Neurotropin attenuates local inflammatory response and inhibits demyelination induced by chronic constriction injury of the mouse sciatic nerve

Nishimoto, Shinji; Okada, Kiyoshi; Tanaka, Hiroyuki; Okamoto, Michio; Fujisawa, Hiroki; Okada, Tomoyuki; Naiki, Mitsuru; Murase, Tsuyoshi; Yoshikawa, Hideki

doi:10.1016/j.biologicals.2016.03.005

Cited by 20 publications

(14 citation statements)

References 26 publications

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“…In this study, we have identified AMPK, PGC-1β, mitochondria, and JNK are the targets of NTP. Moreover, previous studies have also determined NTP can inhibit NF-κB, p38, ERK1/2, HIF-1α, and promote PI3K and AKT activation and brain-derived neurotrophic factor induction as the targets of NTP ( Zhang et al, 2014 ; Nishimoto et al, 2016 ; Fang et al, 2017 , 2019 ; Matsuoka et al, 2018 ; Sakai et al, 2018 ; Zheng et al, 2018 ). We and others have not determined the precise molecular mechanisms of how NTP affects those factors.…”

Section: Discussionmentioning

confidence: 94%

“…Notably, NTP is also cytoprotective against neurodegeneration and neuropathy from anticancer chemotherapy-induced neurotoxicity (Kawashiri et al, 2009) and TNFα-and IL-1β-induced hepatocyte apoptosis (Zhang et al, 2014). Furthermore, NTP inhibits several inflammatory pathways, including NF-κB, JNK, ERK, and p38 MAPK pathways in neurons, microglia, and hepatocytes (Zhang et al, 2014;Nishimoto et al, 2016;Fang et al, 2017;Zheng et al, 2018), and suppresses the induction of TNFα, IL-6, and COX-2 by IL-1β and LPS in intervertebral disk cells, microglia, and hepatocytes (Yoshida et al, 2008;Zhang et al, 2014;Zheng et al, 2018). These anti-inflammatory and cytoprotective effects may be beneficial for patients with NASH, which is driven by inflammation in the liver.…”

Section: Introductionmentioning

confidence: 99%

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Neurotropin Inhibits Lipid Accumulation by Maintaining Mitochondrial Function in Hepatocytes via AMPK Activation

Wang

et al. 2020

Front. Physiol.

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The accumulation of lipid droplets in the cytoplasm of hepatocytes, known as hepatic steatosis, is a hallmark of non-alcoholic fatty liver disease (NAFLD). Inhibiting hepatic steatosis is suggested to be a therapeutic strategy for NAFLD. The present study investigated the actions of Neurotropin (NTP), a drug used for chronic pain in Japan and China, on lipid accumulation in hepatocytes as a possible treatment for NAFLD. NTP inhibited lipid accumulation induced by palmitate and linoleate, the two major hepatotoxic free fatty acids found in NAFLD livers. An RNA sequencing analysis revealed that NTP altered the expression of mitochondrial genes. NTP ameliorated palmitateand linoleate-induced mitochondrial dysfunction by reversing mitochondrial membrane potential, respiration, and β-oxidation, suppressing mitochondrial oxidative stress, and enhancing mitochondrial turnover. Moreover, NTP increased the phosphorylation of AMPK, a critical factor in the regulation of mitochondrial function, and induced PGC-1β expression. Inhibition of AMPK activity and PGC-1β expression diminished the anti-steatotic effect of NTP in hepatocytes. JNK inhibition could also be associated with NTP-mediated inhibition of lipid accumulation, but we did not find the association between AMPK and JNK. These results suggest that NTP inhibits lipid accumulation by maintaining mitochondrial function in hepatocytes via AMPK activation, or by inhibiting JNK.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Neurotropin Inhibits Lipid Accumulation by Maintaining Mitochondrial Function in Hepatocytes via AMPK Activation

Wang

et al. 2020

Front. Physiol.

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“…Previous studies on neurons demonstrated that NTP promotes neurite outgrowth in PC12 cells [ 30 , 31 ], and attenuates the inhibition of neurite outgrowth induced by paclitaxel or oxaliplatin in PC12 cells and DRG neurons [ 32 , 33 ]. Amelioration of demyelination in the chronic constriction injury model [ 15 ] and recovery in a paclitaxel-induced demyelination model [ 32 ] were also observed. These findings remind us of the possibility that NTP brings about a favorable effect in both neurons and SCs and provides a new therapeutic strategy, not only for the treatment of neuropathic pain, but also for nerve regeneration after PNI.…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported that NTP inhibits extracellular signal-regulated kinase (ERK) activity and demyelination induced by chronic constriction injury of a mouse sciatic nerve [ 15 ]. Some studies have identified that activation of protein kinase B (AKT) and mitogen activated protein kinase (MAPK) including ERK pathways play a role in SCs proliferation, differentiation, and dedifferentiation [ 16 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Neurotropin® Accelerates the Differentiation of Schwann Cells and Remyelination in a Rat Lysophosphatidylcholine-Induced Demyelination Model

