Chan Young Shin’s research while affiliated with Konkuk University and other places
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Alzheimer's disease (AD) is a well-known neurodegenerative brain disease, and no curative treatment has yet been developed. The main symptoms include various brain lesions, caused by amyloid β (Aβ) aggregation, and cognitive decline. Therefore, it is believed that substances that control Aβ will inhibit the onset of Alzheimer's disease and slow its progression. In this study, the effect of phyllodulcin, a major component of hydrangea, on Aβ aggregation and brain pathology in an animal model of AD was studied. Phyllodulcin inhibited the aggregation of Aβ and decomposed the pre-aggregated Aβ in a concentration-dependent manner. In addition, it inhibited the cytotoxicity of Aβ aggregates. Oral administration of phyllodulcin improved Aβ-induced memory impairments in normal mice, reduced Aβ deposition in the hippocampus, inhibited the activation of microglia and astrocytes, and improved synaptic plasticity in 5XFAD mice. These results suggest that phyllodulcin may be a candidate for the treatment of AD.
Tetrazoles were designed and synthesized as potential inhibitors of triple monoamine neurotransmitters (dopamine, norepinephrine, serotonin) reuptake based on the functional and docking simulation of compound 6 which were performed in a previous study. The compound structure consisted of a tetrazole-linker (n)-piperidine/piperazine-spacer (m)-phenyl ring, with tetrazole attached to two phenyl rings (R1 and R2). Altering the carbon number in the linker (n) from 3 to 4 and in the spacer (m) from 0 to 1 increased the potency of serotonin reuptake inhibition. Depending on the nature of piperidine/piperazine, the substituents at R1 and R2 exerted various effects in determining their inhibitory effects on monoamine reuptake. Docking study showed that the selectivity of tetrazole for different transporters was determined based on multiple interactions with various residues on transporters, including hydrophobic residues on transmembrane domains 1, 3, 6, and 8. Co-expression of dopamine transporter, which lowers dopamine concentration in the biophase by uptaking dopamine into the cells, inhibited the dopamine-induced endoctytosis of dopamine D2 receptor. When tested for compound 40 and 56, compound 40 which has more potent inhibitory activity on dopamine reuptake more strongly disinhibited the inhibitory activity of dopamine transporter on the endocytosis of dopamine D2 receptor. Overall, we identified candidate inhibitors of triple monoamine neurotransmitter reuptake and provided a theoretical background for identifying such neurotransmitter modifiers for developing novel therapeutic agents of various neuropsychiatric disorders.
Parabens are widely used preservatives in cosmetics and pharmaceutical products and are approved as food additives. These chemicals have been considered safe for many years. However, the literature classifies parabens as endocrine-disrupting chemicals, and an assessment of their influence on the endocrine system and systemic toxicity is important. This study explored long-term systemic toxicity, effects on the endocrine system, and toxicokinetic behavior after repeated subcutaneous administration of butylparaben to Sprague–Dawley rats. Rats were treated with vehicle (4% Tween 80) or butylparaben at dose levels of 2, 10, and 50 mg/kg/day for 13 weeks. Assessment of systemic toxicity and endocrine-disrupting effects was based on mortality; clinical signs; body weight; food and water consumption; ophthalmological findings; urinalysis; hematology and clinical biochemistry; organ weights; necropsy and histopathological findings; regularity and length of the estrous cycle; semen quality; and toxicokinetic behavior. Female uterine weight and estrous cycle, and male semen quality indicated no estrogenic effects. Butylparaben induced local irritation at the injection site in both sexes at a dose of 50 mg/kg/day, but systemic toxicity was not observed. Therefore, the no-observed-adverse-effect level of butylparaben is set at 50 mg/kg/day in rats of both sexes. Butylparaben was without endocrine system effects at this dose. Butylparaben displays dose-dependent systemic exposure up to the maximum dose of 50 mg/kg/day and repeated administration of butylparaben for 13 weeks shows no bioaccumulation.
