Publications by authors named "Kyu-Yong Lee"

54 Publications

Efficacy and safety of GV1001 in patients with moderate-to-severe Alzheimer's disease already receiving donepezil: a phase 2 randomized, double-blind, placebo-controlled, multicenter clinical trial.

Alzheimers Res Ther 2021 03 26;13(1):66. Epub 2021 Mar 26.

Department of Neurology, Hanyang University Guri Hospital, Hanyang University College of Medicine, 153, Gyeongchun-ro, Guri, 11923, South Korea.

Background: Our previous studies showed that GV1001 has various protective effects against β-amyloid and other stressors. Based on these findings, we hypothesized that GV1001 might have beneficial effects in patients with Alzheimer's disease (AD).

Methods: A phase 2, double-blind, parallel-group, placebo-controlled, 6-month randomized clinical trial was performed to evaluate the safety and efficacy of subcutaneously administered GV1001. Between September 2017 and September 2019, 13 centers in South Korea recruited participants. A total of 106 patients were screened, and 96 patients with moderate-to-severe AD were randomized 1:1:1 to the placebo (group 1, n = 31), GV1001 0.56 mg (group 2, n = 33), and 1.12 mg (group 3, n = 32) groups. GV1001 was administered every week for 4 weeks (4 times), followed by every 2 weeks until week 24 (10 times). The primary endpoint was the change in the Severe Impairment Battery (SIB) score from baseline to week 24. The key secondary efficacy endpoints were the change in the Clinical Dementia Rating Sum of Box (CDR-SOB), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), Neuropsychiatric Inventory (NPI), Mini-Mental State Examination, and Global Deterioration Scale scores. The safety endpoints were also assessed based on adverse events, laboratory test results, vital signs, and other observations related to safety.

Results: Group 3 showed less decrease in the SIB score at 12 and 24 weeks compared with group 1 (P < 0.05). These were not significantly observed in group 2. Among the secondary endpoints, only the NPI score showed significantly better improvement in group 2 than in group 3 at week 12; however, there were no other significant differences between the groups. Although the ADCS-ADL and CDR-SOB scores showed a pattern similar to SIB scores, a statistically significant result was not found. Adverse events were similar across all three groups.

Conclusions: The results indicate that GV1001 1.12 mg met the primary endpoint of a statistically significant difference. GV1001 was well tolerated without safety concerns. This study warrants a larger clinical trial.

Trial Registration: ClinicalTrials.gov NCT03184467 . Registered on June 12, 2017.
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http://dx.doi.org/10.1186/s13195-021-00803-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995588PMC
March 2021

Telmisartan Inhibits the NLRP3 Inflammasome by Activating the PI3K Pathway in Neural Stem Cells Injured by Oxygen-Glucose Deprivation.

Mol Neurobiol 2021 Apr 6;58(4):1806-1818. Epub 2021 Jan 6.

Department of Neurology, Hanyang University Guri Hospital, 153, Gyeongchun-ro, Guri, 11923, South Korea.

Angiotensin II receptor blockers (ARBs) have been shown to exert neuroprotective effects by suppressing inflammatory and apoptotic responses. In the present study, the effects of the ARB telmisartan on the NLRP3 inflammasome induced by oxygen-glucose deprivation (OGD) in neural stem cells (NSCs) were investigated, as well as their possible association with the activation of the PI3K pathway. Cultured NSCs were treated with different concentrations of telmisartan and subjected to various durations of OGD. Cell counting, lactate dehydrogenase, bromodeoxyuridine, and colony-forming unit assays were performed to measure cell viability and proliferation. In addition, the activity of intracellular signaling pathways associated with the PI3K pathway and NLRP3 inflammasome was evaluated. Telmisartan alone did not affect NSCs up to a concentration of 10 μM under normal conditions but showed toxicity at a concentration of 100 μM. Moreover, OGD reduced the viability of NSCs in a time-dependent manner. Nevertheless, treatment with telmisartan increased the viability and proliferation of OGD-injured NSCs. Furthermore, telmisartan promoted the expression of survival-related proteins and mRNA while inhibiting the expression of death-related proteins induced by OGD. In particular, telmisartan attenuated OGD-dependent expression of the NLRP3 inflammasome and its related signaling proteins. These beneficial effects of telmisartan were blocked by a PI3K inhibitor. Together, these results indicate that telmisartan attenuated the activation of the NLRP3 inflammasome by triggering the PI3K pathway, thereby contributing to neuroprotection.
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http://dx.doi.org/10.1007/s12035-020-02253-1DOI Listing
April 2021

Use of methotrexate in the management of recurrent Tolosa-Hunt syndrome: Two case reports.

Medicine (Baltimore) 2020 Apr;99(17):e19882

Department of Neurology.

Rationale: Tolosa-Hunt syndrome (THS) is rare condition characterized by painful ophthalmoplegia that usually responds well to corticosteroid. About a half of THS patients experience recurrence within intervals of months to years from initial presentation. Recurrence is more common in younger patients, and can be ipsilateral, contralateral, or bilateral. Cyclosporine, azathioprine, methotrexate, mycophenolate mofetil, infliximab, and radiotherapy can be considered as second-line treatment. However, there is insufficient evidence for treatments preventing recurrence of THS.

Patient Concerns: We experienced two patients with THS that recurred twice while tapering or after ceasing corticosteroid administration.

Diagnosis: Both patients were diagnosed as recurrent THS.

Interventions: Methotrexate was treated with a combination of corticosteroid after THS recurred twice with corticosteroid therapy alone.

Outcomes: After adding methotrexate to the steroid regimen, their symptoms were successfully regulated and ceased to recur LESSONS:: These cases add to the evidence for the use of methotrexate as a second-line therapeutic agent for those patients with recurrent THS attacks. Further studies are in need to prove the risk and benefits of second-line treatments in THS.
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http://dx.doi.org/10.1097/MD.0000000000019882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220784PMC
April 2020

A Case of Anti-NMDA Receptor Encephalitis with Normal Findings on Initial Diagnostic Tests.

