Novel mGluR5 Positive Allosteric Modulator Improves Functional Recovery,Attenuates Neurodegeneration,and Alters Microglial Polarization after Experimental Traumatic Brain Injury

Traumatic brain injury (TBI) causes microglial activation and related neurotoxicity that contributes to chronic neurodegeneration and loss of neurological function. Selective activation of metabotropic glutamate receptor 5 (mGluR5) by the orthosteric agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), is neuroprotective in experimental models of TBI, and has potent anti-inflammatory effects in vitro. However, the therapeutic potential of CHPG is limited due to its relatively weak potency and brain permeability. Highly potent, selective and brain penetrant mGluR5 positive allosteric modulators (PAMs) have been developed and show promise as therapeutic agents. We evaluated the therapeutic potential of a novel mGluR5 PAM, VU0360172, after controlled cortical impact (CCI) in mice. Vehicle, VU0360172, or VU0360172 plus mGluR5 antagonist (MTEP), were administered systemically to CCI mice at 3 h post-injury; lesion volume, hippocampal neurodegeneration, microglial activation, and functional recovery were assessed through 28 days post-injury. Anti-inflammatory effects of VU0360172 were also examined in vitro using BV2 and primary microglia. VU0360172 treatment significantly reduced the lesion, attenuated hippocampal neurodegeneration, and improved motor function recovery after CCI. Effects were mediated by mGluR5 as co-administration of MTEP blocked the protective effects of VU0360172. VU0360172 significantly reduced CD68 and NOX2 expression in activated microglia in the cortex at 28 days post-injury, and also suppressed pro-inflammatory signaling pathways in BV2 and primary microglia. In addition, VU0360172 treatment shifted the balance between M1/M2 microglial activation states towards an M2 pro-repair phenotype. This study demonstrates that VU0360172 confers neuroprotection after experimental TBI, and suggests that mGluR5 PAMs may be promising therapeutic agents for head injury.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-014-0298-6) contains supplementary material, which is available to authorized users.     

Cell grouping and Golgi architecture of the hypoglossal nucleus of the rat

The hypoglossal nucleus of the rat has been investigated by Nissl and Golgi techniques. Both techniques reveal that neurons within the nucleus are grouped into readily definable pools. Identification of these pools has been based on certain objective criteria described in detail in the text. Existing experimental data support a relationship between pools of hypoglossal motoneurons and muscle groups of the tongue on one hand, and functional but simple movements on the other.As hypoglossal neurons show considerable variation in size, shape, neuronal density per pool, and dendritic arborization patterns, the extent to which these structural features of the nucleus coupled with the versatility of the afferent field terminals may determine complex, patterned, and fine movements of the tongue is discussed against a background of established principles of neuromuscular motor mechanisms.     

Parameters of glucose metabolism and the aging brain: a magnetization transfer imaging study of brain macro- and micro-structure in older adults without diabetes

Given the concurrent, escalating epidemic of diabetes mellitus and neurodegenerative diseases, two age-related disorders, we aimed to understand the relation between parameters of glucose metabolism and indices of pathology in the aging brain. From the Leiden Longevity Study, 132 participants (mean age 66 years) underwent a 2-h oral glucose tolerance test to assess glucose tolerance (fasted and area under the curve (AUC) glucose), insulin sensitivity (fasted and AUC insulin and homeostatic model assessment of insulin sensitivity (HOMA-IS)) and insulin secretion (insulinogenic index). 3-T brain MRI was used to detect macro-structural damage (atrophy, white matter hyper-intensities, infarcts and/or micro-bleeds) and magnetization transfer imaging (MTI) to detect loss of micro-structural homogeneity that remains otherwise invisible on conventional MRI. Macro-structurally, higher fasted glucose was significantly associated with white matter atrophy (P = 0.028). Micro-structurally, decreased magnetization transfer ratio (MTR) peak height in gray matter was associated with higher fasted insulin (P = 0.010), AUC_insulin (P = 0.001), insulinogenic index (P = 0.008) and lower HOMA-IS index (P < 0.001). Similar significant associations were found for white matter. Thus, while higher glucose was associated with macro-structural damage, impaired insulin action was associated more strongly with reduced micro-structural brain parenchymal homogeneity. These findings offer some insight into the association between different parameters of glucose metabolism (impairment of which is characteristic of diabetes mellitus) and brain aging.     

