• The Korean Journal of Physiology and Pharmacology
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• v.25 no.6
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• pp.565-574
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• 2021

Astrocytes are activated in response to brain damage. Here, we found that expression of Kir4.1, a major potassium channel in astrocytes, is increased in activated astrocytes in the injured brain together with upregulation of the neural stem cell markers, Sox2 and Nestin. Expression of Kir4.1 was also increased together with that of Nestin and Sox2 in neurospheres formed from dissociated P7 mouse brains. Using the Kir4.1 blocker BaCl₂ to determine whether Kir4.1 is involved in acquisition of stemness, we found that inhibition of Kir4.1 activity caused a concentration-dependent increase in sphere size and Sox2 levels, but had little effect on Nestin levels. Moreover, induction of differentiation of cultured neural stem cells by withdrawing epidermal growth factor and fibroblast growth factor from the culture medium caused a sharp initial increase in Kir4.1 expression followed by a decrease, whereas Sox2 and Nestin levels continuously decreased. Inhibition of Kir4.1 had no effect on expression levels of Sox2 or Nestin, or the astrocyte and neuron markers glial fibrillary acidic protein and β-tubulin III, respectively. Taken together, these results indicate that Kir4.1 may control gain of stemness but not differentiation of stem cells.

• Journal of Veterinary Science
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• v.21 no.3
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• pp.44.1-44.10
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• 2020

Background: Congenital portosystemic shunt (cPSS) is one of the most common congenital disorders diagnosed in dogs. Hepatic encephalopathy (HE) is a frequent complication in dogs with a cPSS and is a major cause of morbidity and mortality. Despite HE been a major cause of morbidity in dogs with a cPSS, little is known about the cellular changes that occur in the central nervous system of dogs with a cPSS. Objectives: The objective of this study was to characterise the histological changes in the cerebral cortex and cerebellum of dogs with cPSS with particular emphasis on astrocyte morphology. Methods: Eight dogs with a confirmed cPSS were included in the study. Results: Six dogs had substantial numbers of Alzheimer type II astrocytes and all cases had increased immunoreactivity for glial fibrillary acidic protein in the cerebral cortex, even if there were minimal other morphological changes. Conclusions: This study demonstrates that dogs with a cPSS have marked cellular changes in the cerebral cortex and cerebellum. The cellular changes that occur in the cerebral cortex and cerebellum of dogs with spontaneously arising HE are similar to changes which occur in humans with HE, further validating dogs with a cPSS as a good model for human HE.

• Journal of Ginseng Research
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• v.46 no.3
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• pp.408-417
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• 2022

Background: Korean Red Ginseng extract (KRGE) has been used as a health supplement and herbal medicine. Astrocytes are one of the key cells in the central nervous system (CNS) and have bioenergetic potential as they stimulate mitochondrial biogenesis. They play a critical role in connecting the brain vasculature and nerves in the CNS. Methods: Brain samples from KRGE-administered mice were tested using immunohistochemistry. Treatment of human brain astrocytes with KRGE was subjected to assays such as proliferation, cytotoxicity, Mitotracker, ATP production, and O₂ consumption rate as well as western blotting to demonstrate the expression of proteins related to mitochondria functions. The expression of hypoxia-inducible factor-1α (HIF-1α) was diminished utilizing siRNA transfection. Results: Brain samples from KRGE-administered mice harbored an increased number of GFAP-expressing astrocytes. KRGE triggered the proliferation of astrocytes in vitro. Enhanced mitochondrial biogenesis induced by KRGE was detected using Mitotracker staining, ATP production, and O₂ consumption rate assays. The expression of proteins related to mitochondrial electron transport was increased in KRGE-treated astrocytes. These effects were blocked by HIF-1α knockdown. The factors secreted from KRGE-treated astrocytes were determined, revealing the expression of various cytokines and growth factors, especially those related to angiogenesis and neurogenesis. KRGE-treated astrocyte conditioned media enhanced the differentiation of adult neural stem cells into mature neurons, increasing the migration of endothelial cells, and these effects were reduced in the background of HIF-1α knockdown. Conclusion: Our findings suggest that KRGE exhibits prophylactic potential by stimulating astrocyte mitochondrial biogenesis through HIF-1α, resulting in improved neurovascular function.

