Role of CGRP in Neuroimmune Interaction via NF-κB Signaling Genes in Glial Cells of Trigeminal Ganglia

Activation of the trigeminal system causes the release of various neuropeptides, cytokines, and other immune mediators. Calcitonin gene-related peptide (CGRP), which is a potent algogenic mediator, is expressed in the peripheral sensory neurons of trigeminal ganglion (TG). It affects the inflammatory responses and pain sensitivity by modulating the activity of glial cells. The primary aim of this study was to use array analysis to investigate the effect of CGRP on the glial cells of TG in regulating nuclear factor kappa B (NF-κB) signaling genes and to further check if CGRP in the TG can affect neuron-glia activation in the spinal trigeminal nucleus caudalis. The glial cells of TG were stimulated with CGRP or Minocycline (Min) + CGRP. The effect on various genes involved in NF-κB signaling pathway was analyzed compared to no treatment control condition using a PCR array analysis. CGRP, Min + CGRP or saline was directly injected inside the TG and the effect on gene expression of Egr1, Myd88 and Akt1 and protein expression of cleaved Caspase3 (cleav Casp3) in the TG, and c-Fos and glial fibrillary acidic protein (GFAP) in the spinal section containing trigeminal nucleus caudalis was analyzed. Results showed that CGRP stimulation resulted in the modulation of several genes involved in the interleukin 1 signaling pathway and some genes of the tumor necrosis factor pathway. Minocycline pre-treatment resulted in the modulation of several genes in the glial cells, including anti-inflammatory genes, and neuronal activation markers. A mild increase in cleav Casp3 expression in TG and c-Fos and GFAP in the spinal trigeminal nucleus of CGRP injected animals was observed. These data provide evidence that glial cells can participate in neuroimmune interaction due to CGRP in the TG via NF-κB signaling pathway

歯の機械的刺激による神経興奮を放射断層撮影法を用いて検討した予備研究

Dentists often cannot objectively find abnormalities in patients who complain of discomfort or abnormal sensation in their dental occlusion. We hypothesized that abnormal neural transmission from the tooth is related to this occlusal discomfort sensation. Chronic tooth contact habits may induce neural excitation from the tooth to the central nervous system, and may aggravate the sensation of discomfort in the central nervous system. However, the details of neural transmission from the tooth to the central nervous system are still unclear. In this study, we stimulated a rat premolar mechanically and observed activated bran sites using positron emission tomography (PET) and 18F-2-fluoro-2-deoxy-D-glucose (FDG). We anesthetized 5-7-week-old male rats using isoflurane inhalation anesthesia and stimulated the upper right premolar mechanically with an electric von Frey system (Model 1601C, IITC Instruments) by measuring mechanical pressure. Before the tooth mechanical stimulation, we injected FDG through the rat’s caudal vein and then used a stimulation intensity of 100, 200 or 300 g. We recorded FDG accumulation with PET. The PET brain images were separated into four parts (right higher, left higher, right lower and left lower) for analysis and the peak value of striatal uptake (SUV) in each part was analyzed. The PET images showed that the accumulated FDG in the right lower part of the brain was higher with 300 g tooth stimulation than with 100 or 200 g. The data showed that the tooth stimulation site in the lower part of the brain was activated with tooth stimulation by comparing it with the other parts. We also measured SUV in the right and left sensory areas, motor area, hippocampus, trigeminal ganglia (TG) and spinal cord. The TG and sensory area showed more FDG accumulation compared with mouth opening.咬合違和感を訴えて来院した患者に対して，歯科医師は咬合状態に客観的な異常を見つけることができないこともよくある．我々は歯からの神経伝達が咬合違和感と何らかの関連をしているのではないかと仮説を立てて研究を行っている．慢性的な歯への刺激が歯から中枢における神経興奮に関連しており，中枢での咬合違和感を悪化させるのかもしれないと考えられる．しかしながら，歯から中枢への神経伝達の詳細は不明である．この研究ではラットの小臼歯を機械的に刺激して，脳の活動部位を18F-2-フルオロ-2-デオキシ-D-グルコース （FDG）を用いて放射断層撮影法（PET）により計測した．5〜7 週齢のラットをイソフルレンを用いて全身麻酔し，電気的フォンフレイ刺激装置を用いて刺激圧を計測しながら上顎右側小臼歯を刺激した．歯の刺激前にFDG を尾静脈から注射し，100，200，300g の刺激力を用いて刺激した． 脳PET 画像は脳を4 分割（右上，左上，右下，左下）して，ピーク値を計測したところ，右下部においては300g の刺激力は100，200g よりもFDG の集積が観察された．この結果は歯の刺激により脳の右下部位が活動することを示していると考えられる．また，知覚部位，運動部位，海馬，三叉神経節，脊髄に分類して観察したところ，三叉神経節と知覚部位においてFDG の集積が観察された