Dement Neurocogn Disord 2020 Mar 27;19(1):28-30. Epub 2020 Feb 27.

Department of Neurology, Hanyang University College of Medicine, Seoul, Korea.

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http://dx.doi.org/10.12779/dnd.2020.19.1.28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105718PMC
March 2020

Early increment of soluble triggering receptor expressed on myeloid cells 2 in plasma might be a predictor of poor outcome after ischemic stroke.

J Clin Neurosci 2020 Mar 14;73:215-218. Epub 2020 Feb 14.

Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea; Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul, Republic of Korea. Electronic address:

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is derived from cleavage of TREM2, which is expressed on the cell surface of microlgia and other tissue-specific macrophages. In the present study, the changes in the sTREM2 levels after ischemic stroke (IS) and their association with clinical outcomes were evaluated. A total of 43 patients diagnosed with non-cardioembolic IS between June 2011 and May 2014 were consecutively included in this study. Patients treated with intravenous thrombolysis or intra-arterial thrombectomy were excluded. Plasma samples were collected three times (days 1, 7, and 90) after ictus. The sTREM2 level was measured in the samples using the highly sensitive solid-phase proximity ligation assay (SP-PLA). Among the 43 subjects, higher initial NIH stroke scale (NIHSS) score (P = 0.005), early increment of sTREM2 (P < 0.001), and late decrement of sTREM2 (P = 0.002), were more common in patients with poor outcome. Based on multivariate analysis, initial NIHSS score (P = 0.015) and early increment of sTREM2 (P = 0.032) were independently associated with poor outcome. The results from the present study indicate that increment of sTREM2 level at the early phase was a predictor of poor outcome. Serial follow-up of sTREM2 may aid prognosis after stroke.
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http://dx.doi.org/10.1016/j.jocn.2020.02.016DOI Listing
March 2020

LGR5 and Downstream Intracellular Signaling Proteins Play Critical Roles in the Cell Proliferation of Neuroblastoma, Meningioma and Pituitary Adenoma.

Exp Neurobiol 2019 Oct;28(5):628-641

Department of Neurology, Hanyang University Guri Hospital, Guri 11923, Korea.

Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) has been reported to play critical roles in the proliferation of various cancer cells. However, the roles of LGR5 in brain tumors and the specific intracellular signaling proteins directly associated with it remain unknown. Expression of LGR5 was first measured in normal brain tissue, meningioma, and pituitary adenoma of humans. To identify the downstream signaling pathways of LGR5, siRNA-mediated knockdown of was performed in SH-SY5Y neuroblastoma cells followed by proteomics analysis with 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE). In addition, the expression of LGR5-associated proteins was evaluated in LGR5-inhibited neuroblastoma cells and in human normal brain, meningioma, and pituitary adenoma tissue. Proteomics analysis showed 12 protein spots were significantly different in expression level (more than two-fold change) and subsequently identified by peptide mass fingerprinting. A protein association network was constructed from the 12 identified proteins altered by knockdown. Direct and indirect interactions were identified among the 12 proteins. HSP 90-beta was one of the proteins whose expression was altered by knockdown. Likewise, we observed decreased expression of proteins in the hnRNP subfamily following knockdown. In addition, we have for the first time identified significantly higher hnRNP family expression in meningioma and pituitary adenoma compared to normal brain tissue. Taken together, LGR5 and its downstream signaling play critical roles in neuroblastoma and brain tumors such as meningioma and pituitary adenoma.
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http://dx.doi.org/10.5607/en.2019.28.5.628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844835PMC
October 2019

Mitochondria damaged by Oxygen Glucose Deprivation can be Restored through Activation of the PI3K/Akt Pathway and Inhibition of Calcium Influx by Amlodipine Camsylate.

Sci Rep 2019 10 31;9(1):15717. Epub 2019 Oct 31.

Departments of Neurology, Hanyang University Guri Hospital, 11923, Guri, Korea.

Amlodipine, a L-type calcium channel blocker, has been reported to have a neuroprotective effect in brain ischemia. Mitochondrial calcium overload leads to apoptosis of cells in neurologic diseases. We evaluated the neuroprotective effects of amlodipine camsylate (AC) on neural stem cells (NSCs) injured by oxygen glucose deprivation (OGD) with a focus on mitochondrial structure and function. NSCs were isolated from rodent embryonic brains. Effects of AC on cell viability, proliferation, level of free radicals, and expression of intracellular signaling proteins were assessed in OGD-injured NSCs. We also investigated the effect of AC on mitochondrial structure in NSCs under OGD by transmission electron microscopy. AC increased the viability and proliferation of NSCs. This beneficial effect of AC was achieved by strong protection of mitochondria. AC markedly enhanced the expression of mitochondrial biogenesis-related proteins and mitochondrial anti-apoptosis proteins. Together, our results indicate that AC protects OGD-injured NSCs by protecting mitochondrial structure and function. The results of the present study provide insight into the mechanisms underlying the protective effects of AC on NSCs.
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http://dx.doi.org/10.1038/s41598-019-52083-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823474PMC
October 2019

A Sudden Deterioration in Cognitive Functions as the Result of a Central Nervous System Lymphoma.

Dement Neurocogn Disord 2018 Jun 6;17(2):71-72. Epub 2018 Aug 6.

Department of Neurology, Hanyang University Guri Hospital, Guri, Korea.

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http://dx.doi.org/10.12779/dnd.2018.17.2.71DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6427973PMC
June 2018

Sublethal Doses of Zinc Protect Rat Neural Stem Cells Against Hypoxia Through Activation of the PI3K Pathway.

Stem Cells Dev 2019 06 22;28(12):769-780. Epub 2019 Apr 22.

