Crosstalk Between Neuron And Glial Cells in Oxidative Injury And Neuroprotection Part 4

The differential antioxidant response of neurons and astrocytes results from the preferential astrocytic expression of Nrf2, a redox-sensitive transcription factor. 

Astrocytes are the most common non-nerve cells in the human central nervous system. They have different functions, mainly related to nerve cells' energy supply and maintaining the nervous environment's balance. These cells play an important role in the initiation of many neurological diseases, such as Alzheimer's disease, Parkinson's disease and multiple sclerosis, as well as in the repair phase after nerve damage. However, another important role played by astrocytes is their critical role in the maintenance of memory.

Scientists have discovered that astrocytes are more influential than previously thought, playing important roles in memory, learning, and neuroplasticity. During the learning process, communication between neurons is strengthened, and astrocytes release a chemical messenger called neuronal serotonin, which can strengthen communication between neurons, thus Enhancing memory and learning abilities. In addition, astrocytes also protect the health of neurons by engulfing waste and dead cells produced around them, thereby enhancing the overall vitality and function of the brain.

In addition to learning and memory benefits, astrocytes have other benefits. For example, they may keep the brain healthy, thus avoiding the onset of diseases like Parkinson's disease and Alzheimer's disease. In addition, they can strengthen the function of the human immune system, thereby helping the body fight disease and inflammatory responses more effectively.

In conclusion, astrocytes play a critical role in maintaining brain health and memory abilities. Not only that, these magical cells have many potential benefits that are worthy of further study. This demonstrates their importance and, therefore, keeping astrocytes in the brain healthy and active is crucial for our long-term health. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material that has many unique effects, one of which is to improve memory. The efficacy of Cistanche deserticola comes from the multiple active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health through a variety of pathways.

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Nrf2-ARE is a critical pathway for the regulation of the antioxidant defense mechanism because it regulates the expression of phase II detoxifying enzymes and antioxidant genes [127]. 

The higher susceptibility of neurons to ROS is due to the continuous destabilization and degradation of the antioxidant transcriptional activator Nrf2, which regulates the GSH system, the thioredoxin system, and SOD [128,129]. 

Nrf2 is more stable in astrocytes; thus, they dispose of the ROS in the nervous system. Nrf2 induction of glutamate cysteine ligase (GCL) increases GSH synthesis in astrocytes, and GSH precursors are subsequently exported to the extracellular medium [130]. 

Moreover, Nrf2-induced GSH synthesis in astrocytes is used to replenish neuronal GSH through the astrocyte-neuron shuttle. Nrf2-induced molecules, such as GSH-related enzymes and metallothioneins, are more highly expressed in astrocytes than in neurons, indicating that Nrf2 activation in astrocytes protects neurons from oxidative stress [131,132].

Microglia exhibit a surveying phenotype via dynamic crosstalk between microglia and neurons in the healthy brain [133]. M1 microglia promote inflammation by producing proinflammatory cytokines and inducing NO synthase activity. 

M2 microglia regulate immune function and promote repair by secreting anti-inflammatory cytokines [134,135]. 

The function of redox regulators in microglia is unclear, but many antioxidant proteins are linked to inflammation via functional microglia. In the crosstalk between microglia and neurons described in Figure 3, the expression of classical antioxidant proteins is controlled by Nrf2 in microglia [6]. Nrf2 deficiency exacerbates cognitive impairment and reactive microgliosis upon LPS treatment in vivo [136]. 

Heme oxygenase-1 (HO-1), an antioxidant enzyme upregulated by Nrf2, inhibits NOX2 activation upon stimulation with LPS [137]. HO-1, which may facilitate the attenuation of TLR4 signaling by NOX inhibition, is responsible for the conversion of heme to biliverdin and carbon monoxide and functions as an antioxidant enzyme [138]. The overexpression of HO-1 in microglia reduced neurotoxic iron accumulation in aged mice [139]. 

The genetic deletion of microglial-specific proteins and mechanistic interruption of neuronal activity by microglia manipulation showed that microglia modulate neuronal activity. Fractalkine (FKN) is predominantly expressed in the CNS and localized on neuronal cells. 

The FKN receptor (CX3CR1) is exclusively expressed in microglia and neurons and is an interesting signaling axis for communication between microglia and neurons [69,140]. A CX3CR1 deficiency was linked to the disruption of neurogenesis and neural connectivity [141]. 