• Journal of Ginseng Research
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• v.47 no.2
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• pp.319-328
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• 2023

Background: Demyelination has been observed in neurological disorders, motivating researchers to search for components for enhancing remyelination. Previously we found that Rb1, a major ginsenoside in Korean Red Ginseng (KRG), enhances myelin formation. However, it has not been studied whether Rb1 or KRG function in remyelination after demyelination in vivo. Methods: Mice were fed 0.2% cuprizone-containing chow for 5 weeks and returned to normal chow with daily oral injection of vehicle, KRG, or Rb1 for 3 weeks. Brain sections were stained with luxol fast blue (LFB) staining or immunohistochemistry. Primary oligodendrocyte or astrocyte cultures were subject to normal or stress condition with KRG or Rb1 treatment to measure gene expressions of myelin, endoplasmic reticulum (ER) stress, antioxidants and leukemia inhibitory factor (LIF). Results: Compared to the vehicle, KRG or Rb1 increased myelin levels at week 6.5 but not 8, when measured by the LFB⁺ or GST-pi⁺ area within the corpus callosum. The levels of oligodendrocyte precursor cells, astrocytes, and microglia were high at week 5, and reduced afterwards but not changed by KRG or Rb1. In primary oligodendrocyte cultures, KRG or Rb1 increased expression of myelin genes, ER stress markers, and antioxidants. Interestingly, under cuprizone treatment, elevated ER stress markers were counteracted by KRG or Rb1. Under rotenone treatment, reduced myelin gene expressions were recovered by Rb1. In primary astrocyte cultures, KRG or Rb1 decreased LIF expression. Conclusion: KRG and Rb1 may improve myelin regeneration during the remyelination phase in vivo, potentially by directly promoting myelin gene expression.

• The Korean Journal of Pain
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• v.36 no.1
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• pp.51-59
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• 2023

Background: This study investigated the effect of an excess and a deficit of spinal 5-hydroxytryptamine (5-HT) on the mechanical allodynia and neuroglia activation in a rodent pain model of carrageenan inflammation. Methods: Male Sprague-Dawley rats were implanted with an intrathecal (i.t.) catheter to administer the drug. To induce an excess or deficit of 5-HT in the spinal cord, animals were given either three i.t. 5-HT injections at 24-hour intervals or a single i.t. injection of 5,7-dihydroxytryptamine (5,7-DHT) before carrageenan inflammation. Mechanical allodynia was measured using the von Frey test for 0-4 hours (early phase) and 24-28 hours (late phase) after carrageenan injection. The changes in the activation of microglia and astrocyte were examined using immunofluorescence of the dorsal horn of the lumbar spinal cord. Results: Both an excess and a deficit of spinal 5-HT had no or a minimal effect on the intensity of mechanical allodynia during the early phase but prevented the attenuation of mechanical allodynia during the late phase, which was observed in animals not treated with i.t. 5-HT or 5,7-DHT. Animals with an excess or deficit of 5-HT showed stronger activation of microglia, but not astrocyte, during the early and late phases, than did normal animals. Conclusions: Imbalance in the descending 5-HT pathway in the spinal cord could aggravate the mechanical allodynia and enhance the activation of microglia, suggesting that the spinal 5-HT pathway plays an essential role in maintaining the nociceptive processing in balance between facilitation and inhibition in inflammatory pain caused by carrageenan inflammation.

• Korean Journal of Exercise Nutrition
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• v.16 no.2
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• pp.73-84
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• 2012

Thyroid hormones are important for the development of the brain including the cerebellum. In the present study, we investigated the effect of treadmill exercise on the survival of Purkinje neurons and the activation of astrocytes in the cerebellar vermis of hypothyroidism-induced rat pups. On the day of perinatal 14, pregnant rats were divided into two groups (n = 5 in each group): the pregnant control group and the pregnantmethimazole (MMI)-treated group. For the induction of hypothyroidism in the rat pups, MMI was added to the drinking water (0.02% wt/vol), from the day of perinatal 14 to postnatal 49. After delivery, male rat pups born from the pregnant control group were assigned to the control group. Male rat pups born from the MMI-treated group were divided into the hypothyroidism-induction group, the hypothyroidism-induction with treadmill exercise group, and the hypothyroidism-induction with thyroxine (T4) treatment group (n = 10 in each group). The rat pups in the exercise group were forced to run on a treadmill for 30 min once a day for 4 weeks, starting on postnatal day 22. In the hypothyroidism-induced rat pups, motor coordination was reduced and Purkinje cell death and reactive astrocytes in the cerebellar vermis were increased. Treadmill exercise enhanced motor coordination, increased the survival of Purkinje neurons, down-regulated reactive astrocytes, and enhanced brain-derived neurotrophic factor (BDNF) and receptor tyrosine kinase B (TrkB) expressions in the hypothyroidism-induced rat pups. These results suggest that treadmill exercise has beneficial effects in terms of protecting against thyroid dysfunction by increasing T3 and T4 and the related protein, BDNF, as well as TrkB, inhibition on astrocyte activation and the reduction of Purkinje cell loss regarding the cerebellum in hypothyroidism rat pups.

