ReviewAstrocytic nutritional dysfunction associated with hypoxia-induced neuronal vulnerability in stroke-prone spontaneously hypertensive rats
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.
References (112)
- et al.
Nitric oxide accounts for an increased glycolytic rate in activated astrocytes through a glycogenolysis-independent mechanism
Brain Res.
(2002) - et al.
Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation
Cell Metabol.
(2011) Astrocytic energetics during excitatory neurotransmission: what are contributions of glutamate oxidation and glycolysis?
Neurochem. Int.
(2013)- et al.
nNOS downregulation attenuates neuronal apoptosis by inhibiting nNOS-GluR6 interaction and GluR6 nitrosylation in cerebral ischemic reperfusion
Biochem. Biophys. Res. Commun.
(2012) Serine biosynthesis and transport defects
Mol. Genet. Metabol.
(2016)- et al.
Monocarboxylate transporter- dependent mechanism confers resistance to oxygen- and glucose-deprivation injury in astrocyte-neuron co-cultures
Neurosci. Lett.
(2015) - et al.
Changes in extracellular concentration of amino acids in the hippocampus during cerebral ischemia in stroke-prone SHR, stroke-resistant SHR and normotensive rats
Neurosci. Lett.
(1992) - et al.
Roles of l-serine and sphingolipid synthesis in brain development and neuronal survival
Prog. Lipid Res.
(2008) - et al.
Biology of GDNF and its receptors - relevance for disorders of the central nervous system
Neurobiol. Dis.
(2017) - et al.
Expression of glucose transporter-1 and aquaporin-4 in the cerebral cortex of stroke-prone spontaneously hypertensive rats in relation to the blood-brain barrier function
Am. J. Hypertens.
(2006)
Mutation of the trkB gene encoding the high-affinity receptor for brain-derived neurotrophic factor in stroke-prone spontaneously hypertensive rats
Biochem. Biophys. Res. Commun.
Phosphatidylserine in the brain: metabolism and function
Prog. Lipid Res.
Lactate utilization as an energy substrate in ischemic preconditioned rat brain slices
Life Sci.
Excitotoxicity and stroke: identifying novel targets for neuroprotection
Prog. Neurobiol.
Protection of ischemic brain cells is dependent on astrocyte-derived growth factors and their receptors
Exp. Neurol.
Elevated basic fibroblast growth factor levels in stroke-prone spontaneously hypertensive rats
Neuroscience
Intravenous PEP-1-GDNF is protective after focal cerebral ischemia in rats
Neurosci. Lett.
Control of brain energy supply by astrocytes
Curr. Opin. Neurobiol.
Cell-specific modulation of monocarboxylate transporter expression contributes to the metabolic reprograming taking place following cerebral ischemia
Neuroscience
Nanomolar nitric oxide concentrations quickly and reversibly modulate astrocytic energy metabolism
J. Biol. Chem.
Glial cell line-derived neurotrophic factor (GDNF) counteracts hypoxic damage to hippocampal neural network function in vitro
Brain Res.
Post-stroke losartan and captopril treatments arrest hemorrhagic expansion in SHRsp without lowering blood pressure
Vasc. Pharmacol.
Novel role of serine racemase in anti-apoptosis and metabolism
Biochim. Biophys. Acta Gen. Subj.
Expression of aquaporins 1 and 4 in the brain of spontaneously hypertensive rats
Brain Res.
Fructose-1,6-bisphosphate preserves intracellular glutathione and protects cortical neurons against oxidative stress
Brain Res.
Pathological alterations of astrocytes in stroke-prone spontaneously hypertensive rats under ischemic conditions
Neurochem. Int.
Adenosine induces expression of glial cell line-derived neurotrophic factor (GDNF) in primary rat astrocytes
Neurosci. Res.
Glutamate reduces secretion of l-serine in astrocytes isolated from stroke-prone spontaneously hypertensive rats
Neuroscience
Reduced production of lactate during hypoxia and reoxygenation in astrocytes isolated from stroke-prone spontaneously hypertensive rats
Neurosci. Lett.
Microglial IRF5-IRF4 regulatory axis regulates neuroinflammation after cerebral ischemia and impacts stroke outcomes
Proc. Natl. Acad. Sci. U. S. A.
Astrocyte glycogen and lactate: new insights into learning and memory mechanisms
Glia
Nitric oxide switches on glycolysis through the AMP protein kinase and 6-phosphofructo-2-kinase pathway
Nat. Cell Biol.
Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity
J. Neurosci.
New evidence of neuroprotection by lactate after transient focal cerebral ischaemia: extended benefit after intracerebroventricular injection and efficacy of intravenous administration
Cerebrovasc. Dis.
Neuroprotective role of lactate after cerebral ischemia
J. Cerebr. Blood Flow Metabol.
Bioenergetics and redox adaptations of astrocytes to neuronal activity
J. Neurochem.
Synaptic and extrasynaptic glutamate signaling in ischemic stroke
Curr. Med. Chem.
Lactate transport facilitates neurite outgrowth
Biosci. Rep.
Astrocyte-derived thrombospondins mediate the development of hippocampal presynaptic plasticity in vitro
J. Neurosci.
Quantitative analysis of delayed neuronal death in the hippocampal subfields of SHRSP and SHR
Cell. Mol. Neurobiol.
Serine-deficiency syndromes
Curr. Opin. Neurol.
Facilitating postischemic reduction of cerebral lactate in rats
Stroke
Mechanisms of L-serine neuroprotection in vitro include ER proteostasis regulation
Neurotox. Res.
Cystathionine beta- synthase, a key enzyme for homocysteine metabolism, is preferentially expressed in the radial glia/astrocyte lineage of developing mouse CNS
Faseb. J.
L-serine and glycine serve as major astroglia-derived trophic factors for cerebellar Purkinje neurons
Proc. Natl. Acad. Sci. U. S. A.
Altered nitric oxide synthase immunoreactivity in the brain of stroke-prone spontaneously hypertensive rats
Acta Neuropathol.
Induction processes in blood-brain transfer of ketone bodies during starvation
Am. J. Physiol.
Differential effects of transient and sustained activation of BDNF- TrkB signaling
Dev Neurobiol
The contribution of astrocytes to the regulation of cerebral blood flow
Front Neurosci.
Hydrogen sulfide inhibits high-salt diet-induced renal oxidative stress and kidney injury in dahl rats
Oxid Med Cell Longev
Cited by (3)
THE ROLE OF MCT1 TRANSPORTERS IN THE IMPLEMENTATION OF THE NEUROPROTECTIVE EFFECT OF GLIAL CELL-DERIVED NEUROTROPHIC FACTOR
2022, Opera Medica et Physiologica