Abstract

Many medications exhibit clinical benefits that are unrelated to their primary therapeutic uses. In many cases, the mechanisms underpinning these pleotropic effects are unknown. Two commonly prescribed medications that exhibit pleotropic benefits in cardiovascular disease and other diseases associated with chronic inflammation are methotrexate (MTX) and doxycycline (DOX). The vast majority of cardiovascular disease is associated with atherosclerosis. Because atherosclerosis is a chronic inflammatory disease, possible mechanisms by which MTX and DOX reduce inflammation have been investigated. Interestingly, the primary structure of both of these medications contain aromatic phenolic rings, which resemble polyphenols that are known to possess antioxidant activity. Inflammation and oxidative stress are intimately related. Inflammation promotes oxidative stress, which in turn leads to further inflammation; in this way, oxidative stress and inflammation can establish a self-perpetuating cycle. It has been shown that MTX and DOX act as antioxidants and are capable of scavenging free radicals and the reactive oxygen species (ROS) superoxide (O2 [rad]). Furthermore, both MTX and DOX inhibit the formation of malondialdehyde acetaldehyde (MAA) adducts, products of oxidative stress and lipid peroxidation. Importantly, MAA-adducts are highly immunogenic and initiate inflammatory responses; thereby, fueling the cycle of inflammation and oxidative stress that results in chronic inflammation. Thus, reducing the formation of MAA-adducts may ameliorate inflammation that leads to ROS production and in this way, break the self-sustaining cycle of oxidative stress and inflammation. It is possible that the under-recognized antioxidant properties of these medications may be a mechanism by which they and other medications provide pleotropic benefit in the treatment of chronic inflammatory disease.

Original languageEnglish (US)
Article number107413
JournalPharmacology and Therapeutics
Volume205
DOIs
StatePublished - Jan 2020

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Doxycycline
Methotrexate
Cardiovascular Diseases
Antioxidants
Inflammation
Oxidative Stress
Acetaldehyde
Malondialdehyde
Reactive Oxygen Species
Atherosclerosis
Chronic Disease
Polyphenols
Therapeutic Uses
Superoxides
Lipid Peroxidation
Free Radicals

Keywords

  • Cardiovascular disease
  • Doxycycline
  • Inflammation
  • Methotrexate
  • Oxidative stress
  • Reactive oxygen species

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

@article{1cd74eb9411a4d7fb6801413739f4d37,
title = "Relevance of the antioxidant properties of methotrexate and doxycycline to their treatment of cardiovascular disease",
abstract = "Many medications exhibit clinical benefits that are unrelated to their primary therapeutic uses. In many cases, the mechanisms underpinning these pleotropic effects are unknown. Two commonly prescribed medications that exhibit pleotropic benefits in cardiovascular disease and other diseases associated with chronic inflammation are methotrexate (MTX) and doxycycline (DOX). The vast majority of cardiovascular disease is associated with atherosclerosis. Because atherosclerosis is a chronic inflammatory disease, possible mechanisms by which MTX and DOX reduce inflammation have been investigated. Interestingly, the primary structure of both of these medications contain aromatic phenolic rings, which resemble polyphenols that are known to possess antioxidant activity. Inflammation and oxidative stress are intimately related. Inflammation promotes oxidative stress, which in turn leads to further inflammation; in this way, oxidative stress and inflammation can establish a self-perpetuating cycle. It has been shown that MTX and DOX act as antioxidants and are capable of scavenging free radicals and the reactive oxygen species (ROS) superoxide (O2 [rad]−). Furthermore, both MTX and DOX inhibit the formation of malondialdehyde acetaldehyde (MAA) adducts, products of oxidative stress and lipid peroxidation. Importantly, MAA-adducts are highly immunogenic and initiate inflammatory responses; thereby, fueling the cycle of inflammation and oxidative stress that results in chronic inflammation. Thus, reducing the formation of MAA-adducts may ameliorate inflammation that leads to ROS production and in this way, break the self-sustaining cycle of oxidative stress and inflammation. It is possible that the under-recognized antioxidant properties of these medications may be a mechanism by which they and other medications provide pleotropic benefit in the treatment of chronic inflammatory disease.",
keywords = "Cardiovascular disease, Doxycycline, Inflammation, Methotrexate, Oxidative stress, Reactive oxygen species",
author = "Clemens, {Dahn L.} and Duryee, {Michael J.} and Hall, {Johnathan H.} and Thiele, {Geoffrey M.} and Mikuls, {Ted R.} and Klassen, {Lynell W.} and Zimmerman, {Matthew C.} and Anderson, {Daniel R.}",
year = "2020",
month = "1",
doi = "10.1016/j.pharmthera.2019.107413",
language = "English (US)",
volume = "205",
journal = "Pharmacology and Therapeutics",
issn = "0163-7258",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Relevance of the antioxidant properties of methotrexate and doxycycline to their treatment of cardiovascular disease

AU - Clemens, Dahn L.

