Mirogabalin inhibits scratching behavior of spontaneous model mouse of atopic dermatitis

Introduction: Atopic dermatitis (AD) is one of the most prevalent intractable chronic itch diseases worldwide. In recent years, new molecular-targeted drugs have emerged, but side effects and economic challenges remain. Therefore, since it is important for AD patients to have a wider range of treatment options, it is important to explore new therapeutic agents. Gabapentinoids, gabapentin and pregabalin, have been shown to be effective for the clinical treatment of several chronic itch. Recently, mirogabalin (MGB) was developed as a novel gabapentinoid. MGB is a drug for neuropathic pain and has a margin of safety between its side effects and the analgesic effect for animal experiments. Herein, we showed that MGB exhibited an antipruritic effect in a mouse model of AD using NC/Nga mice.Methods and results: The oral administration of MGB (10 mg/kg) inhibited spontaneous scratching behavior in AD mice and its effect was dose dependently. Then, when MGB (10 mg/kg) was orally administrated to healthy mice, it did not affect motor function, including locomotor activity, wheel activity, and coordinated movement. Moreover, gabapentin (100 mg/kg) and pregabalin (30 mg/kg), inhibited spontaneous scratching behavior in AD mice and decreased motor function in healthy mice. Furthermore, intracisternal injection of MGB (10 μg/site) significantly suppressed spontaneous scratching behavior in AD mice.Discussion: In summary, our results suggest that MGB exerts an antipruritic effect via the spinal dorsal horn using NC/Nga mice. We hope that MGB is a candidate for a novel therapeutic agent for AD with relatively few side effects

Fernblock® Upregulates NRF2 Antioxidant Pathway and Protects Keratinocytes from PM2.5-Induced Xenotoxic Stress

Humans in modern industrial and postindustrial societies face sustained challenges from environmental pollutants, which can trigger tissue damage from xenotoxic stress through different mechanisms. Thus, the identification and characterization of compounds capable of conferring antioxidant effects and protection against these xenotoxins are warranted. Here, we report that the natural extract of Polypodium leucotomos named Fernblock®, known to reduce aging and oxidative stress induced by solar radiations, upregulates the NRF2 transcription factor and its downstream antioxidant targets, and this correlates with its ability to reduce inflammation, melanogenesis, and general cell damage in cultured keratinocytes upon exposure to an experimental model of fine pollutant particles (PM2.5). Our results provide evidence for a specific molecular mechanism underpinning the protective activity of Fernblock® against environmental pollutants and potentially other sources of oxidative stress and damage-induced agingThis research was funded by Cantabria Labs and by the Spanish grant from Instituto de Salud Carlos III and MINECO and FEDER funds (PI18/00708). P.D-W is supported by Comunidad Autónoma de Madrid (CAM

Integrin α5β1 expression on dopaminergic neurons is involved in dopaminergic neurite outgrowth on striatal neurons

神経突起が標的神経細胞と相互作用して伸長する仕組みを解明 : 神経細胞移植の治療効果向上に期待. 京都大学プレスリリース. 2017-02-09.During development, dopaminergic neurons born in the substantia nigra extend their axons toward the striatum. However, the mechanisms by which the dopaminergic axons extend the striatum to innervate their targets remain unclear. We previously showed that paired-cultivation of mesencephalic cells containing dopaminergic neurons with striatal cells leads to the extension of dopaminergic neurites from the mesencephalic cell region to the striatal cell region. The present study shows that dopaminergic neurites extended along striatal neurons in the paired-cultures of mesencephalic cells with striatal cells. The extension of dopaminergic neurites was suppressed by the pharmacological inhibition of integrin α5β1. Using lentiviral vectors, short hairpin RNA (shRNA)-mediated knockdown of integrin α5 in dopaminergic neurons suppressed the neurite outgrowth to the striatal cell region. In contrast, the knockdown of integrin α5 in non-dopaminergic mesencephalic and striatal cells had no effect. Furthermore, overexpression of integrin α5 in dopaminergic neurons differentiated from embryonic stem cells enhanced their neurite outgrowth on striatal cells. These results indicate that integrin α5β1 expression on dopaminergic neurons plays an important role in the dopaminergic neurite outgrowth on striatal neurons