1 Department of Neurology, Hanyang University College of Medicine, Seoul, Korea.

Cerebral infarction is one of the major causes of severe morbidity and mortality, and thus, research has focused on developing treatment options for this condition. Zinc (Zn) is an essential element in the central nervous system and has several neuroprotective effects in the brain. In this study, we examined the neuroprotective effects of Zn on neural stem cells (NSCs) exposed to hypoxia. After treatment with several concentrations of Zn, the viability of NSCs under hypoxic conditions was measured by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Trypan blue staining, and a lactate dehydrogenase assay. To evaluate the effect of Zn on the proliferation of NSCs, bromodeoxyuridine/5-bromo-2'-deoxyuridine (BrdU) labeling and colony formation assays were performed. Apoptosis was also examined in NSCs exposed to hypoxia with and without Zn treatment. In addition, a western blot analysis was performed to evaluate the effect of Zn on intracellular signaling proteins. NSC viability and proliferation were decreased under hypoxic conditions, but treatment with sublethal doses of Zn restored viability and proliferation. Sublethal doses of Zn reduced apoptosis caused by hypoxia, increased the expression levels of proteins related to the phosphatidylinositol-3 kinase (PI3K) pathway, and decreased the expression levels of proteins associated with neuronal cell death. These findings confirm that in vivo, sublethal doses of Zn protect NSCs against hypoxia through the activation of the PI3K pathway. Thus, Zn could be employed as a therapeutic option to protect NSCs in ischemic stroke.
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http://dx.doi.org/10.1089/scd.2018.0138DOI Listing
June 2019

Atorvastatin Rejuvenates Neural Stem Cells Injured by Oxygen-Glucose Deprivation and Induces Neuronal Differentiation Through Activating the PI3K/Akt and ERK Pathways.

Mol Neurobiol 2019 Apr 3;56(4):2964-2977. Epub 2018 Aug 3.

Department of Neurology, Hanyang University College of Medicine, Gyeongchun-ro, Guri-Si, 11923, Gyeonggi-do, Republic of Korea.

Oxygen and glucose (OGD) deprivation is one of the most important pathogenic mechanisms in cerebral infarction and is widely used as an in vitro model for ischemic stroke. OGD also damages neural stem cells (NSCs), which are important in brain recovery after cerebral infarction. To enhance recovery, there have been many studies aimed at determining methods to protect NSCs after stroke. Because atorvastatin has diverse protective effects on neural cells, we studied whether it could rejuvenate NSCs injured by OGD. Primary cultured NSCs were exposed to OGD for 8 h, and the main characteristics of stem cells, such as survival, proliferation, migration, and differentiation, were evaluated to confirm the effect of OGD on NSCs. Next, cells were treated with various concentrations of atorvastatin with exposure to OGD for 8 h to confirm whether it could rejuvenate NSCs. OGD significantly affected the survival, proliferation, migration, and differentiation of NSCs. However, treatment with atorvastatin meaningfully restored survival, proliferation, migration, and differentiation of NSCs. These beneficial effects of atorvastatin were blocked by treatment with either a PI3K inhibitor or an ERK inhibitor. In conclusion, OGD damages NSCs and causes them to lose the main characteristics of stem cells so that they cannot contribute to brain recovery after cerebral infarction. However, treatment with atorvastatin after cerebral infarction can effectively rejuvenate NSCs through activating the PI3K and ERK pathways to aid in brain regeneration.
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http://dx.doi.org/10.1007/s12035-018-1267-6DOI Listing
April 2019

Tracking and protection of transplanted stem cells using a ferrocenecarboxylic acid-conjugated peptide that mimics hTERT.

Biomaterials 2018 Feb 14;155:80-91. Epub 2017 Nov 14.

Department of Neurology, Hanyang University Guri Hospital, 153, Gyeongchun-ro, Guri-si, Gyeonggi-do 11923, South Korea; Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul, 04763, South Korea. Electronic address:

In vivo tracking of transplanted stem cells has been a central aim of stem cell therapy. Although many tracking systems have been introduced, no method has yet been validated for clinical applications. We developed a novel sophisticated peptide (GV1001) that mimics hTERT (human telomerase reverse transcriptase) and analysed its ability to track and protect stem cells after transplantation. Ferrocenecarboxylic acid-conjugated GV1001 (Fe-GV1001) efficiently penetrated stem cells with no adverse effects. Moreover, Fe-GV1001 improved the viability, proliferation, and migration of stem cells under hypoxia. After Fe-GV1001-labelled stem cells were transplanted into the brains of rats after stroke, the labelled cells were easily tracked by MRI. Our findings indicate that Fe-GV1001 can be used for the in vivo tracking of stem cells after transplantation into the brain and can improve the efficacy of stem cell therapy by sustaining and enhancing stem cell characteristics under disease conditions.
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http://dx.doi.org/10.1016/j.biomaterials.2017.11.009DOI Listing
February 2018

Effects of aspirin and clopidogrel on neural stem cells.

Cell Biol Toxicol 2018 06 30;34(3):219-232. Epub 2017 Sep 30.

Department of Neurology, Hanyang University College of Medicine, 153 Gyeongchun-ro, Guri-Si, Gyeonggi-do, Seoul, 11923, South Korea.

Cerebral infarction causes severe morbidity and mortality. Most patients with cerebral infarction should take antiplatelet drugs daily, so the effects of those drugs on the regeneration of the brain need to be investigated. Aspirin and clopidogrel are the most widely used antiplatelet drugs for the prevention of ischemic stroke. We investigated the effects of aspirin and clopidogrel on neural stem cells (NSCs). NSCs were dissociated from fetal rat cortex and cultured with basic fibroblast growth factor and N2 medium. To measure the effects of aspirin and clopidogrel on NSCs, NSCs were treated with several concentrations of aspirin, clopidogrel bisulfate, and clopidogrel resinate for 24 h. After the treatment, we measured cell viability by cell counting kit-8, MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay, trypan blue staining, flow cytometry, and lactate dehydrogenase assay. To evaluate their effects on NSC proliferation, we performed BrdU cell proliferation assay and colony-forming unit assay. We compared the intracellular protein level in the NSCs treated with aspirin and two types of clopidogrel, by proteomics analysis. Various viability tests showed that clopidogrel resinate and clopidogrel bisulfate did not affect the viability and proliferation of NSCs whereas aspirin decreased them even at low concentrations which are clinically relevant. Moreover, through the proteomics, it was confirmed that the toxicity of aspirin to NSCs might be associated with the alteration of several intracellular proteins. Taken together, these results suggest that clopidogrel resinate and clopidogrel bisulfate are safe but aspirin could be toxic to NSCs. Therefore, when these antiplatelet agents are prescribed over the long-term, the finding that aspirin could be toxic to NSCs should be considered.
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http://dx.doi.org/10.1007/s10565-017-9412-yDOI Listing
June 2018

Candesartan Restores the Amyloid Beta-Inhibited Proliferation of Neural Stem Cells by Activating the Phosphatidylinositol 3-Kinase Pathway.