DAP12 is another microglia-specific protein that occurs as a result of alterations in glutamate receptor content at synapse through microglial BDNF [142]. In neurotransmission with microglia-specific manipulation, microglia-conditioned media enhanced excitatory postsynaptic potentials and currents in dissociated cell cultures [143]. 

The inhibition of microglial activation by minocycline reduced neuronal cell death and spontaneous recurrent seizures in the rat lithium–pilocarpine model [144].

6. Conclusions

Neurons, which have high energy demands, engage in metabolic and redox crosstalk with surrounding cells for normal brain function. Glia plays essential roles in the redox and metabolic needs of neurons for neurotransmission and survival. 

Several previous studies have demonstrated the molecular and cellular aspects of this glial–neuronal coupling and have used antioxidant therapies to slow down the progression of neurodegeneration [139,145–147]. 

We reviewed oxidant and antioxidant systems in activated due to paracrine redox signaling and the crucial role of neuron–glia crosstalk against oxidative stress in the CNS, where the extracellular space and distance to neighboring cells or cell structures are extremely limited. 

Glial cells show morphological and molecular alterations in response to oxidative injury and regulate neuronal activities under these conditions. This neuron–glia communication plays a critical role in oxidative conditions by delaying neurodegeneration and aberrant neurogenesis via redox-balancing mechanisms.

Author Contributions:

All authors contributed substantially. K.H.L. designed and drafted the manuscript. M.C. assisted with the drafting of the manuscript and preparation of the figures. B.H.L. oversaw the entire project and prepared the draft of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding:

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2016R1D1A3B2008194, NRF-2020R1A2C3008481).

References

1. Jiang, T.; Sun, Q.; Chen, S. Oxidative stress: A major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson's disease and Alzheimer's disease. Prog. Neurobiol. 2016, 147, 1–19. [CrossRef] 

2. Lee, K.H.; Cha, M.; Lee, B.H. Neuroprotective effect of antioxidants in the brain. Int. J. Mol. Sci. 2020, 21, 7152. [CrossRef] 

3. Lee, B.H. Neuroprotection: Rescue from neuronal death in the brain. Int. J. Mol. Sci. 2021, 22, 5525. [CrossRef] [PubMed] 

4. Tanioka, M.; Park, W.K.; Park, J.; Lee, J.E.; Lee, B.H. Lipid emulsion improves functional recovery in an animal model of stroke. Int. J. Mol. Sci. 2020, 21, 7373. [CrossRef] [PubMed] 

5. Chen, Y.; Qin, C.; Huang, J.; Tang, X.; Liu, C.; Huang, K.; Xu, J.; Guo, G.; Tong, A.; Zhou, L. The role of astrocytes in oxidative stress of central nervous system: A mixed blessing. Cell Prolif. 2020, 53, e12781. [CrossRef] 

6. Simpson, D.S.A.; Oliver, P.L. ROS Generation in microglia: Understanding oxidative stress and inflammation in neurodegenerative disease. Antioxidants 2020, 9, 743. [CrossRef]

7. Li, J.; Wuliji, O.; Li, W.; Jiang, Z.-G.; Ghanbari, H.A. Oxidative stress and neurodegenerative disorders. Int. J. Mol. Sci. 2013, 14, 24438–24475. [CrossRef] 

8. Niedzielska, E.; Smaga, I.; Gawlik, M.; Moniczewski, A.; Stankowicz, P.; Pera, J.; Filip, M. Oxidative stress in neurodegenerative diseases. Mol. Neurobiol. 2016, 53, 4094–4125. [CrossRef] [PubMed] 

9. Rao, A.; Balachandran, B. Role of oxidative stress and antioxidants in neurodegenerative diseases. Nutr. Neurosci. 2002, 5, 291–309. [CrossRef] 

10. Bauernfeind, A.L.; Barks, S.K.; Duka, T.; Grossman, L.I.; Hof, P.R.; Sherwood, C.C. Aerobic glycolysis in the primate brain: Reconsidering the implications for growth and maintenance. Brain Struct. Funct. 2013, 219, 1149–1167. [CrossRef] 

11. Cobley, J.N.; Fiorello, M.L.; Bailey, D.M. 13 reasons why the brain is susceptible to oxidative stress. Redox Biol. 2018, 15, 490–503. [CrossRef]

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