• Journal of Life Science
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• v.23 no.9
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• pp.1096-1103
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• 2013

Chronic traumatic encephalopathy (CTE), which is common in athletes, is a progressive neurodegenerative disease and a long-term consequence of repetitive closed head injuries. CTE is regarded as a chronic brain syndrome due to the effects of repetitive traumatic brain injury (TBI). Because neurotrophic factors are neuroprotective in models of brain and spinal cord injuries, we examined the effects of cerebrolysin, a mixture of various neurotrophic factors, on brain pathology in a mouse model of repetitive mild TBI (rmTBI), which is a good model of CTE. Five groups were created and treated as follows: groups 1 and 2: rmTBI for 4 weeks following cerebrolysin injection for 4 weeks; groups 3 and 4: rmTBI for 8 weeks with or without cerebrolysin injection for 4 weeks; group 5: control. We found that p-tau expression was increased in the pyramidal layer of the cortex and hippocampus, particularly the CA3 region, but not in the CA1 region and the dentate gyrus (DG). Intra-tail vein administration of cerebrolysin ($10{\mu}l$ of 1 mg/ml) after/during rmTBI treatment reduced p-tau expression in both the cortex and hippocampus. Histological analysis revealed mild astrocyte activation (increased expression of glial fibrillary acidic protein (GFAP)) but not microglia activation (ionized calcium binding adaptor molecule 1 (iba-1) expression) and peripheral macrophage infiltration (CD45). Additionally, administration of cerebrolysin after rmTBI resulted in reduced astrocyte activation. These observations in rmTBI demonstrated that cerebrolysin treatment reduces phosphorylation of tau and astrocyte activation, attenuates brain pathology, and mitigates function deficits in TBI. Taken together, our observations suggest that cerebrolysin has potential therapeutic value in CTE.

• Biomolecules & Therapeutics
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• v.18 no.2
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• pp.125-134
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• 2010

Bisphenol A (BPA) is one of the most common endocrine disrupters. In the last decade, the number of studies concerning the effects of chronic treatment with BPA on the development of the central nervous system (CNS) has increased. However, little is known about the effects of chronic exposure to BPA on higher brain functions such as memory or psychomotor functions. Here, we report our following findings: (1) Prenatal and neonatal exposure to BPA enhances psychostimulant-induced rewarding effects, results in the up- or downregulation of dopamine receptors, causes memory impairment, and decreases choline acetyltransferase (ChAT) activity. (2) BPA activates astrocytes in vivo and in vitro. These findings suggest that prenatal and neonatal exposure to BPA affects the development of the CNS.

• Korean Journal of Biological Psychiatry
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• v.22 no.2
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• pp.29-33
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• 2015

The brain maintains homeostasis and normal microenvironment through dynamic interactions of neurons and neuroglial cells to perform the proper information processing and normal cognitive functions. Recent post-mortem investigations and animal model studies demonstrated that the various brain areas such as cerebral cortex, hippocampus and amygdala have abnormalities in neuroglial numbers and functions in subjects with mental illnesses including schizophrenia, dementia and mood disorders like major depression and bipolar disorder. These findings highlight the putative role and involvement of neuroglial cells in mental disorders. Herein I discuss the physiological roles of neuroglial cells such as astrocytes, oligodendrocytes, and microglia in maintaining normal brain functions and their abnormalities in relation to mental disorders. Finally, all these findings could serve as a useful starting point for potential therapeutic concept and drug development to cure unnatural behaviors and abnormal cognitive functions observed in mental disorders.

• Korean Journal of Biological Psychiatry
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• v.22 no.2
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• pp.47-54
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• 2015

In the past decade, structural, molecular, and functional changes in glial cells have become a major focus in the search for the neurobiological foundations of schizophrenia. Glial cells, consisting of oligodendrocytes, astrocytes, microglia, and nerve/glial antigen 2-positive cells, constitute a major cell population in the central nervous system. There is accumulating evidence of reduced numbers of oligodendrocytes and altered expression of myelin/oligodendrocyte-related genes that might explain the white matter abnormalities and altered inter- and intra-hemispheric connectivities that are characteristic signs of schizophrenia. Astrocytes play a key role in the synaptic metabolism of neurotransmitters ; thus, astrocyte dysfunction may contribute to certain aspects of altered neurotransmission in schizophrenia. Increased densities of microglial cells and aberrant expression of microglia-related surface markers in schizophrenia suggest that immunological/inflammatory factors are of considerable relevance to the pathophysiology of psychosis. This review describes current evidence for the multifaceted role of glial cells in schizophrenia and discusses efforts to develop glia-directed therapies for the treatment of the disease.