Dement Neurocogn Disord 2017 Sep 30;16(3):64-71. Epub 2017 Sep 30.

Department of Neurology, Hanyang University Guri Hospital, Guri, Korea.

Background And Purpose: Neurogenesis in the adult brain is important for memory and learning, and the alterations in neural stem cells (NSCs) may be an important aspect of Alzheimer's disease (AD) pathogenesis. The phosphatidylinositol 3-kinase (PI3K) pathway has been suggested to have an important role in neuronal cell survival and is highly involved in adult neurogenesis. Candesartan is an angiotensin II receptor antagonist used for the treatment of hypertension and several studies have reported that it also has some neuroprotective effects. We investigated whether candesartan could restore the amyloid-β(25-35) (Aβ) oligomer-inhibited proliferation of NSCs by focusing on the PI3K pathway.

Methods: To evaluate the effects of candesartan on the Aβ oligomer-inhibited proliferation of NSCs, the NSCs were treated with several concentrations of candesartan and/or Aβ oligomers, and MTT assay and trypan blue staining were performed. To evaluate the effect of candesartan on the Aβ-inhibited proliferation of NSCs, we performed a bromodeoxyuridine (BrdU) labeling assay. The levels of p85α PI3K, phosphorylated Akt (pAkt) (Ser473), phosphorylated glycogen sinthase kinase-3β (pGSK-3β) (Ser9), and heat shock transcription factor-1 (HSTF-1) were analyzed by Western blotting.

Results: The BrdU assays demonstrated that NSC proliferation decreased with Aβ oligomer treatment; however, a combined treatment with candesartan restored it. Western blotting displayed that candesartan treatment increased the expression levels of p85α PI3K, pAkt (Ser473), pGSK-3β (Ser9), and HSTF. The NSCs were pretreated with a PI3K inhibitor, LY294002; the effects of candesartan on the proliferation of NSCs inhibited by Aβ oligomers were almost completely blocked.

Conclusions: Together, these results suggest that candesartan restores the Aβ oligomer-inhibited proliferation of NSCs by activating the PI3K pathway.
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http://dx.doi.org/10.12779/dnd.2017.16.3.64DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6427981PMC
September 2017

Analysis of the Expectation of Stem Cell Therapy in Patients with Alzheimer's Disease.

Dement Neurocogn Disord 2016 Dec 31;15(4):129-134. Epub 2016 Dec 31.

Department of Neurology, Hanyang University College of Medicine, Seoul, Korea.

Background And Purpose: Alzheimer's disease (AD) is the most common form of dementia which typically manifests as loss of memory and cognitive functions. Currently, available treatments for AD provide only symptomatic improvement and the benefit is minimal. Stem cell therapy (SCT) has been considered a promising treatment option for AD. We investigated the caregiver's perception about implementation of SCT in their AD patients, and determined the factors related to SCT.

Methods: A total of 100 caregivers, who cared for their AD patients, were interviewed at two hospitals. Structured open and closed questions about SCT for AD were asked by trained interviewers using the conventional in-person method. In addition, 60 dementia-related physicians were randomly interviewed via an e-mail questionnaire.

Results: Of the 100 subjects, 61 caregivers replied that they wanted their AD patients to receive SCT. Approximately 50% of the caregivers expected high improvement in cognitive function, behavioral and psychological symptoms, and activities of daily living, and physical improvements among their AD patients. However, physicians had much lower expectations of improvements in the above parameters. Multi-variate analysis revealed that female gender [odds ratio (OR): 3.747, 95% confidence interval (CI): 1.425-9.851] and familiarity with stem cells (OR: 3.873, 95% CI: 1.290-11.622) were independently associated with caregivers' desire that their AD patients should undergo SCT. The major source of information on SCT was television (76.7%), and the most reliable source of information on SCT was physicians (83.6%).

Conclusions: In this study, many caregivers of AD patients fantasized and overestimated the need for SCT in comparison with physicians' expectation. Therefore, it is necessary for physicians to develop strategies for educating caregivers about the appropriate risks and benefits of SCT.
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http://dx.doi.org/10.12779/dnd.2016.15.4.129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428014PMC
December 2016

Early Activation of Phosphatidylinositol 3-Kinase after Ischemic Stroke Reduces Infarct Volume and Improves Long-Term Behavior.

Mol Neurobiol 2017 09 2;54(7):5375-5384. Epub 2016 Sep 2.

Department of Neurology, Hanyang University College of Medicine, Seoul, South Korea.

