• BMB Reports
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• v.55 no.12
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• pp.621-626
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• 2022

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the degeneration of motor neurons in the spinal cord. Main symptoms are manifested as weakness, muscle loss, and muscle atrophy. Some studies have reported that alterations in sphingolipid metabolism may be intimately related to neurodegenerative diseases, including ALS. Acid sphingomyelinase (ASM), a sphingolipid-metabolizing enzyme, is considered an important mediator of neurodegenerative diseases. Herein, we show that ASM activity increases in samples from patients with ALS and in a mouse model. Moreover, genetic inhibition of ASM improves motor function impairment and spinal neuronal loss in an ALS mouse model. Therefore, these results suggest the role of ASM as a potentially effective target and ASM inhibition may be a possible therapeutic approach for ALS.

• Journal of Environmental Science International
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• v.32 no.10
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• pp.723-729
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• 2023

Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by dopaminergic neuronal loss in the substantia nigra, resulting in reduced dopamine levels and consequent motor dysfunction. Genetic and environmental factors contribute to oxidative stress in PD. Cicadidae Periostracum (CP), a traditional Korean medicine, has shown neuroprotective effects against MPTP-induced neurotoxicity in PD. However, its effects on the 6-hydroxydopamine (6-OHDA) model have not been established. This study examined CP's effects on a 6-OHDA-induced PD model. CP protected against 6-OHDA damage in both in vitro and in vivo studies. Furthermore, CP reduced the production of reactive oxygen species, inhibited apoptosis, preserved dopamine levels, protected tyrosine hydroxylase in the substantia nigra, and improved motor function. These findings suggest that CP may delay PD progression by maintaining the redox balance.

• Korean Journal of Acupuncture
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• v.40 no.3
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• pp.90-98
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• 2023

Objectives : Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide and is characterized by the loss of the dopaminergic neurons in the substantia nigra (SN). In a previous in vitro study, we demonstrated that Sihogyeji-tang (SG), Sihosogan-tang (SS), and Sihocheonggan-tang (SC) have the potential to be candidate medicines for PD. This study aimed to compare the neuroprotective effect of SG, SS, and SC using 1-methyl-4-phenyl-1,2,3,6-tetrahydrophridine (MPTP)-induced PD mouse model. Methods : Eight-week-old male C57BL/6 mice were intraperitoneally administered with 30 mg/kg of MPTP for 5 days and orally administered SG, SS and SC for 12 days from the first MPTP injection. Motor function was assessed using the pole test and the rotarod test. Dopaminergic neuronal survival in the SN and striatum was evaluated through tyrosine-hydroxylase immunohistochemistry. Results : MPTP administration resulted in behavioral impairment and dopaminergic neuronal death in the SN and striatum. In the pole test, treatment with SG, SS, and SC alleviated the MPTP-induced motor dysfunction on day 5 and 12. In the rotarod test, SS and SG alleviated the MPTP-induced motor dysfunction on day 5, while only SS showed improvement on day 12. SS and SG significantly protected dopaminergic neurons in the SN from MPTP toxicity, and all three compounds (SG, SS, and SC) showed significant protection in the striatum. Notably, SS demonstrated superior efficacy in suppressing MPTP-induced motor dysfunction and dopaminergic neuronal death compared to SG and SC. Conclusions : These findings suggest that SS is the most effective formula among SG, SS, and SC for PD, indicating its potential role in the treatment of PD.

• Journal of Korean Biological Nursing Science
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• v.10 no.2
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• pp.176-183
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• 2008

Purpose: The purpose of this study was to identify the effect of Environmental Enrichment (EE) on improvement of motor function in animal models of Parkinson's Disease. Methods: Male C57BL6 mice weighing 25-30 g, at the age of 12 wks were used in this study. The animals were injected MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin, 20 mg/kg in saline, i.p.) 4 times a day at every 2 hr, and raised in EE cage for 14 days. On day 14, after behavior test, all mice were sacrificed for immunohistochemistry. All values were expressed as means$\pm$S.E.M. Statistical significance was evaluated using a one way ANOVA followed by Sheffe test. Results: There was a significant difference between the experimental group and the control group in the behavior test. Also EE significantly reduced of TH positive cell loss in Substantia nigra pars compacta as compared to the result of MPTP treatment. Conclusion: Based on these findings, it is reasonable to assume that the environmental enrichment prevents dopaminergic neuronal loss and improves disarrangement of motor function and behavioral disability induced by MPTP.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2008.04a
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• pp.49-52
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• 2008

