Publications by authors named "Dong Woon Kim"

168 Publications

Vitamin E reduces spasms caused by prenatal stress by lowering calpain expression.

Epilepsy Behav 2021 Jan 27;114(Pt A):107609. Epub 2020 Nov 27.

Department of Medical Science, School of Medicine, Chungnam National University, Daejeon, Republic of Korea; Department of Pediatrics, Chungnam National University Hospital, School of Medicine, Chungnam National University, Daejeon, Republic of Korea. Electronic address:

Background: Prenatal stress increases the susceptibility of infants to seizures and is known to be associated with oxidative stress. Recent studies suggest that vitamin E has beneficial effects in various neurological diseases due to its antioxidant properties. In this study, we investigated the relationship between prenatal stress and vitamin E treatment on N-methyl-D-aspartate (NMDA)-induced spasms.

Methods: We used pregnant female Sprague Dawley rats and induced prenatal stress with an injection of betamethasone on G15. They were then treated orally with 200 mg/kg vitamin E or saline twice a day from G15-G21. On postnatal day 15, NMDA was administered to trigger spasms in offspring. The total number of spasms and latency to the first spasm were recorded. We also measured oxidative stress in the medial cortex using western blot, and calpain activity, thiobarbituric acid reactive substances (TBARS), glutathione (GSH)/GSH/glutathione disulfide (GSSG), superoxide dismutase (SOD) activity, catalase activity, and nitric oxide (NO) assays.

Results: We observed that rats treated with vitamin E while exposed to prenatal stress demonstrated reduced total number and frequency of spasms. Expression of glutamate decarboxylase 67 (GAD67) and K/Cl co-transporter (KCC2) were reduced after prenatal stress; this recovered in the vitamin E treated group. Further, expression of calpain 2 was decreased and various markers of oxidative stress (malondialdehyde (MDA), GSH/GSSG, SOD, catalase, and NO) were reduced in the vitamin E treated group.

Conclusions: Our results provide evidence that vitamin E lowers oxidative stress and decreases seizure susceptibility in rat offspring exposed to prenatal stress. Given the well-known safety profile of vitamin E, these results indicate its potential as a strategy for preventing seizures.
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http://dx.doi.org/10.1016/j.yebeh.2020.107609DOI Listing
January 2021

Protective Effects of ShcA Protein Silencing for Photothrombotic Cerebral Infarction.

Transl Stroke Res 2020 Nov 26. Epub 2020 Nov 26.

Department of Neurology, Chungnam National University College of Medicine and Sejong Hospital, Sejong, 30099, Republic of Korea.

Reactive oxygen species (ROS) exacerbate stroke-induced cell damage. We found that ShcA, a protein that regulates ROS, is highly expressed in a Rose Bengal photothrombosis model. We investigated whether ShcA is essential for mitophagy in ROS-induced cellular damage and determined whether ROS exacerbate mitochondrial dysfunction via ShcA protein expression. Ischemic stroke was generated by Rose Bengal photothrombosis in mice. To silence ShcA protein expression in the mouse brain, ShcA-targeting siRNA-encapsulated nanoparticles were intrathecally injected into the cisterna magna. Upon staining with antibodies against ShcA counterpart caspase-3 or NeuN, we found that the ShcA protein expression was increased in apoptotic neurons. In addition, mitochondrial dysfunction and excessive mitophagy were evident in photothrombotic stroke tissue. Infarct volumes were significantly reduced, and neurological deficits were diminished in the ShcA siRNA nanoparticle-treated group, compared with the negative control siRNA nanoparticle-treated group. We confirmed that the reduction of ShcA expression by nanoparticle treatment rescued the expression of genes, associated with mitochondrial dynamics and mitophagy mediation in a stroke model. This study suggests that the regulation of ShcA protein expression can be a therapeutic target for reducing brain damage with mitochondrial dysfunction caused by thrombotic infarction.
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http://dx.doi.org/10.1007/s12975-020-00874-1DOI Listing
November 2020

Who are the optimal candidates for partial breast irradiation?

Asia Pac J Clin Oncol 2020 Oct 20. Epub 2020 Oct 20.

Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

At the 2017 St. Gallen International Expert Consensus Conference on the Primary Therapy for Early Breast Cancer, the consensus panel recognized "partial breast irradiation as an option for women meeting the low-risk criteria put forward by the American Society for Radiation Oncology/European Society for Radiotherapy and Oncology (ASTRO/ESTRO) guideline," although acknowledging that there was less evidence for this approach. Partial breast irradiation is defined as irradiation localized to the surgical resection cavity only as opposed to the entire breast. Accelerated partial breast irradiation (APBI) involves intensive treatment in a short time period. The methods vary, and three available APBI options are brachytherapy, external beam and intra-operative irradiation. The long-term follow-up results from two large-scale, well-designed phase III randomized clinical trials have been released. However, further discussion of the optimal treatment candidates and delivery method is needed before the clinical application of APBI as a mainstream breast conservation treatment.
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http://dx.doi.org/10.1111/ajco.13462DOI Listing
October 2020

TAP2, a peptide antagonist of Toll-like receptor 4, attenuates pain and cartilage degradation in a monoiodoacetate-induced arthritis rat model.

Sci Rep 2020 10 15;10(1):17451. Epub 2020 Oct 15.

Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, 35015, Republic of Korea.

Because inflammation in osteoarthritis (OA) is related to the Toll-like receptor 4 (TLR4) signaling cascades, TLR4 is a reasonable target for developing therapeutics for OA. Thus, we investigated whether TAP2, a peptide antagonist of TLR4, reduces the monoiodoacetate (MIA)-induced arthritic pain and cartilage degradation in rats. TLR4 expression of human OA chondrocytes and synoviocytes and the knee joint tissue of MIA-induced arthritis were evaluated. MIA-induced arthritic model using Sprague-Dawley rats (6 week-old-male) were treated with TAP2, a TLR4 antagonist, and evaluated with behavioral test, immunohistochemistry, and quantitative PCR. TLR4 was highly expressed in the knee joints of patients with OA and the MIA-induced rat model. Further, a single intraarticular injection of TAP2 (25 nmol/rat) molecules targeting TLR4 on day 7 after MIA injection dramatically attenuated pain behavior for about 3 weeks and reduced cartilage loss in the knee joints and microglial activation in the spinal dorsal horns. Likewise, the mRNA levels of TNFα and IL-1β, reactive oxygen species, and the expression of MMP13 in the knee joints of TAP2-treated rats was significantly decreased by TAP2 treatment compared with the control. Moreover, interestingly, the duration of OA pain relief by TAP2 was much longer than that of chemical TLR4 antagonists, such as C34 and M62812. In conclusion, TAP2 could effectively attenuate MIA-induced arthritis in rats by blocking TLR4 and its successive inflammatory cytokines and MMP13. Therefore, TAP2 could be a prospective therapeutic to treat patients with OA.
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http://dx.doi.org/10.1038/s41598-020-74544-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567100PMC
October 2020

Relationship between arterial stiffness and variability of home blood pressure monitoring.

