Effects of chronic hypoxia on the expression of seladin-1/Tuj1 and the number of dark neurons of hippocampus
Introduction
Hypoxia can damage the blood-brain-barrier by opening tight junctions and increasing its permeability for unicellular and cellular components such as pro-inflammatory cytokines like interleukin-1β (IL-1β), IL-6, IL-10 and tumor necrosis factor (TNF-α) (Heneka et al., 2015a; Zhang and Le, 2010). Inflammatory processes include the proliferation and activity of astrocytes and glial cells as well as the strong activation of the complement system and enhance expression of cytokines (Holmes et al., 2009). A chronic inflammatory neurological condition that occurs following injury to nervous tissue, the disease has been reported in neurodegenerative diseases such as Alzheimer's (Hampel, 2012; Holmes et al., 2009). Neuroinflammation, as an advanced manufacturing process of proinflammatory cytokines (Honarvar et al., 2016), in its acute phase is beneficial to combate pathogens and tissue repair (Zhu et al., 2017). However, chronic neuroinflammatory responses that are triggered by the immune response and inflammatory responses can mediate brain neurodegeneration (Dong and Benveniste, 2001; Heneka et al., 2015b).
There are clinical evidences that hypoxic conditions promote cognitive dysfunction and Alzheimer's disease can increase risk factors for cardiovascular disease (de la Torre, 2012). AD is a dynamic metabolic and neurodegenerative disorder characterized by cerebrovascular and blood–brain barrier (BBB) dysfunction (Di Marco et al., 2015; Zhang and Le, 2010). In addition to neuronal loss, mainly in the cortex and hippocampus (Abolhassani et al., 2017), a progressive loss of memory (dementia) and decline in cognitive functions have been reported (Ashaari et al., 2018; Zhu et al., 2017). Pathological features of AD include accumulation of intracellular neurofibrillary tangles (consist of hyper-phosphorylated microtubule-associated protein called tau), acceleration of extracellular beta amyloid plaques (Aβ) (produced from the amyloid precursor protein [APP]) and up-regulation of β-site APP cleaving enzyme 1 (BACE1)(Bell and Zlokovic, 2009; Liu and Le, 2014). Aβs, which are surrounded by active astrocytes and microglia, initiate inflammatory reactions (Pimplikar et al., 2010; Swerdlow, 2007). Also, it has been shown that seladin-1 as a neuroprotective gene is down-regulated in AD-affected brain regions (Hassanzadeh et al., 2016). Reduction of Seladin-1 due to impaired insulin signaling may have an important role in the AD pathogenesis (Kazkayasi et al., 2016). Seladin-1 is founded in the central nervous system of mammalian (Greeve et al., 2000) and many functions have been attributed to this protein such as balance in plasma membrane cholesterol, regulation of cellular responses against oxidative stress, apoptotic signaling, and inflammatory reaction control (Bloch, 1983). Plus, Tuj1 is a specific factor in neurons that dramatically decreases when neurons are harmed and can be used in neuroscience research to prove neuronal damage (Zhu et al., 2018).
To identify the common causes of neurodegenerative diseases such as AD, it is thought that not only genetic factors but also various environmental exposures result in psychiatric disorders, decreased cognitive performance and biological aging (Biswal et al., 2016) and these multiply the risk of AD (Liu et al., 2016; Lochhead et al., 2017). Existing evidence indicates that AD is strongly induced by the environmental factors including aging, diet and nutrition, insulin deficiency, diabetes and brain trauma (Kazkayasi et al., 2016). Among all of the environmental exposures, chronic hypoxia has been considered recently (Zhang and Le, 2010). Hypoxia, loss of oxygen pressure in the atmosphere which leads to reduce cerebral oxygen supply, can cause neurodegenerative and morphological changes in the hippocampus and induce memory impairment (Kadar et al., 1994).
Animal models are being used as valuable tools for investigating new therapeutic approaches to treatment of human diseases in different fields such as neuroscience. As well, these models are offered for studying the pathological events involved in the processes of disease. Due to the lack of researches to complete understanding the etiology of AD, we need to establish animal models (Benedikz et al., 2009). However, all the available models for AD have limitations and just illustrate one or some of the characteristics of this neurologic disorder. Additionally, no natural models of AD have been introduced yet and thus most of the studies are performed using animal models with the disease phenotypes which activated by manipulation or transgenic animal models (Kaushal et al., 2016).
In this regards, the present study tries to determine association between exposing to global chronic hypoxia and AD dementia features such as memory deficits, neuronal damage in the hippocampus and expression of aging related proteins to introduce a new model of Alzheimer’s disease (AD) dementia.
Section snippets
Animals and experimental design
A total number of 24 male Wistar albino rats (200–250 g, 6-week-old) were purchased from Pharmacy Faculty of Tehran University of Medical Sciences, Tehran, Iran. All animals were maintained in a clean and hygienic environment, on a 12-h light and dark cycle and 23 ± 2 °C temperature, and had access to food and water ad libitum. All procedures were carried out in accordance with the guidelines of the Iranian Council for utilizing and caring of animals and approved by Ethical Committee of Tehran
Effects of exposure to the chronic hypoxia on behavioral alterations in male rats
The Morris water maze test was performed to examine spatial learning and memory related to hippocampus. As shown in Figs. 2a and b, escaped latency increased in rats in a group exposed to chronic hypoxia (Hx) comparing with Co and Sh groups (P < 0.05, Fig. 2). Despite the travel distance increased in Hx group, this was not significantly different compared with Co and Sh groups (P < 0.05, Fig. 2). Additionally, time and distance spent in the target quadrant significantly reduced in Hx group
Discussion
In the present study, we investigated the role of global chronic hypoxia in development of AD dementia characteristics and its adverse effects on memory and learning of animals, hippocampal complex and gene expression of Seladin-1 and Tuj1. Many previous studies have been shown that early life events including environmental exposure can cause neurodegenerative disorder that normally may happen in late life stages such as AD (Liu et al., 2016).
Existing literatures have been demonstrated hypoxic
Conclusion
Taken together, this study indicates that chronic hypoxia activates some molecular pathways that push individuals to AD pathogenesis.
Ethical
Our project was approved by ethical committee of Tehran University of Medical Sciences (no.IR.TUMS.REC. 9,528,381).
Moreover, handling of animals was carried out of the Iranian Council for Use and Care of Animal.
CRediT authorship contribution statement
Simin Mahakizadeh: Investigation, Validation, Writing - original draft. Tahmineh Mokhtari: Software, Formal analysis. Fatemeh Navaee: Resources, Validation. Mahnaz Poorhassan: Resources, Validation. Armin Tajik: Writing - review & editing. Gholamreza Hassanzadeh: Supervision, Funding acquisition.
Declaration of Competing Interest
The author declares no conflict of interest.
Acknowledgments
This work was supported by the Tehran University of Medical Sciences [grant number 94-02-30-28381].
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