Effects of periodontal treatment on carotid intima-media thickness in patients with lifestyle-related diseases: Japanese prospective multicentre observational study

Atherosclerosis, a chronic inflammatory disease in arterial blood vessels, is one of the major causes of death in worldwide. Meanwhile, periodontal disease is a chronic inflammatory disease caused by infection with periodontal pathogens such as P. gingivalis (Porphyromonas gingivalis). Several studies have reported association between periodontal infection and atherosclerosis, but direct investigation about the effects of periodontal treatment on atherosclerosis has not been reported. We have planned Japanese local clinics to determine the relationship between periodontal disease and atherosclerosis under collaborative with medical and dental care. A prospective, multicentre, observational study was conducted including 38 medical patients with lifestyle-related diseases in the stable period under consultation at participating medical clinics and 92 periodontal patients not undergoing medical treatment but who were consulting at participating dental clinics. Systemic and periodontal examinations were performed before and after periodontal treatment. At baseline, LDL-C (low-density lipoprotein cholesterol) levels and percentage (%) of mobile teeth were positively related to plasma IgG (immunoglobulin) antibody titer against P. gingivalis with multivariate analysis. Corresponding to improvements in periodontal clinical parameters after treatment, right and left max IMT (maximum intima-media thickness) levels were decreased significantly after treatment (SPT-S: start of supportive periodontal therapy, SPT-1y: at 1 year under SPT, and SPT-3y: at 3 years under SPT). The present study has clarified our previous univariate analysis results, wherein P. gingivalis infection was positively associated with progression of atherosclerosis. Thus, routine screening using plasma IgG antibody titer against P. gingivalis and periodontal treatment under collaborative with medical and dental care may prevent cardiovascular accidents caused by atherosclerosis.     

Three-dimensional evaluation for augmented bone using guided bone regeneration

OBJECTIVE: This study evaluated new bone regeneration beyond the skeletal envelope within an occlusive titanium cap on rabbit calvaria using microfocus computed tomography images. METHODS: In 10 rabbits, the calvaria was exposed and a circular groove was prepared. After penetrating the marrow, a standard hemispherical titanium cap was placed in the groove and covered with a cutaneous flap. After 1 or 3 months, the animals were killed and the calvariae and titanium caps were dissected. After taking microfocus computed tomography images of the specimens, histological sections were made. The specimens were observed using three-dimensional images constructed from the microfocus computed tomography images, and the histological sections were examined to compute bone parameters. RESULTS: The three-dimensional images and histological specimens showed that new bone formed in flat, cup-like, and dome shapes. The bone parameters trabecular thickness and the proportion of marrow space to the capacity of the titanium cap increased, whereas bone density decreased, and there were significant differences between the 1- and 3-month groups. DISCUSSION: First, a cylinder of new bone formed from the existing bone. Gradually, bone formed along the cap wall and the new tissue formed in a crater indented centrally. Finally, the new tissue formed in the shape of a dome. CONCLUSION: Trabecular bone formed along the wall of the titanium cap, and bone filled the inside of the cap within 3 months.     

Glucagon-like peptide-1: a potent regulator of food intake in humans

Background/Aims—Studiesin animals suggest a physiological role for glucagon-likepeptide-1-(7-36)-amide (GLP-1) in regulating satiety. The role ofGLP-1 in regulating food intake in man has, however, not been investigated.
Subjects—Sixteen healthy male subjects were examined in adouble blind placebo controlled fashion.
Methods—The effect ofgraded intravenous doses (0,0.375, 0.75, and 1.5 pmol/kg/min) ofsynthetic human GLP-1 on food intake and feelings of hunger and satietywas tested in healthy volunteers.
Results—Graded GLP-1infusions resulted in a dose dependent reduction in food intake(maximal inhibition 35%, p<0.001 vcontrol) and a similar reduction in calorie intake (32%; p<0.001). Fluid ingestion was also reduced by GLP-1 (18% reduction, p<0.01). Noovert side effects were produced by GLP-1, but subjects experienced less hunger and early fullness in the period before a meal during GLP-1infusion at the highest dose (p<0.05).
Conclusions—Intravenousinfusions of GLP-1 decrease spontaneous food intake even atphysiological plasma concentrations, implying an important role forGLP-1 in the regulation of the early satiety response in humans.

Keywords:glucagon-like peptide-1; satiety; food intake; hunger and fullness score

     

Clinical application of a new compact computed tomography system for evaluating the outcome of regenerative therapy: a case report

BACKGROUND: The limitations of conventional 2-dimensional (2-D) radiographs have been emphasized in many studies. Because the image is a 2-D map of the 3-dimensional (3-D) tooth and periodontal tissue, these structures may be superimposed on each other. Recently, 3-D image analysis by computed tomography (CT) was introduced to dentistry, but it has been used only rarely in the periodontal field. METHODS: The purpose of this case report was to introduce the clinical application of a newly developed, compact computed tomography system for evaluating the outcome of regenerative therapy in an adult patient with periodontitis (male, aged 55 years). To evaluate the bone defects including furcation involvement, we took an intraoral radiograph and performed CT scanning on tooth #19. We recorded a number of clinical parameters at the time of surgery. We compared the images of the bone defect obtained by CT images and the conventional radiograph with the true bone defect morphology at the surgical site. RESULTS: One year after the periodontal surgery, we again took CT scans and a conventional radiograph, and the new images of the bone defect were compared and evaluated. The new CT images were reconstructed for 3-D evaluation and compared with those taken before surgery. The CT provides 3-D images of excellent quality for evaluating the morphology of the periodontal bone defect and furcation involvement. CONCLUSIONS: We consider that CT is a useful aid in periodontal examination and diagnosis, and in the prediction and evaluation of periodontal treatment outcomes.