Medicine (Baltimore) 2020 Jul;99(30):e21227

Department of Cardiology, Heart Center, College of Medicine, Konyang University, Deajeon, Korea.

Variability of blood pressure (BP) is known as a prognostic value for the subsequent target organ damage in hypertensive patients. Arterial stiffness is a risk factor for cardiovascular morbidity and mortality. The relationship between the arterial stiffness and the BP variability has been controversial. The objective of the present study was to investigate the relationship between arterial stiffness and home BP variability in patients with high normal BP and new onset hypertension (HTN).Four hundred sixty three patients (252 males, 49 ± 12 year-old) with high normal BP or HTN were enrolled. Using radial applanation tonometry, pulse wave analysis (PWA) was performed for evaluation of systemic arterial stiffness. All patients underwent both home BP monitoring (HBPM) and PWA. Home BP variability was calculated as the standard deviation (SD) of 7 measurements of HBPM. Multiple linear regression analysis was performed to estimate and test the independent effects of home BP variability on the arterial stiffness.Mutivariate analysis showed that both systolic and diastolic morning BP variabilities were correlated with arterial stiffness expressed as augmentation pressure (AP, β-coefficient = 1.622, P = .01 and β-coefficient = 1.07, P = .035). The SDs of systolic and diastolic BP of evening were also associated with AP (β-coefficient = 1.843, P = .001 and β-coefficient = 1.088, P = .036). The SDs of morning and evening systolic BP were associated with augmentation index (AI, β-coefficient = 1.583, P = .02 and β-coefficient = 1.792, P = .001) and heart rate (75 bpm) adjusted AI (β-coefficient = 1.592, P = .001 and β-coefficient = 1.792, P = .001).In present study, the variability of systolic BP was closely related with arterial stiffness. The home BP variability might be important indicator of arterial stiffness.
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http://dx.doi.org/10.1097/MD.0000000000021227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387033PMC
July 2020

Poly(lactic-co-glycolic acid) nanomaterial-based treatment options for pain management: a review.

Nanomedicine (Lond) 2020 Aug 6. Epub 2020 Aug 6.

Department of Medical Science, Chungnam National University College of Medicine, Daejeon, 35015, Republic of Korea.

Neuropathic pain is one of the most intense types of chronic pain; it constitutes a pervasive complaint throughout the public health system. With few effective treatments, it remains a significant challenge. Commercially available drugs for neuropathic pain are still limited and have disappointing efficacy. Therefore, chronic neuropathic pain imposes a tremendous burden on patients' quality of life. Recently, the introduction and application of nanotechnology in multiple fields has accelerated the development of new drugs. This review highlights the application of poly(lactic-co-glycolic acid) nanomaterial-based vehicles for drug delivery and how they improve the therapeutic outcomes for neuropathic pain treatment. Finally, future developments for pain research and effective management are presented.
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http://dx.doi.org/10.2217/nnm-2020-0114DOI Listing
August 2020

Extracorporeal shockwave therapy enhances peripheral nerve remyelination and gait function in a crush model.

Adv Clin Exp Med 2020 07;29(7):819-824

Department of Rehabilitation Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.

Background: Conservative treatment, such as electrical stimulation and steroid injection, have been employed in an attempt to improve symptoms after peripheral nerve injury, without significant success. Although non-invasive and safe extracorporeal shockwave therapy (ESWT) can be a practical alternative, the therapeutic effects of ESWT on peripheral nerve remyelination has not been established.

Objectives: To investigate the effects of ESWT on peripheral nerve remyelination and gait function for 5 weeks in a sciatic nerve crush model.

Material And Methods: In total, we divided 97 rats into 5 groups: group 1 - a healthy negative control group; group 2 - 3 weeks after sciatic nerve crush and 3 sessions of ESWT; group 3 - 5 weeks after crush injury with 3 sessions of ESWT; group 4 - 3 weeks after crush injury with no ESWT; and group 5 - 5 weeks after crush injury with no ESWT. The focused ESWT was applied to the unilateral sciatic nerve injury site. One session consisted of 1,500 stimuli, and the session were performed at intervals of 1 week.

Results: The degree of myelination and expression of myelin basic protein at the distal part of the injured sciatic nerve tended to increase in the ESWT groups compared with the no-ESWT groups 3 and 5 weeks after crush injury. Regarding the functional gait recovery, the print width and area of the injured leg in the ESWT groups was significantly larger than that in the no-ESWT groups 3 and 5 weeks after crush injury.

Conclusions: The ESWT may enhance peripheral nerve remyelination and gait function in a nerve crush model. Long-term follow-up after ESWT and investigation of molecular mechanisms will be needed to confirm these therapeutic effects.
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http://dx.doi.org/10.17219/acem/122177DOI Listing
July 2020

Assessment of the conventional radial artery with optical coherent tomography after the snuffbox approach.

Cardiol J 2020 Jul 25. Epub 2020 Jul 25.

Division of Cardiology, Chonnam National University Hospital, Gwangju, Republic of Korea.

Background: This study aimed to evaluate acute injuries of the radial artery (RA) using optical coherence tomography (OCT) in patients who underwent coronary intervention via the snuffbox approach.

Methods: Forty-six patients, who underwent coronary intervention and assessment of the conventional RA using OCT via the snuffbox approach, were enrolled from two university hospitals between August 2018 and August 2019.

Results: The mean age of the patients was 65.1 years. In this study population, 6-French (Fr) sheaths were used. The mean diameter of the conventional RA was 2.89 ± 0.33 mm, and the mean lumen area of the conventional RA was 6.68 ± 1.56 mm². Acute injuries of the conventional RA, after the snuffbox approach, were observed in 5 (10.9%) patients. Intimal tear was observed in the RA in 1 (2.2%) case. Intraluminal thrombi, without vessel injuries, were detected in the RA in 4 (8.7%) cases. However, medial dissection was not observed in the OCT analysis.

