Elsevier

Life Sciences

Volume 253, 15 July 2020, 117703
Life Sciences

Vitamin D3 attenuates lipopolysaccharide-induced cognitive impairment in rats by inhibiting inflammation and oxidative stress

https://doi.org/10.1016/j.lfs.2020.117703Get rights and content

Abstract

Aims

Vitamin D is a well-known endocrine regulator of calcium/phosphate homeostasis and has been reported as having a wide range of activities that are potentially beneficial for human health. This study aimed to investigate the effects of pretreatment of vitamin D3 (100, 1000, and 10,000 IU/kg) against lipopolysaccharide (LPS)-induced cognitive impairment in rats.

Main methods

Male Wistar rats were divided into five groups. The passive avoidance test and Morris water maze (MWM) test were conducted to evaluate the learning and memory function. Oxidative stress markers including malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), total thiol content as well as interleukin (IL)-6 were evaluated in the hippocampus tissue.

Key findings

The intraperitoneal (i.p.) injection of LPS (1 mg/kg) correlates with deficits in passive avoidance and spatial learning in the systemic inflammation model. However, pretreatment with vitamin D3 improved LPS-induced cognitive impairment. In addition, vitamin D3 decreased IL-6 and MDA levels, whereas the activities of CAT, SOD, and total thiol content in the hippocampus tissue were significantly increased.

Significance

In conclusion, our results suggest that vitamin D3 plays a protective role against memory dysfunction caused by LPS-induced inflammation through inhibition of oxidative stress and inflammation in the hippocampus. Vitamin D may be a promising potential therapeutic supplement for the treatment or prevention of learning and memory disorders.

Introduction

Many organisms are frequently subjected to various harmful stimuli during the lifetime. Inflammation is a protective response triggered by tissue damage or bacterial infection [1]. The acute inflammatory response is usually beneficial, while chronic inflammation, non-resolving inflammation, contributes to the progression of neurological diseases [1,2]. Nowadays, it is clear that the brain is involved in the inflammatory response. It has been demonstrated that the peripheral and central immune systems closely linked with each other, in which peripheral inflammation produces a mirror inflammatory reaction in the brain [3].

Inflammation in the nervous system, neuroinflammation, has been considered a major component in the pathophysiology of chronic neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) [4]. It has been suggested that neuroinflammation is involved in the progression of cognitive impairment and AD [5]. Lipopolysaccharide (LPS), known as endotoxin, is an endotoxin from gram-negative bacteria that activates the innate immune response. Systemic administration of LPS not only elicits peripheral an innate immune response but also affects the central nervous system through activation of the proinflammatory cytokines, such as interleukin 6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) signaling in the brain [6]. Systemic exposure to LPS, as a laboratory model of neuroinflammation, is resulted in cognitive impairment by inducing neuroinflammation and oxidative stress in the brain [7]. Therefore, controlling brain oxidative stress and inflammation can be a therapeutic strategy for LPS-induced memory decline.

Vitamin D (D represents D2, D3, or both) is a fat-soluble vitamin generated endogenously in the skin from sun exposure as well as obtained from foods that contain vitamin D [8]. Vitamin D3 (cholecalciferol), as produced in the skin, is inactive, so transported through the bloodstream bound to vitamin D binding protein (DBP) and hydroxylated in the liver to 25-hydroxy vitamin D3 (25-(OH)D3) and further in the kidney to the biologically active form of vitamin D (1α,25(OH)2D3 or calcitriol) [8]. The 1α,25(OH)2D3 in the circulation, bind and activate the vitamin D receptor (VDR) to perform its biologic functions. The wide distribution of VDR suggests that vitamin D contributing to several physiological pathways including brain development, neurological functions, immunomodulation, oxidative stress, and apoptosis.

Mounting evidence indicates that the 1,25(OH)2D3 exerts neuroprotective effects through stimulation of amyloid-β (Aβ) clearance by macrophages of patients with AD [9]. In addition, experimental studies have shown that vitamin D is associated with cognition, and it has been shown that supplementation with vitamin D enhances learning and memory in aged animals [10,11]. The neuroprotective effect of vitamin D is multidimensional, ranging from antioxidant [12], anti-inflammatory [13], and effects to enhance the expression of neurotropic factors, particularly in the hippocampus [14]. These observations suggest that vitamin D3 may reduce the risk of cognitive deficits and AD. However, it remains unknown whether pretreatment with vitamin D3 could improve LPS impaired hippocampus-dependent learning and memory in rats.

In this study, we aim to know how vitamin D3 could exert its potential protecting effects on cognitive functions and examine the effects on modulating the hippocampal levels of oxidant and antioxidant markers and IL-6 by pretreating rats with vitamin D3 before induction of systemic inflammation in rats.

Section snippets

Animals

Male Wistar rats 8 weeks of age and weighing 180-190 g at the beginning of experiments were used in the study. All the rats were housed in plastic cages and maintained in standard conditions of temperature (22 °C ± 2) with a 12–12 h light-dark schedule. Food and water were made available ad libitum. All experiments were approved by the Ethics committee of the AJA University of Medical Sciences (Ethical approval number IR.AJAUMS.REC.1398.089).

Drugs and chemicals

LPS (Escherichia coli serotype O55:B5) was purchased

Spatial learning and memory in the MWM test

Rats in the LPS group displayed significantly longer escape latency and path length to find a hidden platform as compared to the control rats at training days (P < 0.01–0.001), implying learning deficits in the LPS treated rats (Fig. 2A, B). In contrast, rats in the VitD3 1000 group (P < 0.05–0.01) and the VitD310000 group (P < 0.05–0.001), displayed a profoundly shorter latency time and path length has compared to those in the LPS group. Moreover, rats in the VitD3100 group did not show

Discussion

The present study is the first research demonstrating that vitamin D3 could ameliorate cognitive deficits in the LPS-treated rats. Moreover, vitamin D3 decreased the hippocampal content of IL-6 and MDA as well as increased hippocampal levels of total thiol, SOD, and CAT activity, suggesting that antioxidant and anti-inflammatory properties of vitamin D3 might account for the cognitive improvement of vitamin D3.

Previous studies have demonstrated that LPS administration could lead to learning and

Conclusion

To sum up, the current research revealed that vitamin D3 treatment attenuated the LPS-initiated memory (spatial and passive avoidance) impairment as well as oxidative stress and inflammation response in the hippocampus. These results suggest that the protective effects of vitamin D3 on LPS-induced cognitive impairments are associated with promoting the levels of antioxidant enzymes and immune parameters in the brain. Additional experimental and clinical studies will be required to assess the

Declaration of competing interest

The authors declare that they have no competing interests.

Acknowledgments

This research was supported by the research project of the AJA University of Medical Sciences (Grant Number: 97000698).

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