The effects of thymoquinone on hippocampal cytokine level, brain oxidative stress status and memory deficits induced by lipopolysaccharide in rats

doi:10.1016/j.cyto.2017.04.015

Cytokine

Volume 96, August 2017, Pages 173-184

https://doi.org/10.1016/j.cyto.2017.04.015 Get rights and content

Abstract

Objective

The study objective was to determine the protective effects of thymoquinone (TQ) on brain tissues oxidative stress status, hippocampal cytokine level, and learning and memory deficits induced by lipopolysaccharide (LPS) in rats.

Methods

Animals were randomly divided into the following groups and treated: (1) Control (saline), (2) LPS (1 mg/kg i.p.), (3–5) 2, 5 or 10 mg/kg TQ extract 30 min before LPS injection. The treatment was started since two weeks before the behavioral experiments and continued during the behavioral tests (LPS injected 2 h before each behavioral experiment). Finally, the brains were removed for biochemical assessments.

Results

Morris water maze (MWM) test results showed that LPS increased escape latency compared to control group whereas TQ decreased them vs. LPS group. In passive avoidance (PA) test, LPS reduced the latency to enter the dark compartment vs. control group, while TQ treatment attenuated this effect of LPS. Additionally, LPS increased interleukin-6 (IL-6) and tumor necrosis alpha (TNF-α) in the hippocampal tissues. It also elevated malondialdehyde (MDA) and nitric oxide (NO) metabolites and decreased thiol content, superoxide dismutase (SOD) and catalase (CAT) in both hippocampus and cortex vs. control group, while TQ decreased IL-6, TNF-α, MDA and NO metabolites and increased thiol content, SOD and CAT compared to LPS group.

Conclusion

Findings of current study indicated that TQ improved LPS-induced learning and memory impairments induced by LPS in rats by attenuating the hippocampal cytokine levels and brain tissues oxidative damage.

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, which is associated with memory and cognitive impairments especially in the elderly population. A relationship between neuroinflammation and neurodegenerative diseases such as AD has been well documented. There are many evidence showing the significant influence of immune systems on mental functions such as learning, memory and neuronal plasticity [1]. Additionally, inflammation has been evidenced as a major reasons of disturbed learning and memory [2], [3]. On the other hand, systemic inflammation has been reported to be accompanied with oxidative stress status, which the later also has a critical role in memory and learning impairments [4]. Previous findings showed that inflammation may cause dysfunction in central cholinergic system in both hippocampal tissues and cerebral cortex in rats [5]. On the other hand researcher found that acetylcholine receptor antagonists have a detrimental effect on memory and this fact was emphasized by studding on Alzheimer's patient [6].

Tissue damages and infection through activating of microglia can increase proinflammatory cytokines and mediators specially in hippocampus and eventually by neuronal dysfunction and defects in cell proliferation and differentiation of the neuronal progenitor cells can lead to suppressing of neurogenesis, memory, learning and long term potentiation (LTP) [7]. In addition, many studies have shown that inflammation induced by lipopolysaccharide (LPS) resulted in learning and memory impairments through releasing of pro-inflammatory cytokines and inducing of reactive oxygen species (ROS) production [8], [9]. There is also a good confirmation that oxidative stress contribute in the central nervous system (CNS) disorder pathogenesis and also in learning and memory impairments [10].

Thus it is suggested that protecting against the oxidative injury and use of agents with antioxidant, anti-inflammatory and acetyl cholinesterase (AchE) inhibitory properties can reverse the memory impairment. So researcher found that thymoquinone (TQ), the most active component of the volatile oil of Nigella sativa seed, is one of this agent and exert anti-inflammatory and neuroprotective effects [11], [12]. Traditionally and experimentally, Nigella sativa and TQ have been used for their therapeutic effects on many degenerative diseases like Parkinson, AD and schizophrenia [13], [14], [15]. Therefore, in the current study we aimed the effects of TQ on LPS induced learning and memory impairments, hippocampal cytokine level and brain tissues oxidative damage in rats.

Section snippets

Animals

Twelve weeks-old male Wistar rats (240 ± 10 g) were purchased from local animal house located in Mashhad University of Medical Sciences, then accommodated in groups of 5 in individually ventilated cages and kept under standard conditions (temperature 22 ± 2 °C, humidity of 54 ± 2% and 12 h light/dark cycle). Food and water were freely available. The Ethical Committee of Animal Research approved the experimental procedures.

Chemicals and groups

LPS (Sigma-Aldrich Chemical Co) freshly dissolved in sterile saline prior to

The results of Morris water maze

According to the results of MWM test, training was associated with a reduction in the escape latency in all animals. Fig. 1A demonstrates a significant difference in the elapsed time across the 5-day training period between LPS and control groups (P < 0.05–P < 0.01). Additionally, MWM results demonstrated that the animals of LPS group didn’t remember location of the platform when they were examined in the probe trial. The LPS group spent lower time in the target quadrant compared to control group (P

Discussion

The present investigation aimed at elucidating mechanistically the possible protective effects of TQ against LPS-induced spatial and non-spatial memory impairments in rats. Although different mechanisms may contribute to create memory impairment, it has been clarified in recent years that inflammation plays a key roles in this process [22]. Inflammation of the brain has been suggested to induce tissue damages through increasing of activity of microglia and astrocytes in the brain [23]. LPS, the

Conclusion

In conclusion, the results of current study indicated that TQ improves learning and memory impairments induced by LPS in rats. Moreover, the effects of TQ are accompanied with attenuating hippocampal cytokine levels and improving of oxidative damage biomarkers in the brain tissues.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgments

The results are part of a M.Sc. student’s thesis. The authors appreciate the Vice Chancellor for Research and Technology, Mashhad University of Medical Sciences for financial support (grant No. 940755).

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The effects of thymoquinone on hippocampal cytokine level, brain oxidative stress status and memory deficits induced by lipopolysaccharide in rats

Abstract

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Animals

Chemicals and groups

The results of Morris water maze

Discussion

Conclusion

Conflict of interest

Acknowledgments

Brain Behav. Immun.

Brain Behav. Immun.

Biol. Psychiat.

World Neurosurg.

Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease

Free Radical Biol. Med.

Methods Enzymol.

Methods Enzymol.

Brain Behav. Immun.

Pharmacol. Biochem. Behav.

Neurosci. Res.

Neurobiol. Aging

Behav. Brain Res.

Pharmacol. Ther.

Int. J. Biochem. Cell Biol.

Ageing Res. Rev.

Free Radical Biol. Med.

Neurobiol. Aging

Brain Res.

Behav. Brain Res.

J. Tradit. Complement Med.

J. Tradit. Complement. Med.

HPB

Int. Immunopharmacol.

Chem. Biol. Interact.

Pharmacol. Rep.

J. Neuroimmunol.

Int. Immunopharmacol.

Biomed. Pharmacother.

Life Sci.

Neurobiol. Aging

Stress and memory: a selective review on recent developments in the understanding of stress hormone effects on memory and their clinical relevance

J. Neuroendocrinol.

Brain region-specific alterations in the gene expression of cytokines, immune cell markers and cholinergic system components during peripheral endotoxin-induced inflammation

Mol. Med.

Cholinergic imaging in dementia spectrum disorders

Eur J Nucl Med Mol Imag