Phosphatidylinositol 3-kinases (PI3Ks) have recently been implicated in apoptosis and ischemic cell death. We tested the efficacy of early intervention with a peptide PI3K activator in focal cerebral ischemia. After determining the most effective dose (24 μg/kg) and time window (2 h after MCAO) of treatment, a total of 48 rats were subjected to middle cerebral artery occlusion (MCAO). Diffusion weighted MRI (DWI) was performed 1 h after MCAO and rats with lesion sizes within a predetermined range were randomized to either PI3K activator or vehicle treatment arms. Fluid attenuated inversion recovery (FLAIR) MRI, neurological function, western blots, and immunohistochemistry were blindly assessed. Initial DWI lesion volumes were nearly identical between two groups prior to treatment. However, FLAIR showed significantly smaller infarct volumes in the PI3K activator group compared with vehicle (146 ± 81 mm and 211 ± 96 mm, p = 0.045) at 48 h. The PI3K activator group also had better neurological function for up to 2 weeks. In addition, PI3K activator decreased the number of TUNEL-positive cells in the peri-infarct region compared with the control group. Western blot and immunohistochemistry showed increased expression of phosphorylated Akt (Ser473) and GSK-3β (Ser9) and decreased expression of cleaved caspase-9 and caspase-3. Our results suggest a neuroprotective role of early activation of PI3K in ischemic stroke. The use of DWI in the randomization of experimental groups may reduce bias.
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http://dx.doi.org/10.1007/s12035-016-0063-4DOI Listing
September 2017

Neural stem cells injured by oxidative stress can be rejuvenated by GV1001, a novel peptide, through scavenging free radicals and enhancing survival signals.

Neurotoxicology 2016 07 2;55:131-141. Epub 2016 Jun 2.

Department of Neurology, Hanyang University College of Medicine, Seoul, South Korea; Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul, South Korea. Electronic address:

Oxidative stress is a well-known pathogenic mechanism of a diverse array of neurological diseases, and thus, numerous studies have attempted to identify antioxidants that prevent neuronal cell death. GV1001 is a 16-amino-acid peptide derived from human telomerase reverse transcriptase (hTERT). Considering that hTERT has a strong antioxidant effect, whether GV1001 also has an antioxidant effect is a question of interest. In the present study, we aimed to investigate the effects of GV1001 against oxidative stress in neural stem cells (NSCs). Primary culture NSCs were treated with different concentrations of GV1001 and/or hydrogen peroxide (H2O2) for various time durations. The H2O2 decreased the viability of the NSCs in a concentration-dependent manner, with 200μM H2O2 significantly decreasing both proliferation and migration. However, treatment with GV1001 rescued the viability, proliferation and migration of H2O2-injured NSCs. Consistently, free radical levels were increased in rat NSCs treated with H2O2, while co-treatment with GV1001 significantly reduced these levels, especially the intracellular levels. In addition, GV1001 restored the expression of survival-related proteins and reduced the expression of death-associated ones in NSCs treated with H2O2. In conclusion, GV1001 has antioxidant and neuroprotective effects in NSCs following treatment with H2O2, which appear to be mediated by scavenging free radicals, increasing survival signals and decreasing death signals.
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http://dx.doi.org/10.1016/j.neuro.2016.05.022DOI Listing
July 2016

Neuroprotective Effects of Acetyl-L-Carnitine Against Oxygen-Glucose Deprivation-Induced Neural Stem Cell Death.

Mol Neurobiol 2016 12 8;53(10):6644-6652. Epub 2015 Dec 8.

Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul, Republic of Korea.

Deprivation of oxygen and glucose is the main cause of neuronal cell death during cerebral infarction and can result in severe morbidity and mortality. In general, the neuroprotective therapies that are applied after ischemic stroke have been unsuccessful, despite many investigations. Acetyl-L-carnitine (ALCAR) plays an important role in mitochondrial metabolism and in modulating the coenzyme A (CoA)/acyl-CoA ratio. We investigated the protective effects of ALCAR against oxygen-glucose deprivation (OGD) in neural stem cells (NSCs). We measured cell viability, proliferation, apoptosis, and intracellular signaling protein levels after treatment with varying concentrations of ALCAR under OGD for 8 h. ALCAR protected NSCs against OGD by reducing apoptosis and restoring proliferation. Its protective effects are associated with increases in the expression of survival-related proteins, such as phosphorylated Akt (pAkt), phosphorylated glycogen synthase kinase 3b (pGSK3b), B cell lymphoma 2 (Bcl-2), and Ki-67 in NSCs that were injured by OGD. ALCAR also reduced the expression of death-related proteins, such as Bax, cytosolic cytochrome C, cleaved caspase-9, and cleaved caspase-3. We concluded that ALCAR exhibits neuroprotective effects against OGD-induced damage to NSCs by enhancing the expression of survival signals and decreasing that of death signals.
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http://dx.doi.org/10.1007/s12035-015-9563-xDOI Listing
December 2016

Activation of the phosphatidylinositol 3-kinase pathway plays important roles in reduction of cerebral infarction by cilnidipine.

J Neurochem 2015 Oct 31;135(1):186-93. Epub 2015 Aug 31.

Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul, Korea.

Cerebral infarction causes permanent neuronal loss inducing severe morbidity and mortality. Because hypertension is the main risk factor for cerebral infarction and most patients with hypertension take antihypertensive drugs daily, the neuroprotective effects and mechanisms of anti-hypertensive drugs need to be investigated. Cilnidipine, a long-acting, new generation 1,4-dihydropyridine inhibitor of both L- and N-type calcium channels, was reported to reduce oxidative stress. In this study, we investigated whether cilnidipine has therapeutic effects in an animal model of cerebral infarction. After determination of the most effective dose of cilnidipine, a total of 128 rats were subjected to middle cerebral artery occlusion. Neurobehavioral function test and brain MRI were performed, and rats with similar sized infarcts were randomized to either the cilnidipine group or the control group. Cilnidipine treatment was performed with reperfusion after 2-h occlusion. Western blots and immunohistochemistry were also performed after 24-h occlusion. Initial infarct volume on diffusion-weighted MRI was not different between the cilnidipine group and the control group; however, fluid-attenuated inversion recovery MRI at 24 h showed significantly reduced infarct volume in the cilnidipine group compared with the control group. Cilnidipine treatment significantly decreased the number of triphosphate nick end labeling-positive cells compared to the control group. Western blot and immunohistochemistry showed increased expression of phosphorylated Akt (Ser473), phosphorylated glycogen synthase kinase-3β, and Bcl-2 and decreased expression of Bax and cleaved caspase-3. These results suggest that cilnidipine, which is used for the treatment of hypertension, has neuroprotective effects in the ischemic brain through activation of the PI3K pathway. We investigated whether cilnidipine has neuroprotective effects on ischemic stroke in an animal model. We have demonstrated that the neuroprotective effect of cilnidipine is associated with the activation of the PI3K pathway. Considering the daily use of antihypertensive drugs for patients with hypertension, cilnidipine could be beneficial for patients with ischemic stroke.
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http://dx.doi.org/10.1111/jnc.13254DOI Listing
October 2015

Increased VEGF and decreased SDF-1α in patients with silent brain infarction are associated with better prognosis after first-ever acute lacunar stroke.