Conclusions: This retrospective OCT-based study showed that the diameter of the conventional RA was 2.89 mm and acute vessel injury of the conventional RA was rare in patients who underwent coronary intervention via the snuffbox approach.
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http://dx.doi.org/10.5603/CJ.a2020.0097DOI Listing
July 2020

Treatment with AAV1-Rheb(S16H) provides neuroprotection in a mouse model of photothrombosis-induced ischemic stroke.

Neuroreport 2020 09;31(13):971-978

School of Life Sciences, Kyungpook National University.

We recently reported that upregulation of the constitutively active ras homolog enriched in brain [Rheb(S16H)], which induces the activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, can protect adult neurons, mediated by the induction of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), in animal models of neurodegenerative diseases. Here we show that neuronal transduction of Rheb(S16H) using adeno-associated virus serotype 1 provides neuroprotection in a mouse model of photothrombosis-induced ischemic stroke. Rheb(S16H)-expressing neurons exhibited neurotrophic effects, such as mTORC1 activation, increases in neuronal size, and BDNF production, in mouse cerebral cortex. Moreover, the upregulation of neuronal Rheb(S16H) significantly attenuated ischemic damage and behavioral impairments as compared to untreated mice, suggesting that Rheb(S16H) upregulation in cortical neurons may be a useful strategy to treat ischemic stroke.
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http://dx.doi.org/10.1097/WNR.0000000000001506DOI Listing
September 2020

The effect of antiplatelet drug on coronary endothelial and microvascular function: comparison with ticagrelor and clopidogrel.

Korean J Intern Med 2020 Jun 23. Epub 2020 Jun 23.

Department of Internal Medicine, College of Medicine, Chungbuk National University, Cheongju, Korea.

Background/aims: Coronary endothelial and microvascular function play important roles in cardiovascular disease. We aimed to evaluate the effect of ticagrelor on coronary artery function and tested the antiplatelet effect of low dose ticagrelor in East-Asian patients.

Methods: Sixty-one consecutive patients with non-significant coronary disease were included in the study. Initially, patients were randomized in 1:1:1 ratio to receive drugs: ticagrelor 90 mg twice a day (bid; n = 22), ticagrelor 45 mg bid (n = 19) or clopidogrel 75 mg once a day (qd; n = 20) and then divided into two groups (ticagrelor vs clopidogrel) for evaluation of coronary artery function, and three groups for evaluation of antiplatelet function. Endothelial dysfunction was measured by coronary flow reserve (CFR), and changes in the levels of asymmetric dimethylarginine (ADMA), cluster of differentiation (CD) 40 ligand, and P-selectin. Microvascular function was evaluated as index of microvascular resistance (IMR). Platelet reactivity was assessed by VerifyNow P2Y12 assay.

Results: The levels of CFR, ADMA, and CD 40 ligand were not different between the two groups. However, P-selectin was lower in the ticagrelor group compared with clopidogrel group. IMR was significantly lower in the ticagrelor group compared with clopidogrel group (median, 15.0 [interquartile range, 12.0 to 21.0] vs. 47.5 [23.0 to 67.5], p = 0.014). There was significant difference in platelet inhibition among the three groups (ticagrelor 90 mg bid vs. ticagrelor 45 mg bid vs. clopidogrel 75 mg qd; 85.57 ± 47.63 vs. 120.33 ± 51.09 vs. 256.42 ± 55.10, p < 0.001).

Conclusions: It is hypothesized that ticagrelor might ameliorate the coronary microvascular function. When compared with clopidogrel, low dose ticagrelor exhibited satisfactory antiplatelet effect in the present study.
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http://dx.doi.org/10.3904/kjim.2019.293DOI Listing
June 2020

Traditional Korean herbal formulae, Yuk-Mi-Ji-Hwang-Tang, ameliorates impairment of hippocampal memory ability by chronic restraint stress of mouse model.

J Ethnopharmacol 2020 Oct 13;260:113102. Epub 2020 Jun 13.

Department of Neurology Disorders, Dunsan Hospital, Daejeon University, Daejeon, Republic of Korea. Electronic address:

Ethnopharmacological Relevance: Yuk-Mi-Jihwang-Tang (YJT) has been popularly prescribed to treat aging related disorders over than hundreds of years in East Asia countries.

Aim Of The Study: To investigate possible modulatory actions of YJT on chronic restraint stress (CRS)-induced neurodegeneration on hippocampus neuronal injuries.

Materials And Methods: Mice were orally administered with YJT (100, 200, or 400 mg/kg) or ascorbic acid (100 mg/kg) before 4 h of stress for 28 days. Morris water maze task was completed from day 24th to 28th, and stress hormones and biochemical analyzes were measured.

Results: Four weeks of the CRS abnormally affected memory impairments by measurement of escape latency and time spent in the target quadrant. Additionally, neurotransmitters were also drastically altered in serum or hippocampus protein levels by CRS. Gene expressions for 5-hydroxytryptamine (5-HT) receptor, 5-HT-transport, and tryptophan hydroxylase were also altered, whereas YJT led to normalize the above alterations. Additionally, YJT also beneficially worked on endogenous redox system as well as inflammatory reactions in the hippocampal neurons. We observed that hippocampal excitotoxicity was induced by CRS which were evidenced by depletion of phosphor-cAMP response element-binding protein, brain-derived neurotrophic factor, nuclear factor erythroid-2-related factor 2, heme oxygenase-1 and abnormally increases of acetylcholine esterase activities in hippocampus protein levels; however, YJT considerably improved the above pathological conditions.

Conclusions: Our findings supported YJT enhance memory function via regulation of hippocampal excitotoxicity-derived memory impairment, stress hormone, and endogenous redox, respectively.
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http://dx.doi.org/10.1016/j.jep.2020.113102DOI Listing
October 2020

Preventive Effects of Neuroprotective Agents in a Neonatal Rat of Photothrombotic Stroke Model.

Int J Mol Sci 2020 May 24;21(10). Epub 2020 May 24.

Department of Medical Science, Chungnam National University, Daejeon 35015, Korea.

