Crosstalk Between Neuron And Glial Cells in Oxidative Injury And Neuroprotection Part 2

3. Astrocytes

3.1. Astrocytes in the Brain

Astrocytes are the most dynamic and abundant human brain cells responsible for maintaining brain homeostasis. Astrocytes are called territorial cells and have several extended processes communicating with adjacent cells; thus, they form organized anatomical domains with associated functional syncytia [26]. 

Astrocytes are an essential cell type in the brain. These cells are responsible for protecting and supporting neurons and maintaining the normal functioning of the entire nervous system. In recent years, more and more studies have shown that astrocytes are also closely related to the formation and maintenance of human memory.

Research has found that astrocytes can affect synaptic connections between neurons, thereby affecting the formation and storage of memories. These glial cells can also remove garbage and other harmful substances from neurons. While maintaining the health of the nervous system, they also help improve our memory.

In addition, scientists have discovered that astrocytes produce a molecule called FGF2, which plays an important role in improving learning and memory. Experiments have found that increasing the content of FGF2 in astrocytes can significantly improve the learning ability and memory of mice.

Even more exciting, some studies have shown that maintaining a healthy lifestyle can promote astrocyte growth and function. For example, regular exercise, a healthy diet, and adequate sleep can promote the growth and function of astrocytes, which can help improve our memory.

Therefore, although some adverse factors in life, such as excessive drinking or the use of certain drugs, will affect the growth and function of astrocytes, there are still many measures we can take to improve their function. As long as we maintain a positive attitude and live as healthily as possible, we can potentially have stronger memories and better neurological health. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche deserticola can also promote the growth and repair of nerve cells, thus enhancing the connectivity and function of neural networks. These effects can help improve memory, learning, and thinking speed, and may also prevent the development of cognitive dysfunction and neurodegenerative diseases.

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Astrocytes project vascular processes (astrocytic end-feet) onto intraparenchymal blood vessels and ensheath the vessel surfaces to control the movement of molecules and cells between the vascular compartment and the brain [27]. 

Human astrocytes are usually classified into four subdivisions based on their neuroanatomy [28]. First, interlaminar astrocytes have a round cell body and short processes and are located in layer I of the cortex. Second, protoplasmic astrocytes are found in gray matter and are located in layers II–VI of the cortex. They are the most abundant astrocytes and have numerous processes and a bushy morphology. 

Third, varicose projection astrocytes are located in layers V–VI and have short spiny processes with from one to five longer processes that may function in long-distance communication within the cortex. Fourth, fibrous astrocytes are located in white matter and are larger cells containing fewer processes. Fibrous astrocyte processes send numerous extensions to contact oligodendroglia that wrap myelinated axons [29]. 

Astrocytes are also classified into types I–III according to their morphological characteristics, such as cell body size, number of processes, thickness of processes, direction of processes, and length of processes. 

Type I astrocytes are characterized by a small cell body and numerous short processes. Type II astrocytes are characterized by a bipolar shape and long processes. Type III astrocytes are characterized by a star shape and long processes [30,31]. 

The function of astrocytes is to aid neurons by playing supportive roles in synaptic function and the modulation of neurotransmission. The processes of astrocytes ensheath synapses and contain a variety of receptors for neurotransmitters, cytokines, growth factors, and ion channels. 

Astrocytes are affected by intracellular Ca2+ release by extracellular glutamate, and maintain the ionic balance of synapses by increasing intracellular Ca2+ levels following the secretion of numerous gliotransmitters, such as glutamate, purines, GABA, and D-serine [32,33] Neurons are highly sensitive to small changes in the brain microenvironment, even though their metabolic consumption is high. 

The role of astrocytes in the normal brain is the maintenance of extracellular homeostasis through glutamate uptake and recycling, K+ buffering, supplying energy substrates, pH buffering, and defense against oxidative stress [28].

3.2. Astrocytes in Oxidative Injury

Astrocytes exist in a resting or reactive state in the brain, as shown in Figure 2. Reactive astrocytes release inflammatory cytokines including TNF and ROS, and form glial scars that impede axon regeneration and neurite outgrowth [34–36]. 

Activated astrocytes aid in the recovery of brain function after injury but can be neurotoxic. Reactive astrocytes release nitric oxide (NO) into the extracellular space; this can lead to neuronal injury and death by increasing lipid peroxidation, mitochondrial impairment, and inducing DNA strand breaks [37]. 

The astrocytic antioxidant system balances ROS (superoxides, hydroxyl radicals, and nitric monoxide) that are naturally produced during oxygen metabolism by the CNS [38]. Oxidative stress in reactive astrocytes leads to long-term effects on specific proteins, including connexins, glutamate transporters, and enzymes, which affect interactions between astrocytes and neurons [39]. 

