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Targeting memory loss with aspirin, a molecular mechanism perspective for future therapeutic approaches

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Abstract

Acetylsalicylic acid (ASA), also known as aspirin, was discovered in 1897 as an acetylated form of salicylate. It has been widely used for its anti-inflammatory and antiplatelet effects. It is commonly used for its cardiovascular benefits and is prescribed as secondary prophylaxis after a heart attack. Furthermore, low-dose, long-term ASA is used to reduce the risk of heart attack and stroke in individuals without prior cardiovascular disease. Acetylsalicylic acid acts as a non-selective inhibitor of cyclooxygenase (COX), which inhibits the synthesis of prostaglandins and prevents pro-inflammatory cytokines. Findings suggest that targeting cytokines and growth factors could be a potential therapeutic strategy for reducing neuroinflammation and slowing down the progression of dementia. Additionally, prostaglandins contribute to synaptic plasticity and can act as retrograde messengers in synapses. Research has implicated COX-1, one of the isoforms of the enzyme, in neuroinflammation and neurodegenerative disorders. The inhibition of COX-1 might potentially prevent impairments in working memory and reduce neuroinflammation caused by beta-amyloid proteins in some conditions, such as Alzheimer’s disease (AD). Cyclooxygenase-2, an inducible form of the enzyme, is expressed in cortical and hippocampal neurons and is associated with long-term synaptic plasticity. The inhibition or knockout of COX-2 has been shown to decrease long-term potentiation, a process involved in memory formation. Studies have also demonstrated that the administration of COX-2 inhibitors impairs cognitive function and memory acquisition and recall in animal models. There remains a debate regarding the effects of aspirin on dementia and cognitive decline. Although some studies suggest a possible protective effect of non-steroidal anti-inflammatory drugs, including aspirin, against the development of AD, others have shown inconsistent evidence. This review provides an overview of the effects of ASA or its active metabolite salicylate on learning, memory, and synaptic plasticity.

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Abbreviations

COX:

Cyclooxygenase

PG:

Prostaglandins

ASICs:

Acid-sensing ion channels

ASA:

Acetylsalicylic acid

DAT:

Dementia of the Alzheimer's type

HD:

Huntington's disease

PD:

Parkinson's disease

AD:

Alzheimer’s disease

Aβ:

Amyloid-β

CNS:

Central nervous system

PD-D:

Parkinson’s disease dementia

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

MCI:

Mild cognitive impairment

AlCl3:

Aluminium trichloride

NSAIDs:

Non-steroidal anti-inflammatory drugs

RR:

Relative risk

RCT:

Randomized controlled trial

MMSE:

Mini-Mental State Examination

VD:

Vascular dementia

CHD:

Coronary heart disease

TFEB:

Transcription factor EB

PPARα:

Peroxisome proliferator-activated receptor alpha

5XFAD:

5X familial Alzheimer's disease

TXA2:

Thromboxane A2

NMDA:

N-Methyl-D-aspartate

HFS:

High-frequency stimulation

LTP:

Long-term potentiation

DG:

Dentate gyrus

siRNA:

Short interfering RNA

PP:

Perforant pathway

LPS:

Lipopolysaccharide

mEPSCs:

Miniature excitatory postsynaptic currents

CA1:

Cornu ammonis 1

TBS:

Theta burst stimulation

EP2:

PGE2 receptor 2 subtype

Gq:

G protein q

PLC:

Phospholipase C

IP3:

Inositol 1,4,5-trisphosphate

PTX:

Pertussis toxin

cAMP:

Cyclic adenosine monophosphate

EPSPs:

Excitatory postsynaptic potentials

PPI:

Paired-pulse index

PK:

Protein kinase

Gs:

G protein s

fEPSP:

Field excitatory postsynaptic potential

IL:

Interleukin

NF-κB:

Nuclear factor kappa-light-chain enhancer of activated B

Aβ1–40:

Amyloid β-Protein1–40

TNF-α:

Necrosis factor alpha

NFTs:

Neurofibrillary tangles

CREB:

cAMP response element-binding protein

LBD:

Ligand-binding domain

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

Tyr 314:

Tyrosine 314

TAU:

Tubulin associated unit

ROS:

Reactive oxygen species

MCP:

Monocyte chemo attractant protein

MIP:

Macrophage inflammatory protein

MEK:

Mitogen-activated protein kinase kinase

JNK:

C-Jun N-terminal kinase

ADAM:

Metalloprotease

TACE:

TNF-α converting enzyme

sAPP:

Soluble amyloid precursor protein

Th2:

T helper cell type 2

CCL:

C–C motif chemokine ligand

MCSFs:

Macrophage colony-stimulating factors

CSF:

Cerebrospinal fluid

NGF:

Nerve growth factors

VEGF:

Vascular endothelial growth factor

PNS:

Peripheral nervous system

INFs:

Interferons

CXCL10:

C-X-C motif ligand

CDK:

Cyclin-dependent kinase

ASA-CS:

Acetylsalicylic acid-chitosan-encapsulated drug delivery system

IHC:

Immunohistochemical analysis

LXA4:

Lipoxin A4

Aps:

β-Amyloid plaques

TR-FRET:

Time-resolved-Förster’s resonance energy transfer

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Authors and Affiliations

  1. Department of Physiology, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran

    Masoumeh Gholami, Mehdi Sadegh & Nahid Khodayari

  2. Department of Neuroscience, School of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran

    Masoumeh Koroush-arami

  3. Markey Cancer Center, University of Kentucky, Lexington, KY, USA

    Shaghayegh Norouzi

  4. Department of Urologic Surgery, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran

    Rasoul Jafari Arismani

  5. Medical Student, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran

    Erfan Asadi & Mohammad Amini

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  1. Masoumeh Gholami
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  2. Mehdi Sadegh
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  3. Masoumeh Koroush-arami
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  4. Shaghayegh Norouzi
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  6. Erfan Asadi
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  7. Mohammad Amini
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  8. Nahid Khodayari
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Contributions

MG, EA, MA and NK have gathered study data and written the manuscript. MG, MS, MK, SN, RJA have provided critical revision of final manuscript. MG have contributed to the study design. All authors approved the final version of the manuscript.

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Correspondence to Masoumeh Gholami.

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Gholami, M., Sadegh, M., Koroush-arami, M. et al. Targeting memory loss with aspirin, a molecular mechanism perspective for future therapeutic approaches. Inflammopharmacol 31, 2827–2842 (2023). https://doi.org/10.1007/s10787-023-01347-1

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