Neonatal ischemic stroke has a higher incidence than childhood stroke. Seizures are the first sign for the need for clinical assessment in neonates, but many questions remain regarding treatments and follow-up modalities. In the absence of a known pathophysiological mechanism, only supportive care is currently provided. Stroke-induced microglia activation and neuroinflammation are believed to play a central role in the pathological progression of neonatal ischemic stroke. We induced a photothrombotic infarction with Rose Bengal in neonatal rats to investigate the effects of pre- and post-treatment with Aspirin (ASA), Clopidogrel (Clop), and Coenzyme Q10 (CoQ10), which are known for their neuroprotective effects in adult stroke. Pre-stroke medication ameliorates cerebral ischemic injury and reduces infarct volume by reducing microglia activation, cellular reactive oxygen species (ROS) production, and cytokine release. Post-stroke administration of ASA, Clop, and CoQ10 increased motor function and reduced the volume of infarction, and the statistical evidence was stronger than that seen in the pre-stroke treatment. In this study, we demonstrated that ASA, Clop, and CoQ10 treatment before and after the stroke reduced the scope of stroke lesions and increased behavioral activity. It suggests that ASA, Clop, and CoQ10 medication could significantly have neuroprotective effects in the neonates who have suffered strokes.
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http://dx.doi.org/10.3390/ijms21103703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279317PMC
May 2020

CX3CR1-Targeted PLGA Nanoparticles Reduce Microglia Activation and Pain Behavior in Rats with Spinal Nerve Ligation.

Int J Mol Sci 2020 May 14;21(10). Epub 2020 May 14.

Department of Anesthesiology and Pain Medicine, Chungnam National University Hospital, 282 Munhwa-ro, Jung-gu, Daejeon 35015, Korea.

Activation of CX3CR1 in microglia plays an important role in the development of neuropathic pain. Here, we investigated whether neuropathic pain could be attenuated in spinal nerve ligation (SNL)-induced rats by reducing microglial activation through the use of poly(D,L-lactic-co-glycolic acid) (PLGA)-encapsulated CX3CR1 small-interfering RNA (siRNA) nanoparticles. After confirming the efficacy and specificity of CX3CR1 siRNA, as evidenced by its anti-inflammatory effects in lipopolysaccharide-stimulated BV2 cells in vitro, PLGA-encapsulated CX3CR1 siRNA nanoparticles were synthesized by sonication using the conventional double emulsion (W/O/W) method and administered intrathecally into SNL rats. CX3CR1 siRNA-treated rats exhibited significant reductions in the activation of microglia in the spinal dorsal horn and a downregulation of proinflammatory mediators, as well as a significant attenuation of mechanical allodynia. These data indicate that the PLGA-encapsulated CX3CR1 siRNA nanoparticles effectively reduce neuropathic pain in SNL-induced rats by reducing microglial activity and the expression of proinflammatory mediators. Therefore, we believe that PLGA-encapsulated CX3CR1 siRNA nanoparticles represent a valuable new treatment option for neuropathic pain.
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http://dx.doi.org/10.3390/ijms21103469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279022PMC
May 2020

p66shc siRNA-Encapsulated PLGA Nanoparticles Ameliorate Neuropathic Pain Following Spinal Nerve Ligation.

Polymers (Basel) 2020 Apr 29;12(5). Epub 2020 Apr 29.

Department of Medical Science, Chungnam National University College of Medicine, Daejeon 35015, Korea.

p66shc, a member of the shc adaptor protein family, has been shown to participate in regulation of mitochondrial homeostasis, apoptosis, and autophagosome formation. The present study was performed to investigate whether p66shc siRNA-encapsulated poly(d,l-lactic--glycolic acid) nanoparticles (p66shc siRNA-PLGA NPs) can attenuate spinal nerve ligation (SNL)-induced neuropathic pain in rats. The SNL-induced pain behavior was decreased in the p66shc siRNA-PLGA NP-treated group compared with the scrambled siRNA-PLGA NP-treated group. In the L5 spinal cord of the p66shc siRNA-PLGA NP-treated group, expression levels of phosphorylated p66shc, cleaved caspase-3, p62, and PINK1, as well as microglial activation, were also decreased. In addition, p66shc knockdown using p66shc siRNA reduced the expression levels of cleaved caspase-3, p62, and PINK1, as well as proinflammatory mediators in the HO-treated HT22 neuronal cells. These results suggest that downregulation of p66shc expression in the spinal cord using p66shc siRNA-PLGA NPs could reduce the SNL-induced neuropathic pain by attenuating the SNL-induced aberrant autophagic, mitophagic, and neuroinflammatory processes in rats.
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http://dx.doi.org/10.3390/polym12051014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284875PMC
April 2020

p66shc siRNA Nanoparticles Ameliorate Chondrocytic Mitochondrial Dysfunction in Osteoarthritis.

Int J Nanomedicine 2020 8;15:2379-2390. Epub 2020 Apr 8.

Department of Medical Science, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea.

Background: Osteoarthritis (OA) is the most common type of joint disease associated with cartilage breakdown. However, the role played by mitochondrial dysfunction in OA remains inadequately understood. Therefore, we investigated the role played by p66shc during oxidative damage and mitochondrial dysfunction in OA and the effects of p66shc downregulation on OA progression.

Methods: Monosodium iodoacetate (MIA), which is commonly used to generate OA animal models, inhibits glycolysis and biosynthetic processes in chondrocytes, eventually causing cell death. To observe the effects of MIA and poly(lactic--glycolic acid) (PLGA)-based nanoparticles, histological analysis, immunohistochemistry, micro-CT, mechanical paw withdrawal thresholds, quantitative PCR, and measurement of oxygen consumption rate and extracellular acidification rate were conducted.

Results: p-p66shc was highly expressed in cartilage from OA patients and rats with MIA-induced OA. MIA caused mitochondrial dysfunction and reactive oxygen species (ROS) production, and the inhibition of p66shc phosphorylation attenuated MIA-induced ROS production in human chondrocytes. Inhibition of p66shc by PLGA-based nanoparticles-delivered siRNA ameliorated pain behavior, cartilage damage, and inflammatory cytokine production in the knee joints of MIA-induced OA rats.

Conclusion: p66shc is involved in cartilage degeneration in OA. By delivering p66shc-siRNA-loaded nanoparticles into the knee joints with OA, mitochondrial dysfunction-induced cartilage damage can be significantly decreased. Thus, p66shc siRNA PLGA nanoparticles may be a promising option for the treatment of OA.
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http://dx.doi.org/10.2147/IJN.S234198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152540PMC
August 2020

miRNA 146a-5p-loaded poly(d,l-lactic-co-glycolic acid) nanoparticles impair pain behaviors by inhibiting multiple inflammatory pathways in microglia.