E22Δ Mutation in Amyloid β-Protein Promotes β-Sheet Transformation, Radical Production, and Synaptotoxicity, But Not Neurotoxicity

Oligomers of 40- or 42-mer amyloid β-protein (Aβ40, Aβ42) cause cognitive decline and synaptic dysfunction in Alzheimer's disease. We proposed the importance of a turn at Glu22 and Asp23 of Aβ42 to induce its neurotoxicity through the formation of radicals. Recently, a novel deletion mutant at Glu22 (E22Δ) of Aβ42 was reported to accelerate oligomerization and synaptotoxicity. To investigate this mechanism, the effects of the E22Δ mutation in Aβ42 and Aβ40 on the transformation of β-sheets, radical production, and neurotoxicity were examined. Both mutants promoted β-sheet transformation and the formation of radicals, while their neurotoxicity was negative. In contrast, E22P-Aβ42 with a turn at Glu22 and Asp23 exhibited potent neurotoxicity along with the ability to form radicals and potent synaptotoxicity. These data suggest that conformational change in E22Δ-Aβ is similar to that in E22P-Aβ42 but not the same, since E22Δ-Aβ42 exhibited no cytotoxicity, unlike E22P-Aβ42 and wild-type Aβ42

Co-morbidity of progressive supranuclear palsy and amyotrophic lateral sclerosis : a clinical-pathological case report

Background: The coexistence of distinct neurodegenerative diseases in single cases has recently attracted greater attention. The phenotypic co-occurrence of progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS) has been documented in several cases. That said, the clinicopathological comorbidity of these two diseases has not been demonstrated. Case presentation: A 77-year-old man presented with gait disturbance for 2 years, consistent with PSP with progressive gait freezing. At 79 years old, he developed muscle weakness compatible with ALS. The disease duration was 5 years after the onset of PSP and 5months after the onset of ALS. Neuropathological findings demonstrated the coexistence of PSP and ALS. Immunohistochemical examination confirmed 4-repeat tauopathy, including globose-type neurofibrillary tangles, tufted astrocytes, and oligodendroglial coiled bodies as well as TAR DNA-binding protein 43 kDa pathology in association with upper and lower motor neuron degeneration. Immunoblotting showed hyperphosphorylated full-length 4-repeat tau bands (64 and 68 kDa) and C-terminal fragments (33 kDa), supporting the diagnosis of PSP and excluding other parkinsonian disorders, such as corticobasal degeneration. Genetic studies showed no abnormalities in genes currently known to be related to ALS or PSP. Conclusions: Our case demonstrates the clinicopathological comorbidity of PSP and ALS in a sporadic patient. The possibility of multiple proteinopathies should be considered when distinct symptoms develop during the disease course

HMGB1 inhibitor glycyrrhizin attenuates intracerebral hemorrhage-induced injury in rats.

