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Review
. 2020 Sep 4;9(9):830.
doi: 10.3390/antiox9090830.

Oxidative Stress and Neuroinflammation as a Pivot in Drug Abuse. A Focus on the Therapeutic Potential of Antioxidant and Anti-Inflammatory Agents and Biomolecules

Pablo Berríos-Cárcamo  1 , Mauricio Quezada  1 , María Elena Quintanilla  2 , Paola Morales  2   3 , Marcelo Ezquer  1 , Mario Herrera-Marschitz  2 , Yedy Israel  2 , Fernando Ezquer  1
Affiliations
Review

Oxidative Stress and Neuroinflammation as a Pivot in Drug Abuse. A Focus on the Therapeutic Potential of Antioxidant and Anti-Inflammatory Agents and Biomolecules

Pablo Berríos-Cárcamo et al. Antioxidants (Basel). .

Abstract

Drug abuse is a major global health and economic problem. However, there are no pharmacological treatments to effectively reduce the compulsive use of most drugs of abuse. Despite exerting different mechanisms of action, all drugs of abuse promote the activation of the brain reward system, with lasting neurobiological consequences that potentiate subsequent consumption. Recent evidence shows that the brain displays marked oxidative stress and neuroinflammation following chronic drug consumption. Brain oxidative stress and neuroinflammation disrupt glutamate homeostasis by impairing synaptic and extra-synaptic glutamate transport, reducing GLT-1, and system Xc- activities respectively, which increases glutamatergic neurotransmission. This effect consolidates the relapse-promoting effect of drug-related cues, thus sustaining drug craving and subsequent drug consumption. Recently, promising results as experimental treatments to reduce drug consumption and relapse have been shown by (i) antioxidant and anti-inflammatory synthetic molecules whose effects reach the brain; (ii) natural biomolecules secreted by mesenchymal stem cells that excel in antioxidant and anti-inflammatory properties, delivered via non-invasive intranasal administration to animal models of drug abuse and (iii) potent anti-inflammatory microRNAs and anti-miRNAs which target the microglia and reduce neuroinflammation and drug craving. In this review, we address the neurobiological consequences of brain oxidative stress and neuroinflammation that follow the chronic consumption of most drugs of abuse, and the current and potential therapeutic effects of antioxidants and anti-inflammatory agents and biomolecules to reduce these drug-induced alterations and to prevent relapse.

Keywords: drug addiction; neuroinflammation; oxidative stress; treatment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Drugs of abuse increase the levels of brain oxidative stress and trigger a self-perpetuating cycle that sustains neuroinflammation. Drugs of abuse promote the release of dopamine (DA), which is either rapidly spontaneously oxidized or metabolized via monoamine oxidase B (MAO-B) and cyclooxygenase 1/2 (COX1/2), generating superoxide ion and hydrogen peroxide, thus increasing oxidative stress. Oxidative stress generated by drugs of abuse can impair mitochondrial function, further increasing oxidative stress production. The rise in oxidative stress promotes the nuclear translocation and activation of NF-κB in microglia. Cocaine, ethanol, and opioids promote the activation of Toll-like receptor 4 (TLR4), which also activates microglial NF-κB. In the nucleus, NF-κB promotes the increase in the expression of the pro-oxidant enzymes NADPH-oxidase (NOX) and inducible nitric oxide synthase (iNOS), and of pro-inflammatory cytokines tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and monocyte chemoattractant protein-1 (MCP-1). The increase of oxidative stress and pro-inflammatory cytokines promote the activation of microglia and astrocytes via the activation of NF-κB directly or via additional mitochondrial impairment, which further perpetuates the brain oxidative stress and inflammation cycle.
Figure 2
Figure 2
The tripartite synapse and glutamate homeostasis. When glutamate homeostasis is maintained, GLT-1 removes glutamate from the synaptic cleft, and the glial system Xc− releases glutamate to the extrasynaptic location, which activates the inhibitory metabotropic glutamate receptors 2 and 3 (mGluR2/3) which inhibits synaptic glutamate release. Drugs of abuse alter glutamate homeostasis by increasing the levels of oxidative stress, which impair GLT-1 activity and reduce the activity of system Xc−. Both effects potentiate cued-induced increases in post-synaptic glutamate tone. Drugs of abuse also strengthen glutamatergic transmission by promoting the recruitment of Ca2+ permeable AMPA receptors (CP-AMPAR). Antioxidants like N-acetylcysteine (NAC) normalize glutamate homeostasis by increasing the levels of cystine, activating both the system Xc− and mGluR2/3, also increasing GSH and reducing oxidative stress, which recovers GLT-1 activity. Administration of secretome derived from mesenchymal stem cells (MSCs) also reduces drug consumption by reducing oxidative stress and recovering GLT-1 activity.
Figure 3
Figure 3
The effect of pro- and anti-inflammatory miRNA modulation in animal models of drug addiction. Ethanol consumption increases the levels of miR-155 and miR-146 in the cerebellum. Pro-inflammatory miR-155 expression promotes increases levels of pro-inflammatory cytokines and NF-κB activity and inhibits anti-inflammatory proteins like the suppressor of cytokine signaling (SOCS-1). Anti-inflammatory miR-124 microglial expression reduces pro-inflammatory cytokines, iNOS, and TLR4 levels; the effect that is inhibited in the striatum of animal models of cocaine or ethanol consumption.
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