Air pollution has become one of the most serious issues for human health and has been shown to be particularly concerning for neural and cognitive health. Recent studies suggest that fine particulate matter of less than 2.5 (PM2.5), common in air pollution, can reach the brain, potentially resulting in the development and acceleration of various neurological disorders including Alzheimer’s disease, Parkinson’s disease, and other forms of dementia, but the underlying pathological mechanisms are not clear. Astaxanthin is a red-colored phytonutrient carotenoid that has been known for anti-inflammatory and neuroprotective effects. In this study, we demonstrated that exposure to PM2.5 increases the neuroinflammation, the expression of proinflammatory M1, and disease-associated microglia (DAM) signature markers in microglial cells, and that treatment with astaxanthin can prevent the neurotoxic effects of this exposure through anti-inflammatory properties. Diesel particulate matter (Sigma-Aldrich) was used as a fine particulate matter 2.5 in the present study. Cultured rat glial cells and BV-2 microglial cells were treated with various concentrations of PM2.5, and then the expression of various inflammatory mediators and signaling pathways were measured using qRT-PCR and Western blot. Astaxanthin was then added and assayed as above to evaluate its effects on microglial changes, inflammation, and toxicity induced by PM2.5. PM2.5 increased the production of nitric oxide and reactive oxygen species and upregulated the transcription of various proinflammatory markers including Interleukin-1β (IL-1β), Interleukin-6 (IL-6), Tumor necrosis factor α (TNFα), inducible nitric oxide synthase (iNOS), triggering receptor expressed on myeloid cells 2 (TREM2), Toll-like receptor 2/4 (TLR2/4), and cyclooxygenase-2 (COX-2) in BV-2 microglial cells. However, the mRNA expression of IL-10 and arginase-1 decreased following PM2.5 treatment. PM2.5 treatment increased c-Jun N-terminal kinases (JNK) phosphorylation and decreased Akt phosphorylation. Astaxanthin attenuated these PM2.5-induced responses, reducing transcription of the proinflammatory markers iNOS and heme oxygenase-1 (HO-1), which prevented neuronal cell death. Our results indicate that PM2.5 exposure reformulates microglia via proinflammatory M1 and DAM phenotype, leading to neurotoxicity, and the fact that astaxanthin treatment can prevent neurotoxicity by inhibiting transition to the proinflammatory M1 and DAM phenotypes. These results demonstrate that PM2.5 exposure can induce brain damage through the change of proinflammatory M1 and DAM signatures in the microglial cells, as well as the fact that astaxanthin can have a potential beneficial effect on PM2.5 exposure of the brain.
Post-stroke dementia (PSD) is a major neurodegenerative consequence of stroke. Tauopathy has been reported in diverse neurodegenerative diseases. We investigated the cognitive impairment and pathomechanism associated with tauopathy in a rat model of PSD by modeling acute ischemic stroke and underlying chronic cerebral hypoperfusion (CCH). We performed middle cerebral artery occlusion (MCAO) surgery in rats to mimic acute ischemic stroke, followed by bilateral common carotid artery occlusion (BCCAo) surgery to mimic CCH. We performed behavioral tests and focused on the characterization of tauopathy through histology. Parenchymal infiltration of cerebrospinal fluid (CSF) tracers after intracisternal injection was examined to evaluate glymphatic function. In an animal model of PSD, cognitive impairment was aggravated when BCCAo was combined with MCAO. Tauopathy, manifested by tau hyperphosphorylation, was prominent in the peri-infarct area when CCH was combined. Synergistic accentuation of tauopathy was evident in the white matter. Microtubules in the neuronal axon and myelin sheath showed partial colocalization with the hyperphosphorylated tau, whereas oligodendrocytes showed near-complete colocalization. Parenchymal infiltration of CSF tracers was attenuated in the PSD model. Our experimental results suggest a hypothesis that CCH may aggravate cognitive impairment and tau hyperphosphorylation in a rat model of PSD by interfering with tau clearance through the glymphatic system. Therapeutic strategies to improve the clearance of brain metabolic wastes, including tau, may be a promising approach to prevent PSD after stroke.
