Review
Astrocytic nutritional dysfunction associated with hypoxia-induced neuronal vulnerability in stroke-prone spontaneously hypertensive rats

https://doi.org/10.1016/j.neuint.2020.104786Get rights and content

Highlights

  • Role of astrocytes in development of stroke in SHRSP/Izm model has been discussed.

  • In SHRSP/Izm, neuronal death is induced upon reoxygenation after hypoxia.

  • Reduced production of GDNF and L-serine contributes to diminished neuronal survival.

  • Differences between SHRSP/Izm and WKY/Izm properties may induce neuronal death.

Abstract

Stroke-prone spontaneously hypertensive rats (SHRSP) is a valuable animal model to investigate human strokes. SHRSP Izumo strain (Izm) neurons are highly sensitive to blood supply changes. Furthermore, SHRSP/Izm astrocytes show various abnormalities upon hypoxic stimulation compared to control Wistar Kyoto (WKY/Izm) rats. This study aimed to describe stroke-related characteristics of SHRSP/Izm-derived neurons and astrocytes. In addition, we discuss the role of astrocytes in the development of stroke in SHRSP/Izm model. In SHRSP/Izm, neuronal death is induced upon reoxygenation after hypoxia. Furthermore, it was shown that SHRSP/Izm astrocytes show significantly reduced lactate production and supply ability to nerve cells when subjected to hypoxic stimulation. In particular, decreased lactate production and monocarboxylic acid transporter (MCT) expression in SHRSP/Izm astrocytes are factors that induce neuronal cell death. Remarkable differences in glial cell line-derived neurotrophic factor (GDNF) expression and L-serine production were also observed in SHRSP/Izm-derived astrocytes compared to WKY/Izm. Reduced production of both GDNF and L-serine contributes to diminished neuronal survival. The differences between SHRSP/Izm and WKY/Izm astrocyte cellular properties may contribute to compromised neuronal nutrition and induction of neuronal death. These properties are likely to be the factors that enhance stroke in SHRSP/Izm.

Introduction

Stroke-prone spontaneously hypertensive rats (SHRSP) have severe hypertension and therefore have high risk of stroke with aging. Most SHRSP die from cerebrovascular diseases. Thus, this strain is widely used as a model to investigate human stroke, to elucidate the mechanism of stroke, and to test antihypertensive or other drugs (Yamori, 1991; Richer et al., 1997; Smeda et al., 2018). The blood pressure of SHRSP Izumo strain (Izm) begins to rise shortly after birth; it reaches 250 mmHg by week 18 and rises to 300 mmHg at 20 weeks of age. Most individuals develop cerebrovascular disorders and die from cerebral hemorrhage or cerebral infarction (Yamori, 1991). SHRSP/Izm was isolated from Wistar Kyoto rats (WKY/Izm). Therefore, WKY/Izm strain is used as a control to SHRSP/Izm strain.

Previous studies have shown that SHRSP/Izm strain had higher neuronal vulnerability and multiple aberrant cellular properties of astrocytes compared to WKY/Izm rats (Yamagata et al., 2010b; Yamagata, 2012). It was also demonstrated that neuronal cell death induced by ischemia due to carotid artery ligation was significantly higher in SHRSP/Izm compared to WKY/Izm (Tagami et al., 1997, 1998; Yamagata et al., 2010b). The occlusion of the carotid artery and subsequent oxygen reperfusion has been established as a condition that strongly induces neuronal cell death (Kirino et al., 1984). In addition, neuronal cell death during cerebral ischemia and oxygen reperfusion has been used as a model for neuronal cell death due to stroke (Ryou and Mallet, 2018). Furthermore, it was found that the production of lactic acid, L-serine, and glial cell-derived neurotrophic factor (GDNF) in SHRSP/Izm-derived astrocytes was significantly lower compared to WKY/Izm-derived astrocytes (Yamagata et al., 2010b, 2012). Differences between SHRSP astrocytes and WKY astrocytes were observed with respect to growth rate, induction of tight junctions, aquaporin 4 level, lactate production and transport, adhesion molecule expression level, GDNF expression level, and L-serine production and transport (Table 1). In particular, both lactic acid and L-serine are essential for survival of neuronal cells (Talukdar et al., 2017), and GDNF is a neurotrophic factor, that contributes to neuronal survival and differentiation (Ibanez and Andressoo, 2017). Meanwhile, astrocytes not only provide nutritional support to neuronal cells, but also contribute to the blood-brain barrier (BBB) formation. Previously, we showed that SHRSP/Izm astrocytes may have lower BBB-inducing function compared to WKY/Izm (Yamagata et al., 1997). Cellular properties of SHRSP/Izm astrocytes are different from those of WKY/Izm, suggesting that they may be deeply involved in stroke-induced neuronal cell death.