J Stroke Cerebrovasc Dis 2015 Mar 16;24(3):704-10. Epub 2015 Jan 16.

Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea; Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science and Engineering, Seoul, Republic of Korea. Electronic address:

Background: Pre-existing silent brain infarctions (SBIs) have been reported to be associated with better outcomes after first-ever symptomatic ischemic stroke, although the mechanism of this remains unclear. We investigated the association between SBIs, outcomes of acute lacunar infarction, and biomarkers including vascular endothelial growth factor (VEGF), stromal cell-derived factor-1α (SDF-1α), macrophage migration inhibitory factor (MIF), and high-mobility group box-1 (HMGB1).

Methods: A total of 68 consecutive patients diagnosed with first-ever lacunar infarction (<20 mm) within 24 hours of symptom onset were included in this study. Clinical, laboratory, and imaging data were obtained. Plasma levels of VEGF, SDF-1α, MIF, and HMGB1 were assessed using Enzyme-Linked Immunosorbent Assay kits.

Results: SBIs were noted in 31 of the 68 patients. Although the initial National Institutes of Health Stroke Scale scores were not related with the presence of SBIs (P = .313), patients with SBIs had better outcomes at 3 months (P = .029). Additionally, plasma VEGF levels were higher (P = .035) and SDF-1α levels were lower (P < .001) in patients with SBIs. Logistic regression analysis indicated that VEGF and SDF-1α were independently associated with the presence of SBIs.

Conclusions: SBIs are associated with favorable outcomes in patients with first-ever acute lacunar infarction and higher levels of VEGF, and lower levels of SDF-1α in these patients may contribute to their more favorable prognosis.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.11.021DOI Listing
March 2015

Atorvastatin Protects NSC-34 Motor Neurons Against Oxidative Stress by Activating PI3K, ERK and Free Radical Scavenging.

Mol Neurobiol 2016 Jan 11;53(1):695-705. Epub 2015 Jan 11.

Department of Neurology, Hanyang University College of Medicine, 249-1 Gyomun-dong, Guri-si, Gyeonggi-do, South Korea.

Although statins, or hydroxymethylglutaryl coenzyme A (HMG-Co A) reductase inhibitors, are generally used to decrease levels of circulating cholesterol, they have also been reported to have neuroprotective effects through various mechanisms. However, recent results have indicated that they may be harmful in patients with amyotrophic lateral sclerosis (ALS). In this study, we investigate whether atorvastatin protects motor neuron-like cells (NSC-34D) from oxidative stress. To evaluate the effects of atorvastatin or hydrogen peroxide or both on NSC-34D cells, the cells were treated with various combinations of these agents. To evaluate the viability of the cells, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and trypan blue staining were performed. Levels of free radicals and intracellular signaling proteins were evaluated using the fluorescent probe 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and Western blotting, respectively. Atorvastatin protected NSC-34D cells against oxidative stress in a concentration-dependent manner. This neuroprotective effect of atorvastatin was blocked by LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor and by FR180204, a selective extracellular signal-related kinase (ERK) inhibitor. Atorvastatin treatment increased the expression levels of p85αPI3K, phosphorylated Akt, phosphorylated glycogen synthase kinase-3β, phosphorylated ERK, and Bcl-2, which are proteins related to survival. Furthermore, atorvastatin decreased the levels of cytosolic cytochrome C, Bax, cleaved caspase-9, and cleaved caspase-3, which are associated with death in oxidative stress-injured NSC-34D cells. We conclude that atorvastatin has a protective effect against oxidative stress in motor neurons by activating the PI3K and ERK pathways as well as by scavenging free radicals. These findings indicate that statins could help protect motor neurons from oxidative stress.
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http://dx.doi.org/10.1007/s12035-014-9030-0DOI Listing
January 2016

1,25-dyhydroxyvitamin D3 attenuates L-DOPA-induced neurotoxicity in neural stem cells.

Mol Neurobiol 2015 Apr 8;51(2):558-70. Epub 2014 Aug 8.

Department of Neurology, Hanyang University College of Medicine, Seoul, South Korea.

The neurotoxicity of levodopa (L-DOPA) on neural stem cells (NSCs) and treatment strategies to protect NSCs from this neurotoxicity remain to be elucidated. Recently, an active form of vitamin D3 has been reported to display neuroprotective properties. Therefore, we investigated the protective effect of 1,25-dyhydroxyvitamin D3 (calcitriol) on L-DOPA-induced NSC injury. We measured cell viability via the cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) assays and Annexin V/PI staining followed by flow cytometry, cell proliferation using the BrdU and colony-forming unit (CFU) assays, cell differentiation via immunocytochemistry, the levels of free radicals via 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining, apoptosis via DAPI and TUNEL staining, and intracellular signaling protein expression via Western blot. Antibody microarrays were also employed to detect changes in the expression of prosurvival- and death-related proteins. Treatment of NSCs with L-DOPA reduced their viability and proliferation. This treatment also increased the levels of free radicals and decreased the expression levels of intracellular signaling proteins that are associated with cell survival. However, simultaneous exposure to calcitriol significantly reduced these effects. The calcitriol-mediated protection against L-DOPA toxicity was blocked by the phosphoinositide 3-kinase (PI3K) inhibitor LY294004. L-DOPA also inhibited the expression of Nestin and Ki-67, and co-treatment with calcitriol alleviated these effects. The expression levels of GFAP, DCX, and Tuj1 were not significantly affected by treatment with L-DOPA or calcitriol. Calcitriol protects against L-DOPA-induced NSC injury by promoting prosurvival signaling, including activation of the PI3K pathway, and reducing oxidative stress.
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http://dx.doi.org/10.1007/s12035-014-8835-1DOI Listing
April 2015

Neuroprotective effects of amlodipine besylate and benidipine hydrochloride on oxidative stress-injured neural stem cells.

