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Targeting Common Signaling Pathways for the Treatment of Stroke and Alzheimer’s: a Comprehensive Review

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Abstract

Neurodegenerative diseases such as stroke and Alzheimer’s disease (AD) are two inter-related disorders that affect the neurons in the brain and central nervous system. Alzheimer’s is a disease by undefined origin and causes. Stroke and its most common type, ischemic stroke (IS), occurs due to the blockade of cerebral blood vessels. As an important feature, both of disorders are associated with irreversible damages to the brain and nervous system. In this regard, finding common signaling pathways and the same molecular origin between these two diseases may be a promising way for their solution. On the basis of literature appraisal, the most common signaling cascades implicated in the pathogenesis of AD and stroke including notch, autophagy, inflammatory, and insulin signaling pathways were reviewed. Furthermore, current therapeutic strategies including natural and synthetic pharmaceuticals aiming modulation of respective signaling factors were scrutinized to ameliorate neural deficits in AD and stroke. Taken together, digging deeper in the common connections and signal targeting can be greatly helpful in understanding and unified treating of these disorders.

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Abbreviations

AD:

Alzheimer’s disease

AGEs:

Advanced glycosylation end products

AMPK:

AMP-activated protein kinase

aPKC:

Atypical protein kinase C

ApoE4:

Apolipoprotein E4

APP:

Amyloid precursor protein

ARE:

Antioxidant responsive element

ASC:

Apoptosis associated speck-like protein containing a caspase recruitment domain

BBB:

Blood-brain barrier

BDNF:

Brain-derived neurotrophic factor

ceRNA:

Competitive endogenous RNA

COX-2:

Cyclooxygenase

CXCL8:

Chemokine (C–X–C motif) ligand 8

DAMP:

DNA-binding/damage-associated molecular pattern

DSL:

Delta/serrate/LAG2

4EBP1:

4E binding protein 1

EPO:

Erythropoietin

ERKs:

Extracellular signal-regulated kinases

GAS5:

Growth arrest-specific 5

GLP-1:

Glucagon-like peptide-1

FPRL1:

Formyl peptide receptor-like 1

GFAP:

Glial fibrillary acidic protein

HLJDD:

Huang-Lian-Jie-Du-Decotion

HMGB-1:

High-mobility group protein 1

IBA-1:

Ionized calcium binding adapter molecule 1

IGFs:

Insulin-like growth factors

IL-1β:

Interleukin-1β

iNOS:

Inducible nitric oxide synthase

IS:

Ischemic stroke

IRAKs:

Interleukin-1 receptor-associated kinases

JNKs:

C-Jun NH2-terminal kinases

KKS:

Kallikrein-kinin system

LDL:

Low-density lipoproteins

5-LOX:

5-Lipoxygenase

Lrrfip1:

Leucine-rich repeat flightless-1 interaction protein 1

MAPKs:

Mitogen-activated protein kinases

MCAO:

Middle cerebral artery occlusion

MCAO:

Middle cerebral artery occlusion

MMP-9:

Matrix metalloproteinase 9

mTOR:

Mammalian target of rapamycin

MyD88:

Myeloid differentiation primary response protein 88

NICD:

Notch intracellular domain

NLRP3:

NOD-like receptor pyrin domain-containing 3 protein

NR4A2:

Nuclear receptor subfamily 4 group A member 2

Nrf2:

Nuclear erythroid 2-related factor 2

PAEs:

Purified anthocyanin extracts

PKA:

Protein kinase A

PKC:

Protein kinase C

p70S6K:

Ribosomal protein S6 kinase beta-1

PPAR-α:

Peroxisome proliferator-activated receptor-α

ROS:

Reactive oxygen species

SAAT2:

Excitatory amino acid transporter subtype 2

TCA:

Trans-cinnamaldehyde

TK:

Tissue kallikrein

TLRs:

Toll-like receptors

TNF-α:

Tumor necrosis factor-α

ULK1:

Unc-51-like kinase 1

XIAP:

X-linked inhibitor of apoptosis

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This study was funded by Kermanshah University of Medical Sciences, Kermanshah, Iran.

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Authors and Affiliations

  1. Pharmaceutical Science Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Sedigheh Eskandari

  2. Department of Biology, Faculty of Science, Razi University, Kermanshah, Iran

    Soraya Sajadimajd

  3. Department of Biology and Biotechnology, Faculty of Sciences, University of Kurdistan, Sanandaj, Iran

    Loghman Alaei

  4. Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran

    Zhaleh Soheilikhah & Hossein Derakhshankhah

  5. Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran

    Gholamreza Bahrami

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  1. Sedigheh Eskandari
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Eskandari, S., Sajadimajd, S., Alaei, L. et al. Targeting Common Signaling Pathways for the Treatment of Stroke and Alzheimer’s: a Comprehensive Review. Neurotox Res 39, 1589–1612 (2021). https://doi.org/10.1007/s12640-021-00381-7

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