Stroke strongly induces neuronal damage; however the preventive role of non-neuronal brain cells, especially astrocytes, has not been extensively studied. The characteristics of neurons and astrocytes in SHRSP/Izm can be used as a model to study high blood pressure-induced strokes in humans, offering new hints for stroke prevention. Neuronal vulnerability of SHRSP/Izm to ischemic stimulation is induced by oxidative stress (Yamagata et al., 2010b, 2012), and the supply of lactic acid, GDNF, and L-serine is likely to reduce neuronal cell death. However, there are very few reports on SHRSP astrocytes associated with stroke susceptibility. This review focuses on the role of astrocytes in neuronal vulnerability and its relation to stroke development in SHRSP/Izm.

Section snippets

SHRSP/Izm neuron vulnerability induced by reoxygenation after hypoxia

Brain tissue neurons are highly vulnerable to hypoxic conditions. In vivo and in vitro experiments have shown that SHRSP/Izm neurons are more sensitive than WKY/Izm and strongly induce apoptosis and neuronal death in hypoxic conditions (Tagami et al.,1997, 1999) (Fig. 1). Reoxygenation after hypoxia (H/R) produces many reactive oxygen species (ROS) and induces death or injury of neuronal cells. For example, reperfusion after transient ischemia did not cause a significant neuronal loss in

Inhibitory effect of progesterone, vitamin E, and lercanidipine on SHRSP/Izm neuronal cell death

Progesterone plays a neuroprotective role during ischemic brain injury. For example, it has been shown to inhibit neuronal cell death during MCAO in SHRSP (Yousuf et al., 2016). Administration of progesterone (8 mg/kg) 1 h after aortic occlusion in SHRSP prevented MCAO-induced neuronal damage and restored brain function. Progesterone was found to suppress macrophage and astrocyte activation and to reduce superoxide anion production and apoptosis rates. Therefore, progesterone may suppress

Sensitivity of SHRSP-derived astrocytes to oxidative stress

SHRSP is a model used to investigate hypertension with stroke (Yamori, 1991), whereas SHR have severe hypertension without induction of stroke (Ikeda et al., 1991). A report indicated that SHRSP-derived astrocytes are more susceptible to oxidative stress and are more likely to induce cell death compared to the ones derived from SHR (Juman et al., 2016). It was further shown that SHRSP-derived astrocytes had significantly reduced total thiol content, hydrogen sulfide (H2S) production, and

Lactic acid production in astrocytes and its supply to neuronal cells

Blood glucose is the main source of energy for the brain. In addition, lactic acid is important for neuron protection in pathological conditions such as long-term starvation (Gjedde and Crone, 1975) and cerebral ischemia (Berthet et al., 2009). Lactic acid produced from astrocytes was shown to be important for neuronal activity in glucose deficiency (Wyss et al., 2011). Moreover, it has been demonstrated that lactate supply from astrocytes is required for the maintenance of neuronal function (

Regulation of lactate production and MCT expression in cultured astrocytes derived from SHRSP/Izm

Stroke is caused by a decrease in cerebral blood flow due to cerebral ischemia. Reduced supply of oxygen and glucose to the brain not only exacerbates the survival of nerve cells, but also increases excess glutamate release from the neuronal cells. Excess glutamate induces extreme activation of glutamate receptors, causing a rapid increase in calcium levels in neuronal cells. Rapid increase in intracellular calcium concentration excessively induces membrane potential and cell membrane

Regulation of GDNF production in SHRSP/Izm-derived astrocytes

Several neurotrophic factors have been shown to support neuronal survival and regulation of brain function (Mitre et al., 2017). GDNF was originally produced from glial cells and was identified as a specific neuroprotective factor for dopaminergic neurons (Lin et al., 1993). Later, it was suggested that GDNF could affect the migration and differentiation of hippocampal neural stem cells (Yoo et al., 2012). In a focal cerebral ischemia model, GDNF significantly reduced MCAO-induced infarct

L-serine role in neuronal survival and its production in SHRSP/Izm-derived astrocytes

L-serine is a potent neurotrophic factor, precursor of phosphatidyl-L-serine, L-cysteine, nucleotides, sphingolipids, and neurotransmitters such as D-serine and glycine (Hirabayashi and Furuya, 2008; Kim et al., 2014). It plays an important role in survival, development and function of the CNS neurons (de Koning, and Klomp, 2004). In the CNS, L-serine is biosynthesized by enzymes such as 3-phosphoglycerate dehydrogenase (3PGDH), phosphoserine aminotransferase (PSAT), and phosphoserine

Conclusion

Astrocytes have multiple functions in the CNS, such as maintenance of brain homeostasis (Marina et al., 2018), support of neurons and control of energy supply (Nortley and Attwell, 2017), recycling of neurotransmitters (Schousboe, 2019), control of blood flow (Howarth, 2014), and removal of neuronal synapses (Crawford et al., 2012). Thus, impaired or abnormal functions of astrocytes may strongly accelerate neuronal damage. In this article, we have focused on SHRSP/Izm-derived neuron and

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

None.

Acknowledgements

None.

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