P38 siRNA-Encapsulated PLGA Nanoparticles Alleviate Neuropathic Pain Behavior in Rats By Inhibiting Microglia Activation

Shin, Juhee; Yin, Yuhua; Park, Hyewon; Park, Seungjo; Triantafillu, Ursula L.; Kim, Yonghyun; Kim, Sang Ryong; Lee, Sun Yeul; Kim, Do Kyung; Hong, Jinpyo; Kim, Dong Ho

doi:10.2217/nnm-2018-0054

Cited by 48 publications

(46 citation statements)

References 25 publications

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“…Neuropathic pain models that are associated with persistent LPA signaling and subsequent activation of MAPK cascades might be candidates for such an approach [42]. Indeed, a series of recent reports demonstrated that pharmacological intervention strategies that attenuate MAPK signaling pathways (either directly or indirectly) alleviate hyperalgesia in preclinical animal models of neuropathic pain [58][59][60][61]. In one of our earlier proteome studies, we have shown that LPA affects the abundance of a number of metabolic enzymes involved in glycolysis [20].…”

Section: Discussionmentioning

confidence: 97%

MAPK signaling determines lysophosphatidic acid (LPA)-induced inflammation in microglia

Plastira

Bernhart

Joshi

et al. 2020

J Neuroinflammation

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Background: In the extracellular environment, lysophosphatidic acid (LPA) species are generated via autotaxin (ATX)-mediated hydrolysis of lysophospholipid precursors. Members of the LPA family are potent lipid mediators transmitting signals via six different G protein-coupled LPA receptors (LPAR1-6). The LPA signaling axis is indispensable for brain development and function of the nervous system; however, during damage of the central nervous system, LPA levels can increase and aberrant signaling events counteract brain function. Here, we investigated regulation of the ATX/LPA/LPAR axis in response to lipopolysaccharide-induced systemic inflammation in mice and potential neurotoxic polarization programs in LPA-activated primary murine microglia. Methods: In vivo, LPAR1-6 expression was established by qPCR in whole murine brain homogenates and in FACSsorted microglia. ELISAs were used to quantitate LPA concentrations in the brain and cyto-/chemokine secretion from primary microglia in vitro. Transcription factor phosphorylation was analyzed by immunoblotting, and plasma membrane markers were analyzed by flow cytometry. We used MAPK inhibitors to study signal integration by the JNK, p38, and ERK1/2 branches in response to LPA-mediated activation of primary microglia. Results: Under acute and chronic inflammatory conditions, we observed a significant increase in LPA concentrations and differential regulation of LPAR, ATX (encoded by ENPP2), and cytosolic phospholipase A2 (encoded by PLA2G4A) gene expression in the brain and FACS-sorted microglia. During pathway analyses in vitro, the use of specific MAPK antagonists (SP600125, SB203580, and PD98059) revealed that JNK and p38 inhibition most efficiently attenuated LPA-induced phosphorylation of proinflammatory transcription factors (STAT1 and-3, p65, and c-Jun) and secretion of IL-6 and TNFα. All three inhibitors decreased LPA-mediated secretion of IL-1β, CXCL10, CXCL2, and CCL5. The plasma membrane marker CD40 was solely inhibited by SP600125 while all three inhibitors affected expression of CD86 and CD206. All MAPK antagonists reduced intracellular COX-2 and Arg1 as well as ROS and NO formation, and neurotoxicity of microglia-conditioned media.

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Section: Discussionmentioning

confidence: 97%

MAPK signaling determines lysophosphatidic acid (LPA)-induced inflammation in microglia

Plastira

Bernhart

Joshi

et al. 2020

J Neuroinflammation

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“…An MTT assay was performed in order to test the cell viability caused by siRNA-encapsulated PLGA nanoparticles as per the manufacturer's instructions. Detailed procedures can also be found in previous reports [35].…”

Section: Cytotoxicity Assaymentioning

confidence: 99%

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

et al. 2020

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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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“…RSS373234; Thermo Fisher, USA) or scrambled siRNA (catalog no. 12935400; Thermo Fisher) were prepared using an emulsification/ solvent evaporation method 32 and their physical characteristics were analyzed with the Zetasizer Nano ZS90 (Malvern Instruments, UK). 23 The NP synthesis and characterization are shown in the Figure 1.…”

Section: Poly(lactic-co-glycolic Acid) Nanoparticles Preparationmentioning

confidence: 99%

<p>p66shc siRNA Nanoparticles Ameliorate Chondrocytic Mitochondrial Dysfunction in Osteoarthritis</p>

Shin

Park

Shin

et al. 2020

IJN

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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-co-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 MIAinduced 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 nanoparticlesdelivered 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 dysfunctioninduced 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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P38 siRNA-Encapsulated PLGA Nanoparticles Alleviate Neuropathic Pain Behavior in Rats By Inhibiting Microglia Activation

Abstract: As p38 in the spinal microglia plays a critical role in neuropathic pain, we expect that p38 siRNA NPs could be a promising tool for the treatment of neuropathic pain.

Cited by 48 publications

References 25 publications

MAPK signaling determines lysophosphatidic acid (LPA)-induced inflammation in microglia

MAPK signaling determines lysophosphatidic acid (LPA)-induced inflammation in microglia

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

<p>p66shc siRNA Nanoparticles Ameliorate Chondrocytic Mitochondrial Dysfunction in Osteoarthritis</p>

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