EPM:

Elevated plus maze

ERK:

Extracellular signal-related kinase

EZM:

Elevated zero maze

FAAD:

Fas-associated death domain protein

FRAP:

FKBP-12-rapamycin associated protein (also known as mTOR and RAFT-1)

FST:

Forced swim test

GABAA:

γ-Aminobutyric acid A

GFAP:

Glial fibrillary acidic protein

GIP:

Glucose-dependent insulinotropic polypeptide

GLP-1:

Glucagon-like peptide-1

GM-CSF:

Colony-stimulating factor

GPx:

Glutathione peroxidase

GR:

Glutathione reductase

GRP94:

Glucose-regulated protein of 94 kDa

GSH:

Reduced form of glutathione

GSK3:

Glycogen synthase kinase 3 beta

GSSG:

Oxidized form of glutathione

HD:

Huntington disease

GST:

Glutathione S-transferase

HDL:

High density lipoprotein

HNE:

4-Hydroxynonenal

HPA:

Hypothalamic–pituitary–adrenal

IFN-γ:

Interferon gamma

IGF-1:

Insulin-like growth factor-1

IL:

Interleukin (1,2,3,4,5,6,7,8,9,10,11,12)

iNOS:

Inducible nitric oxide synthase

IRE1α:

Inositol-requiring transmembrane kinase/endoribonuclease 1α

IsoLGs:

Isolevuglandins

JAK/STAT:

Janus kinase (JAK)/signal transducer and activator of transcription (STAT)

LCAT:

Lecithin-cholesterol acyltransferase

LC3:

Microtubule-associated protein 1A/1B-light chain 3

LDL:

Low density lipoprotein

LKB1:

Liver kinase B1

MDA:

Malondialdehyde

MDD:

Major depressive disorder

MiR-141:

MicroRNA 141

MND:

Motor neuron disease

MOMP:

Mitochondrial outer membrane permeabilization

MS:

Multiple sclerosis

MSA:

Multiple system atrophy

mTORC1:

Mammalian target of rapamycin complex 1

MWM:

Morris water maze

NADPH/NAD+ :

Nicotinamide adenine dinucleotide phosphate/nicotinamide adenine dinucleotide

NGF:

Neural growth factor

NF-kb:

Nuclear factor κB

NO:

Nitric oxide

NORT:

Novel object recognition task

NOS-NO:

Nitric oxide synthase-nitric oxide

nNOS:

Neuronal nitric oxide synthase

NRF-1:

Nuclear respiratory factor 1

NSF:

Novelty suppressed feeding

OFT:

Open field test

OGT:

O-linked β-N-acetylglucosamine (O-GlcNAc) transferase

ONE:

4-Oxononenal

OSI:

Oxidative stress index

PARP:

Poly-ADP ribose polymerase

PD:

Parkinson disease

PDIA:

Protein disulfide-isomerase

PERK:

Protein kinase RNA-like endoplasmic reticulum kinase

Pit-1:

Pituitary transcriptional factor-1

PGC1α:

Peroxisome proliferator-activated receptor-gamma coactivator

PNS:

Peripheral nervous system

PON 1:

Serum paraoxonase and arylesterase 1

PP2A:

Protein phosphatase 2

PRD:

Pelvic radiation disease

Preb:

Prolactin regulatory element-binding

PTP:

Permeability transition pore

RAGE:

Receptor for advanced glycation end products

RAM:

Radial arm maze

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SCA:

Spinocerebellar ataxia

SIRT-SirT1:

Silent mating type information regulation 2 homolog

SMAC:

Second mitochondria-derived activator of caspase

SMA:

Spinal muscular atrophy

SOD:

Super oxide dismutase

ST:

Splash test

STZ :

Streptozotocin

TAC:

Total antioxidant capacity

TAS:

Total antioxidant status

TBARS:

Thiobarbituric acid reactive substances

TC:

Total cholesterol

Tfam:

Transcription factor A mitochondrial

TGF-β:

Transforming growth factor beta

TLRs:

Toll-like receptors

TNF-α:

Tumor necrosis factor alpha

TOS:

Total oxidant status

TREM-1:

Triggering receptor expressed on myeloid cells 1

TST:

Tail suspension tests

TRAIL:

Tumor necrosis factor-related apoptosis-inducing ligand

TXNIP:

Thioredoxin-interacting protein

ULK:

Unc-51-like autophagy activating kinase

VEGF:

Vascular endothelial growth factor

VLDL:

Very low density protein

XIAP:

X-linked inhibitor of apoptosis

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Authors and Affiliations

  1. Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Fatemeh Karami, Hamidreza Jamaati, Maryam Shokrian Zeini, Mina Gholami, Mohammad Darabi & Majid Motaghinejad

  2. Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, MN, 55108, USA

    Natalie Coleman-Fuller

  3. University of South Florida College of Public Health and Institute for Integrative Toxicology, Michigan State University, East Lansing, USA

    A. Wallace Hayes

  4. Cognitive and Neuroscience Research Center (CNRC), Amir-Almomenin Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran

    Mahsa Salehirad

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  1. Fatemeh Karami
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Contributions

Conceptualization: MM. Data curation: FK, HJ and MSZ. Formal analysis: AWH and NC-F. Funding acquisition: None declared. Investigation and methodology: MG and MD. Project administration: MM and HJ. Resources and software: MG. Design of figures: MG. Preparation of tables: MS. Supervision: MM. Validation, visualization, writing, review, and editing: MM, AWH, and NC-F.

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Correspondence to Majid Motaghinejad.

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Karami, F., Jamaati, H., Coleman-Fuller, N. et al. Is metformin neuroprotective against diabetes mellitus-induced neurodegeneration? An updated graphical review of molecular basis. Pharmacol. Rep 75, 511–543 (2023). https://doi.org/10.1007/s43440-023-00469-1

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  • DOI: https://doi.org/10.1007/s43440-023-00469-1

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