Parkinson's disease is characterized by motor disturbances and dopaminergic neurodegeneration. parkin and PINK1, two most critical Parkinson's disease-associated genes, have been intensively studied to address the underlying molecular pathogenesis of the disease, but our understanding still remains unclear. Through generation and characterization of Drosophila mutants for PINK1, we show that PINK1 is required for mitochondrial integrity and function in both indirect flight muscles and dopaminergic neurons. Surprisingly, we find that PINK1 mutants share striking phenotypic similarities with parkin mutants. Indeed, transgenic expression of parkin dramatically ameliorates all PINK1 loss-of-function phenotypes, but not vice versa, implicating that Parkin acts downstream of PINK1 in maintaining mitochondrial integrity and function in both muscles and dopaminergic neurons. With the establishment of the PINK1-Parkin pathway, we are trying to further investigate the detailed molecular relationship between PINK1 and Parkin using both mammalian dopaminergic neuronal cells for biochemical analysis and Drosophila model animal for genetic analysis. We believe that elucidating the molecular function of Parkinson's disease-associated genes will be of big help for the ultimate understanding of the pathogenic mechanism of this disease and also for the development of effective drugs for Parkinson's disease.

• Molecules and Cells
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• v.43 no.3
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• pp.228-235
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• 2020

The Drosophila transmembrane semaphorin Sema-1a mediates forward and reverse signaling that plays an essential role in motor and central nervous system (CNS) axon pathfinding during embryonic neural development. Previous immunohistochemical analysis revealed that Sema-1a is expressed on most commissural and longitudinal axons in the CNS and five motor nerve branches in the peripheral nervous system (PNS). However, Sema-1a-mediated axon guidance function contributes significantly to both intersegmental nerve b (ISNb) and segmental nerve a (SNa), and slightly to ISNd and SNc, but not to ISN motor axon pathfinding. Here, we uncover three cis-regulatory elements (CREs), R34A03, R32H10, and R33F06, that robustly drove reporter expression in a large subset of neurons in the CNS. In the transgenic lines R34A03 and R32H10 reporter expression was consistently observed on both ISNb and SNa nerve branches, whereas in the line R33F06 reporter expression was irregularly detected on ISNb or SNa nerve branches in small subsets of abdominal hemisegments. Through complementation test with a Sema-1a loss-of-function allele, we found that neuronal expression of Sema-1a driven by each of R34A03 and R32H10 restores robustly the CNS and PNS motor axon guidance defects observed in Sema-1a homozygous mutants. However, when wild-type Sema-1a is expressed by R33F06 in Sema-1a mutants, the Sema-1a PNS axon guidance phenotypes are partially rescued while the Sema-1a CNS axon guidance defects are completely rescued. These results suggest that in a redundant manner, the CREs, R34A03, R32H10, and R33F06 govern the Sema-1a expression required for the axon guidance function of Sema-1a during embryonic neural development.

• Journal of Ginseng Research
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• v.45 no.3
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• pp.390-400
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• 2021

Background: We recently showed that gintonin, an active ginseng ingredient, exhibits antibrain neurodegenerative disease effects including multiple target mechanisms such as antioxidative stress and antiinflammation via the lysophosphatidic acid (LPA) receptors. Amyotrophic lateral sclerosis (ALS) is a spinal disease characterized by neurodegenerative changes in motor neurons with subsequent skeletal muscle paralysis and death. However, pathophysiological mechanisms of ALS are still elusive, and therapeutic drugs have not yet been developed. We investigate the putative alleviating effects of gintonin in ALS. Methods: The G93A-SOD1 transgenic mouse ALS model was used. Gintonin (50 or 100 mg/kg/day, p.o.) administration started from week seven. We performed histological analyses, immunoblot assays, and behavioral tests. Results: Gintonin extended mouse survival and relieved motor dysfunctions. Histological analyses of spinal cords revealed that gintonin increased the survival of motor neurons, expression of brain-derived neurotrophic factors, choline acetyltransferase, NeuN, and Nissl bodies compared with the vehicle control. Gintonin attenuated elevated spinal NAD(P) quinone oxidoreductase 1 expression and decreased oxidative stress-related ferritin, ionized calcium-binding adapter molecule 1-immunoreactive microglia, S100β-immunoreactive astrocyte, and Olig2-immunoreactive oligodendrocytes compared with the control vehicle. Interestingly, we found that the spinal LPA1 receptor level was decreased, whereas gintonin treatment restored decreased LPA1 receptor expression levels in the G93A-SOD1 transgenic mouse, thereby attenuating neurological symptoms and histological deficits. Conclusion: Gintonin-mediated symptomatic improvements of ALS might be associated with the attenuations of neuronal loss and oxidative stress via the spinal LPA1 receptor regulations. The present results suggest that the spinal LPA1 receptor is engaged in ALS, and gintonin may be useful for relieving ALS symptoms.

