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Neuroprotective effects of dimethyl fumarate against manic-like behavior induced by ketamine in rats

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Abstract

Medications for treating bipolar disorder (BD) are limited and can cause side effects if used chronically. Therefore, efforts are being made to use new agents in the control and treatment of BD. Considering the antioxidant and anti-inflammatory effects of dimethyl fumarate (DMF), this study was performed to examine the role of DMF on ketamine (KET)-induced manic-like behavior (MLB) in rats. Forty-eight rats were randomly divided into eight groups, including three groups of healthy rats: normal, lithium chloride (LiCl) (45 mg/kg, p.o.), and DMF (60 mg/kg, p.o.), and five groups of MLB rats: control, LiCl, and DMF (15, 30, and 60 mg/kg, p.o.), which received KET at a dose of 25 mg/kg, i.p. The levels of total sulfhydryl groups (total SH), thiobarbituric acid reactive substances (TBARS), nitric oxide (NO), and tumor necrosis factor-alpha (TNF-α), as well as the activity of antioxidant enzymes including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in the prefrontal cortex (PFC) and hippocampus (HPC), were measured. DMF prevented hyperlocomotion (HLM) induced by KET. It was found that DMF could inhibit the increase in the levels of TBARS, NO, and TNF-α in the HPC and PFC of the brain. Furthermore, by examining the amount of total SH and the activity of SOD, GPx, and CAT, it was found that DMF could prevent the reduction of the level of each of them in the brain HPC and PFC. DMF pretreatment improved the symptoms of the KET model of mania by reducing HLM, oxidative stress, and modulating inflammation.

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Data availability

The data generated and analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

AJUMS:

Ahvaz Jundishapur University of Medical Sciences

ANOVA:

Analysis of variance

BD:

Bipolar disorder

CAT:

Catalase

DMF:

Dimethyl fumarate

H2O2 :

Hydrogen peroxide

HLM:

Hyperlocomotion

HPC:

Hippocampus

i.p.:

Intraperitoneally

iNOS:

Inducible nitric oxide synthase

KET:

Ketamine

LiCl:

Lithium chloride

MLB:

Manic-like behavior

mitNOS:

Mitochondrial nitric oxide synthase

Nrf2:

Nuclear factor-erythroid 2-related factor 2

OS:

Oxidative stress

PBS:

Phosphate-buffered saline

PFC:

Prefrontal cortex

p.o.:

Per os

ROS:

Reactive oxygen species

SEM:

Standard error of the mean

SH:

Sulfhydryl

SOD:

Superoxide dismutase

TBARS:

Thiobarbituric acid reactive substances

TNF-α:

Tumor necrosis factor-alpha

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Funding

This paper is taken from the Pharm.D thesis of Shiva Saljoughi. The authors grateful to the Vice-Chancellor of Research, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran, for financial support (grant number: B-99001).

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Authors and Affiliations

  1. Medicinal Plant Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Shiva Saljoughi

  2. Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Hadi Kalantar, Reza Azadnasab & Mohammad Javad Khodayar

  3. Department of Toxicology, Faculty of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Hadi Kalantar, Reza Azadnasab & Mohammad Javad Khodayar

Authors
  1. Shiva Saljoughi
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  2. Hadi Kalantar
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  3. Reza Azadnasab
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  4. Mohammad Javad Khodayar
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Contributions

Shiva Saljoughi: methodology, investigation, data curation, writing—original draft. Hadi Kalantar: conceptualization, supervision. Reza Azadnasab: project administration, methodology, investigation, data curation, software. Mohammad Javad Khodayar: conceptualization, methodology, validation, writing—review and editing, supervision, project administration. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Mohammad Javad Khodayar.

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This research was conducted according to the instructions of the Animal Ethics Committee of Ahvaz Jundishapur University of Medical Sciences for the use and care of laboratory animals (Approval ID: IR.AJUMS.ABHC.REC.1399.003).

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Saljoughi, S., Kalantar, H., Azadnasab, R. et al. Neuroprotective effects of dimethyl fumarate against manic-like behavior induced by ketamine in rats. Naunyn-Schmiedeberg's Arch Pharmacol 396, 3007–3016 (2023). https://doi.org/10.1007/s00210-023-02505-6

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