Nanomedicine (Lond) 2020 05 15;15(11):1113-1126. Epub 2020 Apr 15.

Department of Medical Science, Chungnam National University College of Medicine, Daejeon, 35015, Republic of Korea.

We investigated whether miRNA (miR) 146a-5p-loaded nanoparticles (NPs) can attenuate neuropathic pain behaviors in the rat spinal nerve ligation-induced neuropathic pain model by inhibiting activation of the NF-κB and p38 MAPK pathways in spinal microglia. After NP preparation, miR NPs were assessed for their physical characteristics and then injected intrathecally into the spinal cords of rat spinal nerve ligation rats to test their analgesic effects. miR NPs reduced pain behaviors for 11 days by negatively regulating the inflammatory response in spinal microglia. The anti-inflammatory effects of miR 146a-5p along with nanoparticle-based materials make miR NPs promising tools for treating neuropathic pain.
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http://dx.doi.org/10.2217/nnm-2019-0462DOI Listing
May 2020

Author Correction: CD200R/Foxp3-mediated signalling regulates microglial activation.

Sci Rep 2020 Mar 23;10(1):5510. Epub 2020 Mar 23.

Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Daejeon, 301-747, Republic of Korea.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-62310-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090081PMC
March 2020

Suppresses Proliferation, Migration, and Invasion of U87MG Cells by Downregulating Cyclin B1, Phospho-AKT, and Metalloproteinase-9.

Int J Mol Sci 2020 Mar 28;21(7). Epub 2020 Mar 28.

Department of Anesthesia and Pain Medicine, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon 35015, Korea.

Several studies have shown that brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1), an important molecule for maintaining circadian rhythms, inhibits the growth and metastasis of tumor cells in several types of cancer, including lung, colon, and breast cancer. However, its role in glioblastoma has not yet been established. Here, we addressed the function of BMAL1 in U87MG glioblastoma cells with two approaches-loss and gain of function. In the loss of function experiments, cell proliferation in U87MG cells transfected with small interfering RNA (siRNA) targeting BMAL1 was increased by approximately 24% (small interfering (si)-NC 0.91 ± 0.00 vs. si-BMAL1 1.129 ± 0.08) via upregulation of cyclin B1. In addition, cell migration and invasion of BMAL1 siRNA-treated glioblastoma cells were elevated by approximately 20% (si-NC 51.00 ± 1.53 vs. si-BMAL161.33 ± 0.88) and 209% (si-NC 21.28 ± 1.37 vs. si-BMAL1 44.47 ± 3.48), respectively, through the accumulation of phosphorylated-AKT (p-AKT) and matrix metalloproteinase (MMP)-9. Gain of function experiments revealed that adenovirus-mediated ectopic expression of BMAL1 in U87MG cells resulted in a 19% (Adenovirus (Ad)-vector 0.94± 0.03 vs. Ad-BMAL1 0.76 ± 0.03) decrease in cell proliferation compared with the control via downregulation of cyclin B1 and increased early and late apoptosis due to changes in the levels of BCL2-associated X protein (BAX), B-cell lymphoma 2 (BCL-2), and cleaved caspase-3. Likewise, cell migration and invasion were attenuated by approximately 24% (Ad-vector 55.00 ± 0.00 vs. Ad-BMAL1 41.83 ± 2.90) and 49% (Ad-vector 70.01 ± 1.24 vs. Ad-BMAL1 35.55 ± 1.78), respectively, in BMAL1-overexpressing U87MG cells following downregulation of p-AKT and MMP-9. Taken together, our results suggest that BMAL1 acts as an anti-cancer gene by altering the proliferation, migration, and invasion of glioblastoma cells. Therefore, the BMAL1 gene could be a potential therapeutic target in the treatment of glioblastoma.
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http://dx.doi.org/10.3390/ijms21072352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178273PMC
March 2020

CR6 interacting factor 1 deficiency induces premature senescence via SIRT3 inhibition in endothelial cells.

Free Radic Biol Med 2020 04 25;150:161-171. Epub 2020 Feb 25.

Department of Physiology & Medical Science, Chungnam National University College of Medicine, Daejeon, 301-747, Republic of Korea. Electronic address:

Vascular endothelial cell senescence is an important cause of cardiac-related diseases. Mitochondrial reactive oxygen species (mtROS) have been implicated in cellular senescence and multiple cardiovascular disorders. CR6 interacting factor 1 (CRIF1) deficiency has been shown to increase mtROS via the inhibition of mitochondrial oxidative phosphorylation; however, the mechanisms by which mtROS regulates vascular endothelial senescence have not been thoroughly explored. The goal of this study was to investigate the effects of CRIF1 deficiency on endothelial senescence and to elucidate the underlying mechanisms. CRIF1 deficiency was shown to increase the activity of senescence-associated β-galactosidase along with increased expression of phosphorylated p53, p21, and p16 proteins. Cell cycle arrested in the G0/G1 phase were identified in CRIF1-deficient cells using the flow cytometry. Furthermore, CRIF1 deficiency was also shown to increase cellular senescence by reducing the expression of Sirtuin 3 (SIRT3) via ubiquitin-mediated degradation of transcription factors PGC1α and NRF2. Downregulation of CRIF1 also attenuated the function of mitochondrial antioxidant enzymes including manganese superoxide dismutase (MnSOD), Foxo3a, nicotinamide-adenine dinucleotide phosphate, and glutathione via the suppression of SIRT3. Interestingly, overexpression of SIRT3 in CRIF1-deficient endothelial cells not only reduced mtROS levels by elevating expression of the antioxidant enzyme MnSOD but also decreased the expression of cell senescence markers. Taken together, these results suggest that CRIF1 deficiency induces vascular endothelial cell senescence via ubiquitin-mediated degradation of the transcription coactivators PGC1α and NRF2, resulting in decreased expression of SIRT3.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.02.017DOI Listing
April 2020

Lack of prognostic significance for major adverse cardiac events of soluble suppression of tumorigenicity 2 levels in patients with ST-segment elevation myocardial infarction.

Cardiol J 2020 Feb 27. Epub 2020 Feb 27.

Chungbuk Regional Cardiovascular Center, Chungbuk National University Hospital, Cheongju, Korea, Republic Of.

Background: Elevation of soluble suppression of tumorigenicity 2 (sST2) is associated with cardiac fibrosis and hypertrophy. Under investigation herein, was whether sST2 level is associated with major adverse cardiac events (MACE) and left ventricular (LV) remodeling after primary percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI).