Thread shape, cortical bone thickness, and magnitude and distribution of stress caused by the loading of orthodontic miniscrews : finite element analysis

Cortical bone thickness is assumed to be a major factor regulating miniscrew stability. We investigated stress distribution in two miniscrews with different thread shapes (type A and B) and in cortical bone of three different thicknesses using three-dimensional (3D) finite element (FE) models. More specifically, 3D FE models of two different miniscrews were created and placed obliquely or vertically into a cylindrical bone model representing different cortical bone thicknesses. When force was applied to the miniscrew, the stress distribution on the screw surface and in the peri-implant bone was assessed using FE methodology. Miniscrew safety was evaluated using a modified Soderberg safety factor. Screw head displacement increased with a decrease in cortical bone thickness, irrespective of screw type. The smallest minimum principal stresses on the screw surfaces remained constant in type A miniscrews on changes in cortical bone thickness. Minimum principal stresses also appeared on the cortical bone surface. Lower absolute values of minimum principal stresses were seen in type A miniscrews when placed vertically and with upward traction in obliquely placed type B miniscrews. Both miniscrews had acceptable safety factor values. Taken together, orthodontists should select and use the suitable miniscrew for each patient in consideration of bone properties

The role of chemical transmitters in neuron-glia interaction and pain in sensory ganglion

Neuropathic pain (NP) develops because of damage to the peripheral or central nervous system. It results in the hyperalgesia and allodynia. In the recent years, various researchers have studied the involvement of neuro-immune system in causing persistence of pain. The absence of synaptic contacts in the sensory ganglion makes them distinctive in terms of pain related signalling. In sensory ganglia, the neurotransmitters or the other modulators such as inflammatory substances produced by the ganglion cells, because of an injury, are responsible for the cross-excitation between neurons and neuron-glial interaction, thus affecting chemical transmission. This chemical transmission is considered mainly responsible for the chronicity and the persistent nature of neuropathic pain. This review examines the pain signalling due to neurotransmitter or cytokine release within the sensory ganglia. The specific areas focused on include: 1) the role of neurotransmitters released from the somata of sensory neurons in pain , 2) neuron-glia interaction and 3) role of cytokines in neuromodulation and pain

Macrophage Motility in Wound Healing Is Regulated by HIF-1α via S1P Signaling

Accumulating evidence indicates that the molecular pathways mediating wound healing induce cell migration and localization of cytokines to sites of injury. Macrophages are immune cells that sense and actively respond to disturbances in tissue homeostasis by initiating, and subsequently resolving, inflammation. Hypoxic conditions generated at a wound site also strongly recruit macrophages and affect their function. Hypoxia inducible factor (HIF)-1α is a transcription factor that contributes to both glycolysis and the induction of inflammatory genes, while also being critical for macrophage activation. For the latter, HIF-1α regulates sphingosine 1-phosphate (S1P) to affect the migration, activation, differentiation, and polarization of macrophages. Recently, S1P and HIF-1α have received much attention, and various studies have been performed to investigate their roles in initiating and resolving inflammation via macrophages. It is hypothesized that the HIF-1α/S1P/S1P receptor axis is an important determinant of macrophage function under inflammatory conditions and during disease pathogenesis. Therefore, in this review, biological regulation of monocytes/macrophages in response to circulating HIF-1α is summarized, including signaling by S1P/S1P receptors, which have essential roles in wound healing

Macrophage Motility in Wound Healing Is Regulated by HIF-1α via S1P Signaling

Accumulating evidence indicates that the molecular pathways mediating wound healing induce cell migration and localization of cytokines to sites of injury. Macrophages are immune cells that sense and actively respond to disturbances in tissue homeostasis by initiating, and subsequently resolving, inflammation. Hypoxic conditions generated at a wound site also strongly recruit macrophages and affect their function. Hypoxia inducible factor (HIF)-1α is a transcription factor that contributes to both glycolysis and the induction of inflammatory genes, while also being critical for macrophage activation. For the latter, HIF-1α regulates sphingosine 1-phosphate (S1P) to affect the migration, activation, differentiation, and polarization of macrophages. Recently, S1P and HIF-1α have received much attention, and various studies have been performed to investigate their roles in initiating and resolving inflammation via macrophages. It is hypothesized that the HIF-1α/S1P/S1P receptor axis is an important determinant of macrophage function under inflammatory conditions and during disease pathogenesis. Therefore, in this review, biological regulation of monocytes/macrophages in response to circulating HIF-1α is summarized, including signaling by S1P/S1P receptors, which have essential roles in wound healing