The γ-aminobutyric acid A (GABAA) receptor, which contains a chloride channel, is a typical inhibitory neurotransmitter receptor in the central nervous system. Although the GABAergic neurotransmitter system has been discovered to be involved in various psychological behaviors, such as anxiety, convulsions, and cognitive function, its functional changes under conditions of ischemic pathological situation are still uncovered. In the present study, we attempted to elucidate the functional changes in the GABAergic system after transient forebrain ischemia in mice. A bilateral common carotid artery occlusion for 20 min was used to establish a model of transient forebrain ischemia/reperfusion (tI/R). Delayed treatment with diazepam, a positive allosteric modulator of the GABAA receptor, increased locomotor activity in the open field test and spontaneous alternations in the Y-maze test in tI/R mice, but not in shams. Delayed treatment with diazepam did not alter neuronal death or the number of GABAergic neurons in tI/R mice. However, tI/R induced changes in the protein levels of GABAA receptor subunits in the hippocampus. In particular, the most marked increase in the tI/R group was found in the level of α5 subunit of the GABAA receptor. Similar to delayed treatment with diazepam, delayed treatment with imidazenil, an α5-sensitive benzodiazepine, increased spontaneous alternations in the Y-maze in tI/R mice, whereas zolpidem, an α5-insensitive benzodiazepine, failed to show such effects. These results suggest that tI/R-induced changes in the level of the α5 subunit of the GABAA receptor can alter the function of GABAergic drugs in a mouse model of forebrain ischemia.
Sporadic Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder affected by amyloid and vascular pathogenesis. Brain insulin resistance (BIR) has been suggested as one of the pathomechanisms of sporadic AD. We investigated how the amyloid and vascular pathogenesis of AD interacts with BIR. We examined experimental groups mimicking amyloid pathogenesis following intracerebroventriculr (icv) injection of amyloid β or vascular pathogenesis following permanent ligation of the bilateral common carotid arteries in Wistar rats that had undergone icv injection of streptozotocin. Behavioral tests and pathologic studies were performed. Cognitive impairments were induced by BIR superimposed by amyloid or vascular pathogenesis. Neuroinflammation in the white matter and hippocampus was aggravated by an interaction between BIR and vascular pathogenesis. Amyloid-associated pathology in the white matter was enhanced by BIR and vascular pathogenesis. Tau-associated pathology in the hippocampus was altered by BIR in a relation with amyloid or vascular pathogenesis. Our study may provide useful experimental insights based on an integrated approach to the influence of amyloid and vascular pathogenesis on BIR, permitting better understanding of the heterogeneous pathogenesis of sporadic AD. Pathologic responses in sporadic AD may differ depending on amyloid and vascular pathogenesis and may sometimes be synergistically aggravated when combined with BIR.
Despite some innate limitations, animal models are a potent investigative tool when used to model specific symptoms of a disorder. For example, MK-801, an N-methyl-D-aspartate receptor antagonist, is used as a pharmacological tool to induce symptoms found in some neuropsychiatric disorders. However, a close examination of literature suggests that the application window of MK-801 doses is relatively narrow between individual behavioral paradigms, necessitating careful characterization of the evoked behavioral aberrations and the doses used to induce them. Moreover, variation in behaviors depending on the animal strain, gender of the subject, and the timing of administration is observed, making it difficult to compare the behavioral characteristics reported in different studies. We aim to characterize the behavioral aberrations induced by different doses of MK-801 in CD-1 mice and create a ready reference for future studies. We used CD-1 mice to recapitulate behavioral impairments resulting from acute administration of MK-801. In 0.1 mg kg-1, we observed diminished spontaneous alteration during the Y-maze test, while 0.12 mg kg-1 resulted in hyperlocomotion and social deficit. Mice treated with 0.2 and 0.3 mg kg-1 of MK-801 demonstrated a decreased self-grooming. Finally, all doses significantly impaired cliff avoidance behaviors suggesting increased impulsivity. These results affirm that MK-801 can effectively model various symptoms of different neuropsychiatric disorders in a dose-dependent manner. The observed sensitivity against spatial-memory impairment and impulsive behaviors at low concentration of MK-801 suggest that MK801 may modulate cognitive function and impulsivity in even lower concentration before it can modulate other behavioral domains.