Methods: In total, this study included 184 patients who underwent successful primary PCI. A subsequent guideline-based medical follow-up was included (61.4 ± 11.8 years old, 85% male, 21% with Killip class ≥ Ⅰ). sST2 concentration correlations with echocardiographic, angiographic, laboratory parameters, and clinical outcomes in STEMI patients were evaluated.

Results: The median sST2 level was 60.3 ng/mL; 6 (3.2%) deaths occurred within 1 year. The sST2 level correlated with LV ejection fraction (EF) changes from baseline to 6 months (r= -0.273; p = 0.006) after adjustment for echocardiographic parameters including wall motions score index (WMSI). Recovery of LVEF at 6 months was highest in the tertile 1 group (∆6 months - baseline LVEF; tertile 1, p = 0.001; tertile 2, p = 0.319; tertile 3, p = 0.205). The decrease in WMSI at 6 months was greater in the tertiles 1 and 2 groups than in the tertile 3 group (∆6 months - baseline WMSI; tertile 1, p = 0.001; tertile 2, p = 0.013; tertile 3, p = 0.055). There was no association between sST2 levels and short-term (log lank p = 0.598) and long-term (p = 0.596) MACE.

Conclusions: sST2 concentration have predictive value for LV remodeling on echocardiography in patients with STEMI who underwent primary PCI. However, sST2 concentration was not associated with short-term and long-term MACE.
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http://dx.doi.org/10.5603/CJ.a2020.0028DOI Listing
February 2020

p47phox siRNA-Loaded PLGA Nanoparticles Suppress ROS/Oxidative Stress-Induced Chondrocyte Damage in Osteoarthritis.

Polymers (Basel) 2020 Feb 13;12(2). Epub 2020 Feb 13.

Department of Medical Science, Chungnam National University College of Medicine, Daejeon 35015, Korea.

Osteoarthritis (OA) is the most common joint disorder that has had an increasing prevalence due to the aging of the population. Recent studies have concluded that OA progression is related to oxidative stress and reactive oxygen species (ROS). ROS are produced at low levels in articular chondrocytes, mainly by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and ROS production and oxidative stress have been found to be elevated in patients with OA. The cartilage of OA-affected rat exhibits a significant induction of p47phox, a cytosolic subunit of the NADPH oxidase, similarly to human osteoarthritis cartilage. Therefore, this study tested whether siRNA p47phox that is introduced with poly (D,L-lactic-co-glycolic acid) (PLGA) nanoparticles (p47phox si_NPs) can alleviate chondrocyte cell death by reducing ROS production. Here, we confirm that p47phox si_NPs significantly attenuated oxidative stress and decreased cartilage damage in mono-iodoacetate (MIA)-induced OA. In conclusion, these data suggest that p47phox si_NPs may be of therapeutic value in the treatment of osteoarthritis.
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http://dx.doi.org/10.3390/polym12020443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077645PMC
February 2020

Arginase 2 Deficiency Promotes Neuroinflammation and Pain Behaviors Following Nerve Injury in Mice.

J Clin Med 2020 Jan 22;9(2). Epub 2020 Jan 22.

Department of Medical Science, Chungnam National University School of Medicine, Daejeon 35015, Korea.

Microglia, the resident macrophages, act as the first and main form of active immune defense in the central nervous system. Arginase 2 (Arg2) is an enzyme involved in L-arginine metabolism and is expressed in macrophages and nervous tissue. In this study, we determined whether the absence of Arg2 plays a beneficial or detrimental role in the neuroinflammatory process. We then investigated whether the loss of Arg2 potentiated microglia activation and pain behaviors following nerve injury-induced neuropathic pain. A spinal nerve transection (SNT) experimental model was used to induce neuropathic pain in mice. As a result of the peripheral nerve injury, SNT induced microgliosis and astrogliosis in the spinal cord, and upregulated inflammatory signals in both wild-type (WT) and Arg2 knockout (KO) mice. Notably, inflammation increased significantly in the Arg2 KO group compared to the WT group. We also observed a more robust microgliosis and a lower mechanical threshold in the Arg2 KO group than those in the WT group. Furthermore, our data revealed a stronger upregulation of M1 pro-inflammatory cytokines, such as interleukin (IL)-1β, and a stronger downregulation of M2 anti-inflammatory cytokines, including IL4 and IL-10, in Arg2 KO mice. Additionally, stronger formation of enzyme-inducible nitric oxide synthase, oxidative stress, and decreased expression of CD206 were detected in the Arg2 KO group compared to the WT group. These results suggest that Arg2 deficiency contributes to inflammatory response. The reduction or the loss of Arg2 results in the stronger neuroinflammation in the spinal dorsal horn, followed by more severe pain behaviors arising from nerve injury-induced neuropathic pain.
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http://dx.doi.org/10.3390/jcm9020305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073606PMC
January 2020

The injection site in the tarsal tunnel to minimize neurovascular injury for heel pain: an anatomical study.

Surg Radiol Anat 2020 Jun 14;42(6):681-684. Epub 2020 Jan 14.

Anatomy Laboratory, College of Sports Science, Korea National Sport University, Seoul, Korea.

Introduction: The aim of this study was to investigate the location and distribution patterns of neurovascular structures and determine the effective injection point in the tarsal tunnel for heel pain.

Methods: Fifteen adult non-embalmed cadavers with a mean age of 71.5 years were studied. The most inferior point of the medial malleolus of the tibia (MM) and the tuberosity of the calcaneus (TC) were identified before dissection. A line connecting the MM and TC was used as a reference line. The reference point was expressed in absolute distance along the reference line using the MM as the starting point. For measurements using MRI, the depth from the skin was measured to inferior at an interval of 1 cm from the MM.

Results: The posterior tibial artery, lateral plantar nerve, and medial plantar nerve were located from 29.0 to 37.3% of the reference line from the MM. The distribution frequencies of the medial calcaneal nerve on the reference line from the MM were 0%, 8.60%, 37.15%, 37.15%, and 17.10%, respectively. The mean depth of the neurovascular structures was 0.3 cm.

Discussion: This study recommended an effective injection site from 45.0 to 80.0% of the reference line.
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http://dx.doi.org/10.1007/s00276-019-02411-8DOI Listing
June 2020

Bestrophin1-mediated tonic GABA release from reactive astrocytes prevents the development of seizure-prone network in kainate-injected hippocampi.