Matsuoka

Tanaka

Sayanagi

et al. 2018

IJMS

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Neurotropin® (NTP), a non-protein extract of inflamed rabbit skin inoculated with vaccinia virus, is clinically used for the treatment of neuropathic pain in Japan and China, although its effect on peripheral nerve regeneration remains to be elucidated. The purpose of this study was to investigate the effects of NTP on Schwann cells (SCs) in vitro and in vivo, which play an important role in peripheral nerve regeneration. In SCs, NTP upregulated protein kinase B (AKT) activity and Krox20 and downregulated extracellular signal-regulated kinase1/2 activity under both growth and differentiation conditions, enhanced the expression of myelin basic protein and protein zero under the differentiation condition. In a co-culture of dorsal root ganglion neurons and SCs, NTP accelerated myelination of SCs. To further investigate the influence of NTP on SCs in vivo, lysophosphatidylcholine was injected into the rat sciatic nerve, leading to the focal demyelination. After demyelination, NTP was administered systemically with an osmotic pump for one week. NTP improved the ratio of myelinated axons and motor, sensory, and electrophysiological function. These findings reveal novel effects of NTP on SCs differentiation in vitro and in vivo, and indicate NTP as a promising treatment option for peripheral nerve injuries and demyelinating diseases.

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“…A nonprotein extract of inflamed rabbit skin inoculated with vaccinia virus, designated Neurotropin ® (NTP), is prescribed widely in Japan and China for the treatment of chronic pain and other various neurological disorders. In vivo, NTP has demonstrated neuroprotective and anti-inflammatory activity in animal models of Down’s syndrome [ 16 ], Alzheimer’s disease (APP/PS1) [ 17 ], permanent middle cerebral artery occlusion [ 18 ], hypoxic ischemic brain injury [ 19 ], chemotherapy-induced peripheral neuropathy [ 20 , 21 ], and peripheral nerve injuries [ 22 , 23 ]. However, the precise molecular mechanisms underlying these pharmacological actions currently remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotection by Neurotropin through Crosstalk of Neurotrophic and Innate Immune Receptors in PC12 Cells

Fukuda

Nakajima

Mutoh

2020

IJMS

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Infected or damaged tissues release multiple “alert” molecules such as alarmins and damage-associated molecular patterns (DAMPs) that are recognized by innate immune receptors, and induce tissue inflammation, regeneration, and repair. Recently, an extract from inflamed rabbit skin inoculated with vaccinia virus (Neurotropin®, NTP) was found to induce infarct tolerance in mice receiving permanent ischemic attack to the middle cerebral artery. Likewise, we report herein that NTP prevented the neurite retraction in PC12 cells by nerve growth factor (NGF) deprivation. This effect was accompanied by interaction of Fyn with high-affinity NGF receptor TrkA. Sucrose density gradient subcellular fractionation of NTP-treated cells showed heretofore unidentified membrane fractions with a high-buoyant density containing Trk, B subunit of cholera toxin-bound ganglioside, flotillin-1 and Fyn. Additionally, these new membrane fractions also contained Toll-like receptor 4 (TLR4). Inhibition of TLR4 function by TAK-242 prevented the formation of these unidentified membrane fractions and suppressed neuroprotection by NTP. These observations indicate that NTP controls TrkA-mediated signaling through the formation of clusters of new membrane microdomains, thus providing a platform for crosstalk between neurotrophic and innate immune receptors. Neuroprotective mechanisms through the interaction with innate immune systems may provide novel mechanism for neuroprotection.

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Neurotropin attenuates local inflammatory response and inhibits demyelination induced by chronic constriction injury of the mouse sciatic nerve

Cited by 20 publications

References 26 publications

Neurotropin Inhibits Lipid Accumulation by Maintaining Mitochondrial Function in Hepatocytes via AMPK Activation

Neurotropin Inhibits Lipid Accumulation by Maintaining Mitochondrial Function in Hepatocytes via AMPK Activation

Neurotropin® Accelerates the Differentiation of Schwann Cells and Remyelination in a Rat Lysophosphatidylcholine-Induced Demyelination Model

Neuroprotection by Neurotropin through Crosstalk of Neurotrophic and Innate Immune Receptors in PC12 Cells

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