The glutamate uptake by an astrocyte requires a high level of energy, needing more than one ATP molecule for one glutamate take-up. However, the lack of ATP is related to the mechanisms of ROS-induced glutamate uptake blockade in astrocytes [40,41]. Blocking astrocyte glutamate transporters increases neurotoxicity by potentiating neuronal excitability and excitatory neurotransmission [42]. 

Oxidative stress generated by astrocytes mainly occurs through mitochondria-derived oxidative stress, NADPH-derived oxidative stress, and RNS production. Mitochondria are distributed in the cell body and the thin and long processes of astrocytes [43]. Disrupting mitochondrial function and increasing ROS in astrocytes leads to astrogliosis. NADPH-derived oxidative stress significantly affects the physiological function of astrocytes. 

Among the NOX family, NOX2 and NOX4 are the most abundantly expressed NOX isoforms in the CNS [43]. NOX4, but not NOX2 is expressed in astrocytes, and even a low expression of NOX4 regulates oxidative stress in astrocytes [44,45]. 

Astrocytic RNS production also affects astrocyte-derived oxidative stress. The main NOS isoforms, including Ca2+/calmodulin-dependent neuronal NOS, endothelial NOS, and Ca2+-independent inducible NOS, are observed in astrocytes [5,46]. Astrocytic NO leads to astrocyte-induced neuronal degeneration and Cu-Zn superoxide dismutase (SOD1) aggregation in astrocytes, which may induce ischemic/reperfusion CNS injury [47,48].

3.3. Astrocyte-Medicated Antioxidant Defense

Astrocytes are the main cells that maintain glutamate homeostasis, which indirectly affects the balance of oxidative stress, by regulating excitatory amino acids. Astrocytes also prevent excitotoxicity by releasing neurotrophic factors, such as glial-cell-line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF), which support neuronal survival [39,49]. 

For neuroprotection during oxidative stress, astrocytes produce a variety of antioxidant molecules, including GSH, ascorbate, and vitamin E, and activate ROSdetoxifying enzymes, such as GSH S-transferase, GSH peroxidase, thioredoxin reductase, and catalase to improve neuronal survival [26,50,51]. Moreover, astrocytes participate in metal sequestration in the brain to prevent the generation of free radicals by redox-active metals. Astrocytes express high levels of metallothioneins and ceruloplasmin, which are involved in metal binding and ion trafficking [52]. 

Astrocytes can synthesize the GSH tripeptide with glutamate cysteine ligase and GSH synthetase. Astrocytes release GSH into the extracellular space and neurons take up the GSH directly or use extracellular neuronal aminopeptidase N to form glycine and cysteine [53]. 

Reduced neuronal protection against oxidative injury was observed in GSH-depleted astrocytes by limiting the substrate for GSH synthesis in neurons [54]. Astrocytes increase the capacity to synthesize GSH by increasing the capacity to uptake cysteine, thereby enhancing the neuroprotective effect of astrocytes against oxidative stress [5]. Another astrocyte antioxidant defense mechanism is the recycling of ascorbate, which can directly scavenge ROS and act as a cofactor for the recycling of oxidized vitamin E and GSH [2]. 

This recycled ascorbate is used intracellularly in astrocytes and/or released into the extracellular space for neurons to use for their antioxidant defense mechanism. When ascorbic acid enters neurons, it inhibits glucose consumption and stimulates lactate transport. Ascorbic acid regulates the astrocyte-neuron lactate shuttle [55], and neurons produce glutamate, which stimulates ascorbic acid release from astrocytes during glutamatergic synaptic activity [56,57]. 

In the Nrf2-Keap1-ARE pathway, an important endogenous antioxidant system in the CNS, the ROS-inducible transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), regulates the GSH system, the thioredoxin system, and SOD [58]. Nrf2 is produced and ubiquitinated for degradation by binding to the Kelch-like ECH-associated protein 1 (Keap1) under basal conditions [59]. 

However, Keap1 binding to Nrf2 is inhibited by increased oxidative stress conditions, and this allows Nrf2 to escape degradation and interact with antioxidant response elements (AREs) in gene promoters [60,61]. 

Astrocytes show higher basal and stimulated levels of ARE binding by Nrf2 than neurons [62]. In addition, tertiary butylhydroquinone (tBHQ) activates Nrf2 and its downstream antioxidant enzymes, such as reduced coenzyme/quinone oxidoreductase 1 (NQO1), in astrocytes, but not in neurons [63]. 

Astrocytic Nrf2 is the main regulator of oxidative homeostasis as determined by the observation that Nrf2−/− astrocytes have more severe inflammatory responses. Further, the astrocytic dopamine D2 receptor regulates GSH synthesis via Nrf2 transactivation in vivo [64,65].

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