Glia 2020 05 13;68(5):1065-1080. Epub 2019 Dec 13.

Department of Medical Science, College of Medicine and Brain Research Institute, Chungnam National University, Daejeon, Republic of Korea.

Tonic extrasynaptic GABA receptor (GABA R) activation is under the tight control of tonic GABA release from astrocytes to maintain the brain's excitation/inhibition (E/I) balance; any slight E/I balance disturbance can cause serious pathological conditions including epileptic seizures. However, the pathophysiological role of tonic GABA release from astrocytes has not been tested in epileptic seizures. Here, we report that pharmacological or genetic intervention of the GABA-permeable Bestrophin-1 (Best1) channel prevented the generation of tonic GABA inhibition, disinhibiting CA1 pyramidal neuronal firing and augmenting seizure susceptibility in kainic acid (KA)-induced epileptic mice. Astrocyte-specific Best1 over-expression in KA-injected Best1 knockout mice fully restored the generation of tonic GABA inhibition and effectively suppressed seizure susceptibility. We demonstrate for the first time that tonic GABA from reactive astrocytes strongly contributes to the compensatory shift of E/I balance in epileptic hippocampi, serving as a good therapeutic target against altered E/I balance in epileptic seizures.
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http://dx.doi.org/10.1002/glia.23762DOI Listing
May 2020

Pink1-Mediated Chondrocytic Mitophagy Contributes to Cartilage Degeneration in Osteoarthritis.

J Clin Med 2019 Nov 2;8(11). Epub 2019 Nov 2.

Department of Physical Medicine and Rehabilitation, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul 06973, Korea.

Cartilage loss is a central event in the pathogenesis of osteoarthritis (OA), though other than mechanical loading, the biochemical mechanisms underlying OA pathology remain poorly elucidated. We investigated the role of Pink1-mediated mitophagy in mitochondrial fission, a crucial process in OA pathogenesis. We used a monosodium iodoacetate (MIA)-induced rodent model of OA, which inhibits the activity of articular chondrocytes, leading to disruption of glycolytic energy metabolism and eventual cell death. The OA rat cartilage exhibits significant induction of autophagy-related proteins LC3B and p62, similar to human osteoarthritic cartilage. Moreover, expression of Pink1 and Parkin proteins were also increased in OA. Here, we confirm that Pink1-mediated mitophagy leads to cell death in chondrocytes following MIA treatment, while deficiency in Pink1 expression was associated with decreased cartilage damage and pain behaviors in MIA-induced OA. Finally, we found that autophagy and mitophagy-related genes are highly expressed in human osteoarthritic cartilage. These results indicate that OA is a degenerative condition associated with mitophagy, and suggest that targeting the Pink1 pathway may provide a therapeutic avenue for OA treatment.
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http://dx.doi.org/10.3390/jcm8111849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912334PMC
November 2019

Neurotrophic interactions between neurons and astrocytes following AAV1-Rheb(S16H) transduction in the hippocampus in vivo.

Br J Pharmacol 2020 02 27;177(3):668-686. Epub 2019 Dec 27.

School of Life Sciences, Kyungpook National University, Daegu, Korea.

Background And Purpose: We recently reported that AAV1-Rheb(S16H) transduction could protect hippocampal neurons through the induction of brain-derived neurotrophic factor (BDNF) in the rat hippocampus in vivo. It is still unclear how neuronal BDNF produced by AAV1-Rheb(S16H) transduction induces neuroprotective effects in the hippocampus and whether its up-regulation contributes to the enhance of a neuroprotective system in the adult brain.

Experimental Approach: To determine the presence of a neuroprotective system in the hippocampus of patients with Alzheimer's disease (AD), we examined the levels of glial fibrillary acidic protein, BDNF and ciliary neurotrophic factor (CNTF) and their receptors, tropomyocin receptor kinase B (TrkB) and CNTF receptor α(CNTFRα), in the hippocampus of AD patients. We also determined whether AAV1-Rheb(S16H) transduction stimulates astroglial activation and whether reactive astrocytes contribute to neuroprotection in models of hippocampal neurotoxicity in vivo and in vitro.

Key Results: AD patients may have a potential neuroprotective system, demonstrated by increased levels of full-length TrkB and CNTFRα in the hippocampus. Further AAV1-Rheb(S16H) transduction induced sustained increases in the levels of full-length TrkB and CNTFRα in reactive astrocytes and hippocampal neurons. Moreover, neuronal BDNF produced by Rheb(S16H) transduction of hippocampal neurons induced reactive astrocytes, resulting in CNTF production through the activation of astrocytic TrkB and the up-regulation of neuronal BDNF and astrocytic CNTF which had synergistic effects on the survival of hippocampal neurons in vivo.

Conclusions And Implications: The results demonstrated that Rheb(S16H) transduction of hippocampal neurons could strengthen the neuroprotective system and this intensified system may have a therapeutic value against neurodegeneration in the adult brain.
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http://dx.doi.org/10.1111/bph.14882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012949PMC
February 2020

Evans Blue Reduces Neuropathic Pain Behavior by Inhibiting Spinal ATP Release.

Int J Mol Sci 2019 Sep 9;20(18). Epub 2019 Sep 9.

Department of Medical Science, Chungnam National University School of Medicine, Daejeon 35015, Korea.

Upon peripheral nerve injury, vesicular ATP is released from damaged primary afferent neurons. This extracellular ATP subsequently activates purinergic receptors of the spinal cord, which play a critical role in neuropathic pain. As an inhibitor of the vesicular nucleotide transporter (VNUT), Evans blue (EB) inhibits the vesicular storage and release of ATP in neurons. Thus, we tested whether EB could attenuate neuropathic pain behavior induced by spinal nerve ligation (SNL) in rats by targeting VNUT. An intrathecal injection of EB efficiently attenuated mechanical allodynia for five days in a dose-dependent manner and enhanced locomotive activity in an SNL rat model. Immunohistochemical analysis showed that EB was found in VNUT immunoreactivity on neurons in the dorsal root ganglion and the spinal dorsal horn. The level of ATP in cerebrospinal fluid in rats with SNL-induced neuropathic pain decreased upon administration of EB. Interestingly, EB blocked ATP release from neurons, but not glial cells in vitro. Eventually, the loss of ATP decreased microglial activity in the ipsilateral dorsal horn of the spinal cord, followed by a reduction in reactive oxygen species and proinflammatory mediators, such as interleukin (IL)-1β and IL-6. Finally, a similar analgesic effect of EB was demonstrated in rats with monoiodoacetate-induced osteoarthritis (OA) pain. Taken together, these data demonstrate that EB prevents ATP release in the spinal dorsal horn and reduces the ATP/purinergic receptor-induced activation of spinal microglia followed by a decline in algogenic substances, thereby relieving neuropathic pain in rats with SNL.
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http://dx.doi.org/10.3390/ijms20184443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770806PMC
September 2019

Calpain-2 as a Treatment Target in Prenatal Stress-induced Epileptic Spasms in Infant Rats.