Brain aging is an inevitable process characterized by structural and functional changes and is a major risk factor for neurodegenerative diseases. Most brain aging studies are focused on neurons and less on astrocytes which are the most abundant cells in the brain known to be in charge of various functions including the maintenance of brain physical formation, ion homeostasis, and secretion of various extracellular matrix proteins. Altered mitochondrial dynamics, defective mitophagy or mitochondrial damages are causative factors of mitochondrial dysfunction, which is linked to age-related disorders. Etoposide is an anti-cancer reagent which can induce DNA stress and cellular senescence of cancer cell lines. In this study, we investigated whether etoposide induces senescence and functional alterations in cultured rat astrocytes. Senescence-associated β-galactosidase (SA-β-gal) activity was used as a cellular senescence marker. The results indicated that etoposide-treated astrocytes showed cellular senescence phenotypes including increased SA-β-gal-positive cells number, increased nuclear size and increased senescence-associated secretory phenotypes (SASP) such as IL-6. We also observed a decreased expression of cell cycle markers, including Phospho-Histone H3/Histone H3 and CDK2, and dysregulation of cellular functions based on wound-healing, neuronal protection, and phagocytosis assays. Finally, mitochondrial dysfunction was noted through the determination of mitochondrial membrane potential using tetramethylrhodamine methyl ester (TMRM) and the measurement of mitochondrial oxygen consumption rate (OCR). These data suggest that etoposide can induce cellular senescence and mitochondrial dysfunction in astrocytes which may have implications in brain aging and neurodegenerative conditions.
... Longterm potentiation (LTP) is always positively correlated with cognitive function. Consistent with previous studies [46][47][48][49], we found that 5×FAD mice exhibited a significantly impaired LTP when compared with WT mice and such impairment was remarkably restored through chronic CBD administration (Supplementary Fig. 8). ...
... The low remission rate of depression may be due to the slow onset of conventional treatments. A suggested strategy to enhance drug efficacy is combining dopamine with selective serotonin reuptake inhibitors or dual reuptake inhibitors [120,121]. Triple reuptake inhibitors, which target serotonin, norepinephrine, and dopamine reuptake, are gaining interest for their potential to boost dopamine neurotransmission, a feat not achieved by conventional methods [118]. ...
... В противном случае, когда новорожденные крысы подвергались воздействию различных доз бутил-, метил-или пропилпарабена, ранняя фаза фолликулогенеза подавлялась, и экспрессия генов, участвующих в стероидогенезе, нарушалась, в то время как воздействие различных доз парабена на крыс в перипубертатном периоде приводило к уменьшению количества желтых тел в яичниках и истончению фолликулярного эпителия, а также к увеличению частоты обнаружения кистозных фолликулов. У животных, получавших бутил-, изобутил-, пропил-и изопропилпарабены наблюдалась гипертрофия миометрия [36,37]. Введение крысам бутилпарабена на протяжении всей беременности и лактации, по-видимому, не влияло на функцию и развитие яичников у самок потомства [38,39]. ...
... Research shows that PM 2.5 accelerates cognitive decline by affecting glucose metabolism, immune response, and neuroinflammation. Specifically, PM 2.5 exposure promotes microglial cells to switch from the M2 to the M1 phenotype, which secretes large amounts of pro-inflammatory factors (such as IL-1β, TNF-α), exacerbating neuroinflammation and thereby impairing cognitive function [32,33]. Moreover, PM 2.5 directly damages neuronal cells through oxidative stress, affecting the blood-brain barrier and promoting the accumulation of neurodegenerative markers (such as Aβ42 and tau protein), suggesting a potential role in the early pathological development of Alzheimer's disease [34,35]. ...
... Studies have shown that the absence of perivascular AQP4 localization impairs glymphatic exchange in mice and promotes the formation of Aβ plaques [ 49 ]. Chronic cerebral hypoperfusion induces dementia after ischemic stroke in rats by interfering with Aβ and tau clearance via the glymphatic pathway, with neuroinflammatory response that changes AQP4 distribution from perivascular to parenchymal [ 64 ]. Therefore, by improving AQP4 polarization, PBM restores ISF drainage after stroke, thereby preventing PSCI. ...
... GABA-mediated synaptic depression plays a critical role in normal neural functioning [43], and research has shown that abnormalities in GABAA receptor subunits can contribute to various central nervous system disorders, including anxiety disorders, epilepsy, schizophrenia, and insomnia [44][45][46]. The proper expression of GABAA receptor subunits is also closely linked to learning and memory functions [47][48][49]. Studies conducted in mice have demonstrated that knock-out of the Gabrq upstream transcriptional factor Egr-1 leads to a significant decrease in the expression of GABRQ and other GABA receptor subunits in the hippocampal tissue, resulting in long-term spatial memory impairment [50]. ...