AU - Duryee, Michael J.

AU - Hall, Johnathan H.

AU - Thiele, Geoffrey M.

AU - Mikuls, Ted R.

AU - Klassen, Lynell W.

AU - Zimmerman, Matthew C.

AU - Anderson, Daniel R.

PY - 2020/1

Y1 - 2020/1

N2 - Many medications exhibit clinical benefits that are unrelated to their primary therapeutic uses. In many cases, the mechanisms underpinning these pleotropic effects are unknown. Two commonly prescribed medications that exhibit pleotropic benefits in cardiovascular disease and other diseases associated with chronic inflammation are methotrexate (MTX) and doxycycline (DOX). The vast majority of cardiovascular disease is associated with atherosclerosis. Because atherosclerosis is a chronic inflammatory disease, possible mechanisms by which MTX and DOX reduce inflammation have been investigated. Interestingly, the primary structure of both of these medications contain aromatic phenolic rings, which resemble polyphenols that are known to possess antioxidant activity. Inflammation and oxidative stress are intimately related. Inflammation promotes oxidative stress, which in turn leads to further inflammation; in this way, oxidative stress and inflammation can establish a self-perpetuating cycle. It has been shown that MTX and DOX act as antioxidants and are capable of scavenging free radicals and the reactive oxygen species (ROS) superoxide (O2 [rad]−). Furthermore, both MTX and DOX inhibit the formation of malondialdehyde acetaldehyde (MAA) adducts, products of oxidative stress and lipid peroxidation. Importantly, MAA-adducts are highly immunogenic and initiate inflammatory responses; thereby, fueling the cycle of inflammation and oxidative stress that results in chronic inflammation. Thus, reducing the formation of MAA-adducts may ameliorate inflammation that leads to ROS production and in this way, break the self-sustaining cycle of oxidative stress and inflammation. It is possible that the under-recognized antioxidant properties of these medications may be a mechanism by which they and other medications provide pleotropic benefit in the treatment of chronic inflammatory disease.

AB - Many medications exhibit clinical benefits that are unrelated to their primary therapeutic uses. In many cases, the mechanisms underpinning these pleotropic effects are unknown. Two commonly prescribed medications that exhibit pleotropic benefits in cardiovascular disease and other diseases associated with chronic inflammation are methotrexate (MTX) and doxycycline (DOX). The vast majority of cardiovascular disease is associated with atherosclerosis. Because atherosclerosis is a chronic inflammatory disease, possible mechanisms by which MTX and DOX reduce inflammation have been investigated. Interestingly, the primary structure of both of these medications contain aromatic phenolic rings, which resemble polyphenols that are known to possess antioxidant activity. Inflammation and oxidative stress are intimately related. Inflammation promotes oxidative stress, which in turn leads to further inflammation; in this way, oxidative stress and inflammation can establish a self-perpetuating cycle. It has been shown that MTX and DOX act as antioxidants and are capable of scavenging free radicals and the reactive oxygen species (ROS) superoxide (O2 [rad]−). Furthermore, both MTX and DOX inhibit the formation of malondialdehyde acetaldehyde (MAA) adducts, products of oxidative stress and lipid peroxidation. Importantly, MAA-adducts are highly immunogenic and initiate inflammatory responses; thereby, fueling the cycle of inflammation and oxidative stress that results in chronic inflammation. Thus, reducing the formation of MAA-adducts may ameliorate inflammation that leads to ROS production and in this way, break the self-sustaining cycle of oxidative stress and inflammation. It is possible that the under-recognized antioxidant properties of these medications may be a mechanism by which they and other medications provide pleotropic benefit in the treatment of chronic inflammatory disease.

KW - Cardiovascular disease

KW - Doxycycline

KW - Inflammation

KW - Methotrexate

KW - Oxidative stress

KW - Reactive oxygen species

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U2 - 10.1016/j.pharmthera.2019.107413

DO - 10.1016/j.pharmthera.2019.107413

M3 - Review article

C2 - 31626869

AN - SCOPUS:85074329579

VL - 205

JO - Pharmacology and Therapeutics

JF - Pharmacology and Therapeutics

SN - 0163-7258

M1 - 107413

ER -