• Journal of Korean Neurosurgical Society
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• v.49 no.4
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• pp.205-211
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• 2011

Objective : We investigated the neuroprotective effect of anthocyanin, oxygen radical scavenger extracted from raspberries, after traumatic spinal cord injury (SCI) in rats. Methods : The animals were divided into two groups : the vehicle-treated group (control group, n=20) received an oral administration of normal saline via stomach intubation immediately after SCI, and the anthocyanin-treated group (AT group, n=20) received 400 mg/kg of cyanidin 3-O-${\beta}$-glucoside (C3G) in the same way. We compared the neurological functions, superoxide expressions and lesion volumes in two groups. Results : At 14 days after SCI, the AT group showed significant improvement of the BBB score by $16.7{\pm}3.4%$, platform hang by $40.0{\pm}9.1%$ and hind foot bar grab by $30.8{\pm}8.4%$ (p<0.05 in all outcomes). The degree of superoxide expression, represented by the ratio of red fluorescence intensity, was significantly lower in the AT group ($0.98{\pm}0.38$) than the control group ($1.34{\pm}0.24$) (p<0.05). The lesion volume in lesion periphery was $32.1{\pm}2.4\;{\mu}L$ in the control and $24.5{\pm}2.3\;{\mu}L$ in the AT group, respectively (p<0.05), and the motor neuron cell number of the anterior horn in lesion periphery was $8.3{\pm}5.1$ cells/HPF in the control and $13.4{\pm}6.3$ cells/HPF in the AT group, respectively (p<0.05). Conclusion : Anthocyanin seemed to reduce lesion volume and neuronal loss by its antioxidant effect and these resulted in improved functional recovery.

• The Korea Journal of Herbology
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• v.28 no.5
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• pp.21-28
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• 2013

Objectives : The aim of this study was to investigate the neuroprotective effects and mechanisms of Cyperi Rhizoma extracts (CRE) using in vitro and in vivo models of Parkinson's disease (PD). Methods : We evaluated the neuroprotective effect of CRE against 1-methyl-4-phenylpyridinium (MPP+) toxicity using tyrosine hydroxylase immunohistochemistry (IHC) in primary rat mesencephalic dopaminergic neurons. In addition, the effect of CRE was evaluated in mice PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). For evaluations, C57bl/6 mice were orally treated with CRE 50 mg/kg for 5 days and were injected intraperitoneally with MPTP (20 mg/kg) at 2 h intervals on the last day. To identify the CRE affects on MPTP-induced neuronal loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) and striatum of mice, the behavioral tests and IHC analysis were carried out. Also, we conducted nitric oxide (NO) and tumor necrosis factor-alpha (TNF-${\alpha}$) assay in dopaminergic neurons and IHC using glial markers in SNpc of mice to assess the anti-inflammation effects. Results : In primary mesencephalic culture system, CRE protected dopaminergic cells against $10{\mu}M$ MPP+-induced toxicity at 0.2 and $1.0{\mu}g/mL$. In the behavior tests, CRE treated group showed improved motor deteriorations than those in the MPTP only treated group. CRE significantly protected striatal dopaminergic damage from MPTP-induced neurotoxicity in mice. Moreover, CRE inhibited productions of NO and TNF-${\alpha}$ in dopaminergic culture system and activation of astrocyte and microglia in SNpc of the mice. Conclusion : We concluded that CRE shows anti-parkinsonian effect by protecting dopaminergic neurons against MPP+/MPTP toxicities through anti-inflammatory actions.

• BMB Reports
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• v.56 no.5
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• pp.308-313
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• 2023

Phenotypic features such as ataxia and loss of motor function, which are characteristics of Parkinson's disease (PD), are expected to be very closely related to cerebellum function. However, few studies have reported the function of the cerebellum. Since the cerebellum, like the cerebrum, is known to undergo functional and morphological changes due to neuroinflammatory processes, elucidating key functional factors that regulate neuroinflammation in the cerebellum can be a beneficial therapeutic approach. Therefore, we employed PD patients and MPTP-induced PD mouse model to find cytokines involved in cerebellar neuroinflammation in PD and to examine changes in cell function by regulating related genes. Along with the establishment of a PD mouse model, abnormal shapes such as arrangement and number of Purkinje cells in the cerebellum were confirmed based on histological finding, consistent with those of cerebellums of PD patients. As a result of proteome profiling for neuroinflammation using PD mouse cerebellar tissues, fetuin-A, a type of cytokine, was found to be significantly reduced in Purkinje cells. To further elucidate the function of fetuin-A, neurons isolated from cerebellums of embryos (E18) were treated with fetuin-A siRNA. We uncovered that not only the population of neuronal cells, but also their morphological appearances were significantly different. In this study, we found a functional gene called fetuin-A in the PD model's cerebellum, which was closely related to the role of cerebellar Purkinje cells of mouse and human PD. In conclusion, morphological abnormalities of Purkinje cells in PD mice and patients have a close relationship with a decrease of fetuin-A, suggesting that diagnosis and treatment of cerebellar functions of PD patients might be possible through regulation of fetuin-A.