Brain Res 2014 Mar 16;1551:1-12. Epub 2014 Jan 16.

Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea; Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul, Republic of Korea. Electronic address:

Hypertension is associated with oxidative stress. Amlodipine besylate (AB) and benidipine hydrochloride (BH), which are Ca(2+) antagonists, have been reported to reduce oxidative stress. In this study, we examined the neuroprotective effects of AB and BH on oxidative stress-injured neural stem cells (NSCs), with a focus on the phosphatidylinositol 3-kinase (PI3K) pathway and the extracellular signal-regulated kinase (ERK) pathway. After treatment with H2O2, the viability of NSCs decreased in a concentration-dependent manner; however, co-treatment with AB or BH restored the viability of H2O2-injured NSCs. H2O2 increased free radical production and apoptosis in NSCs, whereas co-treatment with AB or BH attenuated these effects. To evaluate the effects of AB or BH on the H2O2-inhibited proliferation of NSCs, we performed BrdU labeling and colony formation assays and found that NSC proliferation decreased upon H2O2 treatment but that combined treatment with AB or BH restored this proliferation. Western blot analysis showed that AB and BH increased the expression of cell survival-related proteins that were linked with the PI3K and ERK pathways but decreased the expression of cell death-related proteins. To investigate whether the PI3K and ERK pathways were directly involved in the neuroprotective effects of AB and BH on H2O2-treated NSCs, NSCs were pretreated with the PI3K inhibitor, LY294002, or the ERK inhibitor, FR180204, which significantly blocked the effects of AB and BH. Together, our results suggest that AB and BH restore the H2O2-inhibited viability and proliferation of NSCs by inhibiting oxidative stress and by activating the PI3K and ERK pathways.
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http://dx.doi.org/10.1016/j.brainres.2014.01.016DOI Listing
March 2014

Novel vaccine peptide GV1001 effectively blocks β-amyloid toxicity by mimicking the extra-telomeric functions of human telomerase reverse transcriptase.

Neurobiol Aging 2014 Jun 26;35(6):1255-74. Epub 2013 Dec 26.

Department of Neurology, Hanyang University College of Medicine, Guri, Gyeonggi, Korea; Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul, Korea. Electronic address:

GV1001 is a 16-amino-acid vaccine peptide derived from the human telomerase reverse transcriptase sequence. We investigated the effects of GV1001 against β-amyloid (Aβ) oligomer-induced neurotoxicity in rat neural stem cells (NSCs). Primary culture NSCs were treated with several concentrations of GV1001 and/or Aβ₂₅₋₃₅ oligomer for 48 hours. GV1001 protected NSCs against the Aβ₂₅₋₃₅ oligomer in a concentration-dependent manner. Aβ₂₅₋₃₅ concentration dependently decreased viability, proliferation, and mobilization of NSCs and GV1001 treatment restored the cells to wild-type levels. Aβ₂₅₋₃₅ increased free radical levels in rat NSCs while combined treatment with GV1001 significantly reduced these levels. In addition, GV1001 treatment of Aβ₂₅₋₃₅-injured NSCs increased the expression level of survival-related proteins, including mitochondria-associated survival proteins, and decreased the levels of death and inflammation-related proteins, including mitochondria-associated death proteins. Together, these results suggest that GV1001 possesses neuroprotective effects against Aβ₂₅₋₃₅ oligomer in NSCs and that these effects are mediated through mimicking the extra-telomeric functions of human telomerase reverse transcriptase, including the induction of cellular proliferation, anti-apoptotic effects, mitochondrial stabilization, and anti-aging and anti-oxidant effects.
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http://dx.doi.org/10.1016/j.neurobiolaging.2013.12.015DOI Listing
June 2014

Coenzyme Q10 restores amyloid beta-inhibited proliferation of neural stem cells by activating the PI3K pathway.

Stem Cells Dev 2013 Aug 10;22(15):2112-20. Epub 2013 Apr 10.

Department of Neurology, Hanyang University College of Medicine, Seoul, Korea.

Neurogenesis in the adult brain is important for memory and learning, and the alterations in neural stem cells (NSCs) may be an important part of Alzheimer's disease pathogenesis. The phosphatidylinositol 3-kinase (PI3K) pathway has been suggested to play an important role in neuronal cell survival and is highly involved in adult neurogenesis. Recently, coenzyme Q10 (CoQ10) was found to affect the PI3K pathway. We investigated whether CoQ10 could restore amyloid β (Aβ)25-35 oligomer-inhibited proliferation of NSCs by focusing on the PI3K pathway. To evaluate the effects of CoQ10 on Aβ25-35 oligomer-inhibited proliferation of NSCs, NSCs were treated with several concentrations of CoQ10 and/or Aβ25-35 oligomers. BrdU labeling, Colony Formation Assays, and immunoreactivity of Ki-67, a marker of proliferative activity, showed that NSC proliferation decreased with Aβ25-35 oligomer treatment, but combined treatment with CoQ10 restored it. Western blotting showed that CoQ10 treatment increased the expression levels of p85α PI3K, phosphorylated Akt (Ser473), phosphorylated glycogen synthase kinase-3β (Ser9), and heat shock transcription factor, which are proteins related to the PI3K pathway in Aβ25-35 oligomers-treated NSCs. To confirm a direct role for the PI3K pathway in CoQ10-induced restoration of proliferation of NSCs inhibited by Aβ25-35 oligomers, NSCs were pretreated with a PI3K inhibitor, LY294002; the effects of CoQ10 on the proliferation of NSCs inhibited by Aβ25-35 oligomers were almost completely blocked. Together, these results suggest that CoQ10 restores Aβ25-35 oligomer-inhibited proliferation of NSCs by activating the PI3K pathway.
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http://dx.doi.org/10.1089/scd.2012.0604DOI Listing
August 2013

The early activation of PI3K strongly enhances the resistance of cortical neurons to hypoxic injury via the activation of downstream targets of the PI3K pathway and the normalization of the levels of PARP activity, ATP, and NAD⁺.

