Elsevier

Life Sciences

Volume 212, 1 November 2018, Pages 9-19
Life Sciences

HTLV-1 infection-induced motor dysfunction, memory impairment, depression, and brain tissues oxidative damage in female BALB/c mice

https://doi.org/10.1016/j.lfs.2018.09.031Get rights and content

Abstract

Aims

The HTLV-1 infection is associated with a neuro-inflammatory disease. In the present study, the behavioral consequences and brain oxidative damages were evaluated in HTLV-1-infected BALB/c mice.

Material and methods

20 female BALB/c mice were divided into two groups comprising control and HTLV-1-infected. The HTLV-1-infected group was inoculated with a 106 MT-2 HTLV-1-infected cell line. Two months later, the behavioral tests were conducted. Finally, oxidative stress was assessed in the cortex and hippocampus tissues.

Key findings

In the HTLV-1-infected group, running time and latency to fall, travel distance and time spent in the peripheral zone, total crossing number and total traveled distance in open field test, the latency of entrance into the dark compartment in the passive avoidance test, the new object exploration percentage, and discrimination ratio were significantly lower than in the control group. The immobility time, time spent in the dark compartment in passive avoidance test, and total exploration time significantly increased in the HTLV-1-infected group compared to the control group. In the cortical tissue of the HTLV-1 group, the malondialdehyde levels were elevated while the total thiol levels decreased in comparison to the control group. The activity of superoxide dismutase in the cortical and hippocampal tissues, and catalase activity in cortical tissue significantly decreased in the HTLV-1 group in comparison to the control group.

Significance

The HTLV-1 infection seems to induce depression-like behavior, motor dysfunction, disruption in working and fear memory and also oxidative stress in the cortex and hippocampus.

Introduction

Human T-lymphotropic virus (HTLV)-1-infection causes two life-threatening diseases, adult T cell leukemia/lymphoma (ATLL) and HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HAM/TSP is a progressive neuroinflammatory disease with motor disabilities due to chronic progressive myelopathy [1,2]. White matter lesions on magnetic resonance imaging (MRI) are frequently seen in the brain of HTLV-1 carriers [3]. It has been reported that asymptomatic HTLV-1 carriers and patients diagnosed with HAM/TSP exhibit higher levels of depression and cognitive impairment than normal controls [4,5]. Some of the cognitive impairments in HAM/TSP patients were associated with motor weakness [4].

It is well known that the hippocampus plays a critical role in cognitive function, therefore the neurodegenerative changes within the hippocampus result in cognitive impairment [6]. Oxidative stress has a crucial role in the development of learning and memory impairments [7,8]. Oxidant radicals contribute to augmented neuronal death in many brain regions, such as the hippocampus, through peroxidation of the membrane lipids, damage to DNA, and protein oxidation [9]. In HTLV-1-infected patients, the total antioxidant capacity in the serum was seen to be significantly reduced, thus indicating that oxidative stress may have a role in the pathogenesis of HTLV-1 [10].

Previous studies indicated that HTLV-1 Tax oncoprotein stimulates reactive oxygen species (ROS) production, apoptosis and cellular DNA damage [[11], [12], [13]]. Câmara et al. demonstrated that in HTLV-1-infected rats, motor behavioral abnormalities and spastic paraparesis in association with the degree of HTLV-1 induced myelopathy; however, the results for serum and peripheral blood mononuclear cells (PBMCs) by polymerase chain reaction (PCR) in rats infected with HTLV-1 MT-2 cells were negative.

Despite, evidences in inducing behavioral deficits in other members of retrovirus family like HIV [14,15], studies regarding the behavioral consequences of HTLV-1 infection is rare. Therefore, in the present study, the behavioral abnormalities in HTLV-1-infected BALB/c mice as well as the oxidative stress markers in the brain tissues were investigated.

Section snippets

Cells

MT-2 (ECACC 08081401), a HTLV-1-infected human T-cell line, was cultured in RPMI-1640 (Caisson, U.S.A) medium supplemented with 10% fetal bovine serum, 0.1% penicillin/streptomycin and 1% l‑glutamine (Gibco, U.K).

Animals

20 adolescent female BALB/c mice (4–6 weeks old, weighing 20–30 g) were housed under normal laboratory conditions at 23 ± 1 °C with a controlled 12-h light/dark cycle and free access to standard food and tap water. The experiments were conducted in accordance with the guiding

The provirus load in PBMCs, splenocytes and mesenteric nodes

The PVL results confirmed infection due to HTLV-1 according to the CTs of amplified HTLV-1 DNA via real time PCR in PBMCs, splenocytes, and mesenteric nodes. Furthermore, since there were no positive results for the human albumin in real-time PCR (TaqMan method) after 45 cycles, these PBMCs were HTLV-1-infected mouse leukocytes. The mean difference of CTs between the groups for the PBMCs, splenocytes, and mesenteric nodes was significant; the CTs mean in the mesenteric nodes was higher than in

Discussion

The HTLV-1 infection in humans is associated with HAM/TSP and ATLL in 2–5% of infected people, in which the prevalence of HAM/TSP in women is two to three times more than men [35]. The HTLV-1 targets the TCD4+ cells and deteriorates the activities of the adaptive immune system inducing autoimmunity in the central nervous system towards HAM/TSP manifestations. The qRT-PCR results of the present study showed that the PBMCs of the mice were infected with HTLV-1 as there was no inoculated human

Conclusion

The results of the present experimental study have demonstrated that a HTLV-1 infection is more likely to induce HAM/TSP-like disease and cause locomotion and memory impairments apart from depression-like behavior in mice. Moreover, as one of the animals in the present study developed progressive HAM/TSP, as confirmed by two neurologists, resulting in death, it can induce severe CNS damages similar to that in humans with the same frequency.

The present study findings might be demonstrated that

Conflict of interest

The authors have no conflict of interest.

Acknowledgments

This work was supported by the Research Council of Mashhad University of Medical Sciences. The results presented in this study were part of a PhD student's thesis.

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