矯正治療中に歯肉退縮した下顎中切歯に対して結合組織移植を行った長期保定症例

歯肉退縮は，矯正治療中や治療後にしばしば生じるリスクのひとつであり，歯根面の露出により審美障害ならびに知覚過敏や根面う蝕などの問題を誘発する． 歯肉退縮の予防を目的とした，矯正治療前の歯周外科処置も報告されているが，現時点では一般的ではなく，実際に歯肉退縮が発生した後，結合組織移植術（CTG）などの歯周形成外科手術によって対応しているのが現状である． 今回我々は，歯性上顎前突患者の矯正治療中に下顎左側中切歯に生じた歯肉退縮に対して，1年10か月間の矯正治療終了後にCTGを施行し，術後6年経過した現在も歯肉退縮の再発を認めず，良好な状態が維持された症例を経験したため報告する．Gingival recession is one of the common risks in clinical orthodontics, and it results in dentinal hyperesthesia and root caries with esthetic problems. Periodontal surgical therapy including connective tissue graft (CTG) has not been routinely performed to prevent gingival recession before orthodontic treatment, and CTG has been conducted when causing gingival recession after orthodontic treatment. In this study, we report a case of dental maxillary protrusion who induced gingival recession in the left lower central incisor during orthodontic treatment. After 1-yesr 10-month orthodontic treatment, a subepithelial CTG procedure was performed. Healing was uneventful, and the grafted site showed a favorable outcome at 6 years postoperatively

Macrophage Motility in Wound Healing Is Regulated by HIF-1α via S1P Signaling

Accumulating evidence indicates that the molecular pathways mediating wound healing induce cell migration and localization of cytokines to sites of injury. Macrophages are immune cells that sense and actively respond to disturbances in tissue homeostasis by initiating, and subsequently resolving, inflammation. Hypoxic conditions generated at a wound site also strongly recruit macrophages and affect their function. Hypoxia inducible factor (HIF)-1α is a transcription factor that contributes to both glycolysis and the induction of inflammatory genes, while also being critical for macrophage activation. For the latter, HIF-1α regulates sphingosine 1-phosphate (S1P) to affect the migration, activation, differentiation, and polarization of macrophages. Recently, S1P and HIF-1α have received much attention, and various studies have been performed to investigate their roles in initiating and resolving inflammation via macrophages. It is hypothesized that the HIF-1α/S1P/S1P receptor axis is an important determinant of macrophage function under inflammatory conditions and during disease pathogenesis. Therefore, in this review, biological regulation of monocytes/macrophages in response to circulating HIF-1α is summarized, including signaling by S1P/S1P receptors, which have essential roles in wound healing

Macrophage Motility in Wound Healing Is Regulated by HIF-1 alpha via S1P Signaling

Accumulating evidence indicates that the molecular pathways mediating wound healing induce cell migration and localization of cytokines to sites of injury. Macrophages are immune cells that sense and actively respond to disturbances in tissue homeostasis by initiating, and subsequently resolving, inflammation. Hypoxic conditions generated at a wound site also strongly recruit macrophages and affect their function. Hypoxia inducible factor (HIF)-1 alpha is a transcription factor that contributes to both glycolysis and the induction of inflammatory genes, while also being critical for macrophage activation. For the latter, HIF-1 alpha regulates sphingosine 1-phosphate (S1P) to affect the migration, activation, differentiation, and polarization of macrophages. Recently, S1P and HIF-1 alpha have received much attention, and various studies have been performed to investigate their roles in initiating and resolving inflammation via macrophages. It is hypothesized that the HIF-1 alpha/S1P/S1P receptor axis is an important determinant of macrophage function under inflammatory conditions and during disease pathogenesis. Therefore, in this review, biological regulation of monocytes/macrophages in response to circulating HIF-1 alpha is summarized, including signaling by S1P/S1P receptors, which have essential roles in wound healing

Analgesic Effect of Tranilast in an Animal Model of Neuropathic Pain and Its Role in the Regulation of Tetrahydrobiopterin Synthesis

Trigeminal neuralgia is unilateral, lancinating, episodic pain that can be provoked by routine activities. Anticonvulsants, such as carbamazepine, are the drugs of choice; however, these possess side-effects. Microvascular decompression is the most effective surgical technique with a higher success rate, although occasionally causes adverse effects. The potential treatment for this type of pain remains unmet. Increased tetrahydrobiopterin (BH4) levels have been reported in association with axonal injury. This study aimed to evaluate the effect of tranilast on relieving neuropathic pain in animal models and analyze the changes in BH4 synthesis. Neuropathic pain was induced via infraorbital nerve constriction. Tranilast, carbamazepine, or saline was injected intraperitoneally to assess the rat’s post-intervention pain response. In the von Frey’s test, the tranilast and carbamazepine groups showed significant changes in the head withdrawal threshold in the ipsilateral whisker pad area. The motor coordination test showed no changes in the tranilast group, whereas the carbamazepine group showed decreased performance, indicating impaired motor coordination. Trigeminal ganglion tissues were used for the PCR array analysis of genes that regulate the BH4 pathway. Downregulation of the sepiapterin reductase (Spr) and aldoketo reductase (Akr) genes after tranilast injection was observed compared to the pain model. These findings suggest that tranilast effectively treats neuropathic pain