Thrombin activates immunocompetent microglia and increases release of inflammatory cytokines under intracerebral hemorrhage (ICH) insults. Also, thrombin injection into the striatum evokes acute necrosis and delayed apoptosis of neurons. A nucleoprotein high-mobility group box 1 (HMGB1) that is released from necrotic cells has been suggested to behave like a cytokine and cause over-facilitation of immune functions. Here we examined the effect of glycyrrhizin, known as an inhibitor of HMGB1, on thrombin-induced injury in rat cortico-striatal slice cultures and in vivo rat ICH model. In slice cultures, thrombin-induced a drastic increase in propidium iodide fluorescence indicating necrotic cell death in the cortical region, and robust shrinkage of the striatal tissue. Glycyrrhizin (10-100 μM) attenuated thrombin-induced cortical injury in a concentration-dependent manner. The protective effect of glycyrrhizin was not mediated by glucocorticoid receptors or modulation of nitric oxide production, but was reversed by exogenous HMGB1 application. The injury induced by a high concentration of HMGB1 was suppressed by glycyrrhizin. In vivo, unilateral injection of type IV collagenase into rat striatum induced ICH associated with brain edema formation, contralateral paralysis and neuron death. Once daily intraperitoneal administration of glycyrrhizin attenuated ICH-induced edema in both the cortex and the basal ganglia, and improved behavioral performance of rats in forelimb placing. Moreover, glycyrrhizin partially but significantly ameliorated ICH-induced neuron loss inside hematoma. These findings suggest that an HMGB1 inhibitor glycyrrhizin is a potential candidate for a remedy for ICH.Thrombin activates immunocompetent microglia and increases release of inflammatory cytokines under intracerebral hemorrhage (ICH) insults. Also, thrombin injection into the striatum evokes acute necrosis and delayed apoptosis of neurons. A nucleoprotein high-mobility group box 1 (HMGB1) that is released from necrotic cells has been suggested to behave like a cytokine and cause over-facilitation of immune functions. Here we examined the effect of glycyrrhizin, known as an inhibitor of HMGB1, on thrombin-induced injury in rat cortico-striatal slice cultures and in vivo rat ICH model. In slice cultures, thrombin-induced a drastic increase in propidium iodide fluorescence indicating necrotic cell death in the cortical region, and robust shrinkage of the striatal tissue. Glycyrrhizin (10-100 μM) attenuated thrombin-induced cortical injury in a concentration-dependent manner. The protective effect of glycyrrhizin was not mediated by glucocorticoid receptors or modulation of nitric oxide production, but was reversed by exogenous HMGB1 application. The injury induced by a high concentration of HMGB1 was suppressed by glycyrrhizin. In vivo, unilateral injection of type IV collagenase into rat striatum induced ICH associated with brain edema formation, contralateral paralysis and neuron death. Once daily intraperitoneal administration of glycyrrhizin attenuated ICH-induced edema in both the cortex and the basal ganglia, and improved behavioral performance of rats in forelimb placing. Moreover, glycyrrhizin partially but significantly ameliorated ICH-induced neuron loss inside hematoma. These findings suggest that an HMGB1 inhibitor glycyrrhizin is a potential candidate for a remedy for ICH

A distinct subtype of Epstein-Barr virus-positive T/NK-cell lymphoproliferative disorder: adult patients with chronic active Epstein-Barr virus infection-like features

The characteristics of adult patients with chronic active Epstein-Barr virus infection are poorly recognized, hindering early diagnosis and an improved prognosis. We studied 54 patients with adult-onset chronic active Epstein-Barr virus infection diagnosed between 2005 and 2015. Adult onset was defined as an estimated age of onset of 15 years or older. To characterize the clinical features of these adults, we compared them to those of 75 pediatric cases (estimated age of onse

Thrombin-induced delayed injury involves multiple and distinct signaling pathways in the cerebral cortex and the striatum in organotypic slice cultures

Thrombin, a serine protease essential for blood coagulation, also plays an important role in cellular injury associated with intracerebral hemorrhage. Here, we show that, in organotypic cortico-striatal slice cultures, thrombin evoked delayed neuronal injury in the cerebral cortex and shrinkage of the striatum. These effects were prevented by cycloheximide and actinomycin D but not by a caspase-3 inhibitor. Thrombin-induced shrinkage of the striatum was abolished by a thrombin inhibitor argatroban or prior heat inactivation of thrombin, and significantly attenuated by a protease-activated receptor-1 antagonist FR171113. However, thrombin-induced cortical injury was not prevented either by heat inactivation or by FR171113, and was only partially inhibited by argatroban. In addition, inhibition of extracelluar signal-regulated kinase (ERK), Src tyrosine kinase and protein kinase C prevented both neuronal injury in the cortex and shrinkage of the striatum, whereas inhibition of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase prevented shrinkage of the striatum only. Thrombin treatment promptly induced phosphorylation of ERK, which was not prevented by inhibition of Src and protein kinase C. Thus, thrombin induces cellular injury in the cerebral cortex and the striatum, by recruiting multiple and distinct signaling pathways in protease activity-independent as well as dependent manner