Mol Neurobiol 2013 Apr 20;47(2):757-69. Epub 2012 Dec 20.

Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea.

Phosphatidylinositol 3-kinase (PI3K) plays several important roles in neuronal survival. Activation of the pathway is essential for the neuroprotective mechanisms of materials that shield neuronal cells from many stressful conditions. However, there have been no reports to date about the effect of the direct activation of the pathway in hypoxic injury of neuronal cells. We investigated whether the direct activation of the PI3K pathway inhibits neuronal cell death induced by hypoxia. Primary cultured cortical neurons (PCCNs) were exposed to hypoxic conditions (less than 1 mol% O2) and/or treated with PI3K activator. Hypoxia reduced the viability of PCCNs in a time-dependent manner, but treatment with PI3K significantly restored viability in a concentration-dependent manner. Among the signaling proteins involved in the PI3K pathway, those associated with survival, including Akt and glycogen synthase kinase-3β, were decreased shortly after exposure to hypoxia and those associated with cell death, including BAX, apoptosis-induced factor, cytochrome c, caspase-9, caspase-3, and poly(ADP-ribose) polymerase (PARP), were increased. However, treatment with PI3K activator normalized the expression levels of those signaling proteins. PARP activity and levels of ATP and NAD(+) altered by hypoxia were also normalized with direct PI3K activation. All these findings suggest that direct and early activation is important for protecting neuronal cells from hypoxic injury.
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http://dx.doi.org/10.1007/s12035-012-8382-6DOI Listing
April 2013

MRI and ultrasonographic findings in idiopathic intracranial hypertension.

Cephalalgia 2013 Jan 20;33(2):139-40. Epub 2012 Nov 20.

Department of Neurology, Hanyang University College of Medicine, Korea.

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http://dx.doi.org/10.1177/0333102412467514DOI Listing
January 2013

Teaching Neuro Images: CSF leaks and spontaneous intracranial hypotension.

Neurology 2012 Nov;79(19):e176

Department of Neurology, Hanyang University College of Medicine, Seoul, Korea.

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http://dx.doi.org/10.1212/WNL.0b013e3182735c56DOI Listing
November 2012

Coenzyme Q10 protects neural stem cells against hypoxia by enhancing survival signals.

Brain Res 2012 Oct 21;1478:64-73. Epub 2012 Aug 21.

Department of Neurology, Hanyang University College of Medicine, Seoul, Korea.

Recanalization and secondary prevention are the main therapeutic strategies for acute ischemic stroke. Neuroprotective therapies have also been investigated despite unsuccessful clinical results. Coenzyme Q10 (CoQ10), which is an essential cofactor for electron transport in mitochondria, is known to have an antioxidant effect. We investigated the protective effects of CoQ10 against hypoxia in neural stem cells (NSCs). We measured cell viability and levels of intracellular signaling proteins after treatment with several concentrations of CoQ10 under hypoxia-reperfusion. CoQ10 protected NSCs against hypoxia-reperfusion in a concentration-dependent manner by reducing growth inhibition and inhibiting free radical formation. It increased the expression of a number of survival-related proteins such as phosphorylated Akt (pAkt), phosphorylated glycogen synthase kinase 3-β (pGSK3-β), and B-cell lymphoma 2 (Bcl-2) in NSCs injured by hypoxia-reperfusion and reduced the expression of death-related proteins such as cleaved caspase-3. We conclude that CoQ10 has effects against hypoxia-reperfusion induced damage to NSCs by enhancing survival signals and decreasing death signals.
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http://dx.doi.org/10.1016/j.brainres.2012.08.025DOI Listing
October 2012

Role of the phosphatidylinositol 3-kinase and extracellular signal-regulated kinase pathways in the neuroprotective effects of cilnidipine against hypoxia in a primary culture of cortical neurons.

Neurochem Int 2012 Dec 24;61(7):1172-82. Epub 2012 Aug 24.

Department of Neuroscience, KAEL-Gemvax Co. Ltd., Seoul, Republic of Korea.

Cilnidipine, a calcium channel blocker, has been reported to have neuroprotective effects. We investigated whether cilnidipine could protect neurons from hypoxia and explored the role of the phosphatidylinositol 3-kinase (PI3K) and extracellular signal-related kinase (ERK) pathways in the neuroprotective effect of cilnidipine. The viability of a primary culture of cortical neurons injured by hypoxia, measured by trypan blue staining and lactate dehydrogenase (LDH) assay, was dramatically restored by cilnidipine treatment. TUNEL and DAPI staining showed that cilnidipine significantly reduced apoptotic cell death induced by hypoxia. Free radical stress and calcium influx induced by hypoxia were markedly decreased by treatment with cilnidipine. Survival signaling proteins associated with the PI3K and ERK pathways were significantly increased while death signaling proteins were markedly decreased in the primary culture of cortical neurons simultaneously exposed to cilnidipine and hypoxia when compared with the neurons exposed only to hypoxia. These neuroprotective effects of cilnidipine were blocked by treatment with a PI3K inhibitor or an ERK inhibitor. These results show that cilnidipine protects primary cultured cortical neurons from hypoxia by reducing free radical stress, calcium influx, and death-related signaling proteins and by increasing survival-related proteins associated with the PI3K and ERK pathways, and that activation of those pathways plays an important role in the neuroprotective effects of cilnidipine against hypoxia. These findings suggest that cilnidipine has neuroprotective effects against hypoxia through various mechanisms, as well as a blood pressure-lowering effect, which might help to prevent ischemic stroke and reduce neuronal injury caused by ischemic stroke.
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http://dx.doi.org/10.1016/j.neuint.2012.08.010DOI Listing
December 2012