... Brain insulin resistance (BIR), unlike T2DM, can manifest without peripheral diabetes and is posited to be associated with AD pathogenesis (Rhea et al. 2024;Andrade et al. 2024) through mechanisms such as neuroinflammation and oxidative stress, which compromise neuronal function (for overview see (Kakoty et al. 2023). The scientific literature also refers to BIR as type 3 diabetes mellitus (T3DM), which is associated with brain-predominant diabetes that contributes to AD (de la Monte 2023; Kciuk et al. 2024;Peng et al. 2024).The aggregation of Aβ peptides in BIR induces inflammatory responses that exacerbate neuronal integrity and cognitive function deterioration (Choi et al. 2020). Nonetheless, BIR does not appear to be unique to AD, since epidemiological research indicates a correlation between diabetes and an elevated risk of Parkinson's disease (PD), with insulin resistance significantly contributing to the degradation of dopaminergic neurons (Kakoty et al. 2023;Sian-Hulsmann et al. 2024). ...
... In particular, systemic administrations of the non-competitive NMDA receptor antagonist MK-801 (dizocilpine), ketamine, and memantine are the most frequently used substances in basic and preclinical animal research [22,25,29]. Although MK-801 is highly used in rodent and fish models [18,22,[34][35][36], ketamine was used in our study as it is one of the most frequently used substances to model psychosis and cognitive deficits in human research. Moreover, although MK-801 is commonly used in preclinical research, ketamine is the only NMDA receptor antagonist that has been extensively tested in clinical settings and is primarily used to model psychosis and cognitive disruption in humans [22,25,37]. ...
... A third limitation of this study centers on the need to further delineate the highly contextual nature by which autophagy is regulated in DNA-damaged cells in the absence or presence of conditions that impair vital functions and/or promote loss of viability. DNA damaging chemical agents, such as etoposide, 6 camptothecin, 60 5-FU, 19 and p-Anilinoaniline (pAA), 59 can invoke off-target effects associated with autophagy activation including mitochondrial damage (etoposide, camptothecin), 88-91 ROS generation (etoposide, camptothecin), 88,90,92 and impaired ribosome biogenesis (5-FU), 93,94 which are associated with autophagy activation that is independent of DNA damage. [95][96][97][98] Our studies described above indicate that etoposide-dependent autophagy activation results only when using concentrations of and exposure to etoposide sufficient to induce DNA damage and detectable loss of cell viability ( Figure S7). ...
... The mPFC, specifically layer 2/3 pyramidal neurons in the brain, has been implicated in altered neuronal responses and ASD-like behaviors (Kim et al. 2019a; Kim et al. 2019b;Yizhar et al. 2011). We recorded resting membrane potential (RMP) and neuronal excitability in layer 2/3 pyramidal neurons of infralimbic cortex (IL) of vehicle -and bicuculline-treated mice. ...
![The toxic effects of PM2.5 treatment on cultured glial cells. Rat primary cultured glial cells were treated in Dulbecco’s modified Eagle’s medium (DMEM)/F12 with increasing concentration of PM2.5 (5, 25, 50, 100 µg/mL) for 24 h. (A) Toxic effects of PM2.5 in cultured glial cells. After 24 h, cell morphology was measured by phase contrast imaging. Bar size = 50 μm. (B) High magnification. Scale bar = 50 μm. (C) Nitrite production in the medium was assessed using Griess reagent. Rat primary cultured glial cells were incubated in DMEM/F12 with increasing concentration of PM2.5 (1, 5, 25, 50, 100 µg/mL) for each incubation time. (D) Intracellular reactive oxygen species (ROS) production was measured by 2′,7′-Dichlorodihydrofluorescein diacetate (H2DCF-DA) fluorescence (490/530 nm). (E) Effect on cell viability was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay. Rat primary cultured glial cells were incubated in DMEM/F12 with increasing concentration of PM2.5 (5, 25, 50, 100 µg/mL) for 24 h. Data represent means ± SEM. (n = 4) * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001; veh (0.1% DMSO) vs. PM2.5.](https://www.researchgate.net/publication/346044546/figure/fig1/AS:11431281388375922@1745168196822/The-toxic-effects-of-PM25-treatment-on-cultured-glial-cells-Rat-primary-cultured-glial_Q320.jpg)