Exp Neurobiol 2019 Aug;28(4):529-536

Department of Medical Science, Chungnam National University, Daejeon 35015, Korea.

Stress can induce a serious epileptic encephalopathy that occurs during early infancy. Recent studies have revealed that prenatal stress exposure is a risk factor for the development of infantile spasms. Our previous work demonstrates that prenatal stress with betamethasone-induced alterations to the expression of the K/Cl co-transporter (KCC2) in gamma-aminobutyric acid (GABA) interneurons lowers the seizure threshold in exposed animals. Here, we further investigated the mechanisms involved in this KCC2 dysfunction and explored possible treatment options. We stressed Sprague-Dawley rats prenatally and further treated dams with betamethasone on gestational day 15, which increases seizure susceptibility and NMDA (N-Methyl-D-aspartate)-triggered spasms on postnatal day 15. In this animal model, first, we evaluated baseline calpain activity. Second, we examined the cleavage and dephosphorylation of KCC2. Finally, we checked the effect of a calpain inhibitor on seizure occurrence. The phosphorylated-N-methyl-Daspartate Receptor 2B (NR2B):non-phosphorylated NR2B ratio was found to be higher in the cortex of the prenatally stressed betamethasone model. We further found that the betamethasone model exhibited increased phosphorylation of calpain-2 and decreased phosphorylation of KCC2 and Glutamic acid decarboxylase 67 (GAD67). After using a calpain inhibitor in prenatal-stress rats, the seizure frequency decreased, while latency increased. GABAergic depolarization was further normalized in prenatal-stress rats treated with the calpain inhibitor. Our study suggests that calpain-dependent cleavage and dephosphorylation of KCC2 decreased the seizure threshold of rats under prenatal stress. Calpain-2 functions might, thus, be targeted in the future for the development of treatments for epileptic spasms.
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http://dx.doi.org/10.5607/en.2019.28.4.529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751866PMC
August 2019

Analgesic Effect of Toll-like Receptor 4 Antagonistic Peptide 2 on Mechanical Allodynia Induced with Spinal Nerve Ligation in Rats.

Exp Neurobiol 2019 Jun 26;28(3):352-361. Epub 2019 Jun 26.

Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Daejeon 35015, Korea.

Neuroinflammation is one of the key mechanisms of neuropathic pain, which is primarily mediated by the Toll-like receptor 4 (TLR4) signaling pathways in microglia. Therefore, TLR4 may be a reasonable target for treatment of neuropathic pain. Here, we examined the analgesic effect of TLR4 antagonistic peptide 2 (TAP2) on neuropathic pain induced by spinal nerve ligation in rats. When lipopolysaccharide (LPS)-stimulated BV2 microglia cells were treated with TAP2 (10 µM), the mRNA levels of proinflammatory mediators, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS), were markedly decreased by 54-83% as determined by quantitative PCR (qPCR) analysis. Furthermore, when TAP2 (25 nmol in 20 µL PBS) was intrathecally administered to the spinal nerve ligation-induced rats on day 3 after surgery, the mechanical allodynia was markedly decreased for approximately 2 weeks in von Frey filament tests, with a reduction in microglial activation. On immunohistochemical and qPCR analyses, both the level of reactive oxygen species and the gene expression of the proinflammatory mediators, such as TNF-α, IL-1β, IL-6, COX-2, and iNOS, were significantly decreased in the ipsilateral spinal dorsal horn. Finally, the analgesic effect of TAP2 was reproduced in rats with monoiodoacetate-induced osteoarthritic pain. The findings of the present study suggest that TAP2 efficiently mitigates neuropathic pain behavior by suppressing microglial activation, followed by downregulation of neuropathic pain-related factors, such as reactive oxygen species and proinflammatory molecules. Therefore, it may be useful as a new analgesic for treatment of neuropathic pain.
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http://dx.doi.org/10.5607/en.2019.28.3.352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614064PMC
June 2019

PINK1 mediates spinal cord mitophagy in neuropathic pain.

J Pain Res 2019 28;12:1685-1699. Epub 2019 May 28.

Department of Anatomy, Brain Research Institute, Chungnam National University School of Medicine, Daejeon 301-747, Republic of Korea.

Mitophagy is the selective engulfment of mitochondria by autophagosomes and the subsequent mitochondrial catabolism by lysosomes. Evidence has suggested an important role for mitochondrial dynamics and mitophagic flux in the development of many different neurodegenerative diseases. The potential role of the mechanism underlying mitochondrial dynamics and mitophagic flux as it may relate to neuropathic pain is not well understood. This is a disease that largely remains an area of mechanistic uncertainty. PINK1 is a PTEN-induced mitochondrial kinase that can be selectively activated under mitochondrial stress conditions and lead to the induction of mitophagy. A neuropathic pain rat model was established via spinal nerve ligation (SNL) and nociception was assayed via the von Frey filament method. Increased expression of PINK1 and the mechanism of mitophagy was detected in GABAergic interneurons of dorsal horn neurons of mice that underwent L5 SNL in comparison to control mice counterparts (n=8, <0.001) by Western blotting, immunohistochemistry and double immunofluorescence staining. Elevated expression of PINK1 appeared to localize selectively to GABAergic interneurons, particularly within autophagic mitochondria as evidenced by co-localization studies of PINK1 with BECN1, LC3II and COX IV on immunofluorescent microscopy. Furthermore, we also detected a significant increase in autophagosomes in dorsal horn neurons of SNL mice and this was consistent with increased autophagic activity as measured by the p62 autophagic substrate. These results demonstrate that neuropathic pain causes aberrant mitophagic flux selectively in GABAergic interneurons and provide evidence implicating mitophagy as an important area of future molecular studies to enhance our understanding of neuropathic pain.
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http://dx.doi.org/10.2147/JPR.S198730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554001PMC
May 2019