Tomomasa Ishikawa

Neurotropin promotes NGF signaling through interaction of GM1 ganglioside with Trk neurotrophin receptor in PC12 cells

Activation of the high-affinity nerve growth factor (NGF) receptor Trk occurs through multiple processes consisted of translocation and clustering within the plasma membrane lipid rafts, dimerization and autophosphorylation. Here we found that a nonprotein extract of inflamed rabbit skin inoculated with vaccinia virus (Neurotropin(®)) enhanced efficiency of NGF signaling. In rat pheochromocytoma PC12 cells overexpressing Trk (PCtrk cells), Neurotropin augmented insufficient neurite outgrowth observed at suboptimal concentration of NGF (2ng/mL) in a manner depending on Trk kinase activity. Cellular exposure to Neurotropin resulted in an accumulation of Trk-GM1 complexes without affecting dimerization or phosphorylation states of Trk. Following NGF stimulation, Neurotropin significantly facilitated the time course of NGF-induced Trk autophosphorylation. These observations provide a unique mechanism controlling efficiency of NGF signaling, and raise the therapeutic potential of Neurotropin for various neurological conditions associated with neurotrophin dysfunction.

Anti-neutral glycolipid antibodies in encephalomyeloradiculoneuropathy

Objective: The aim of this study was to review 4 patients with encephalomyeloradiculoneuropathy (EMRN) and assess for autoantibodies against neutral glycolipids. Methods: We studied the progression of clinical, radiologic, neurophysiologic, and CSF findings, as well as anti-neutral glycolipid antibodies in sera. Results: All patients developed acute or subacute motor weakness and impaired consciousness. Their CSF showed pleocytosis and high immunoglobulin G concentrations. MRI revealed lesions in the brain and spinal cord. Neurophysiologic examinations indicated dysfunction of the spinal cord, nerve roots, and peripheral nerves. Steroid pulsed immunotherapy and/or high dose of IV immunoglobulin replacement therapy resulted in clear and often dramatic clinical improvements. Reactivity to anti-neutral glycolipid antibodies was positive in all patients with acute EMRN but not in the recovery phase. Forty-seven age-matched patients with other neurologic disorders and 28 age-matched healthy volunteers tested negative for reactivity to anti-neutral glycolipid antibodies. Conclusion: The resolution of radiologic and neurologic abnormalities and altered autoantibody titers against neutral glycolipids after immunotherapy suggest that EMRN is caused by an immune-mediated mechanism. These autoantibodies may be useful biomarkers for EMRN.

MR neurography for the evaluation of CIDP.

Introduction: To visualize peripheral nerves in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), we used MR imaging. We also quantified the volumes of the brachial and lumbar plexus and their nerve roots. Methods: Thirteen patients with CIDP and 12 healthy volunteers were enrolled. Whole‐body MR neurography based on diffusion‐weighted whole‐body imaging with background body signal suppression (DWIBS) was performed. Peripheral nerve volumes were calculated from serial axial MR images. Results: The peripheral nervous system was visualized with 3‐dimensional reconstruction. Volumes ranged from 8.7 to 49.5 cm3/m2 in the brachial plexus and nerve roots and from 10.2 to 53.5 cm3/m2 in the lumbar plexus and nerve roots. Patients with CIDP had significantly larger volumes than controls (P < 0.05), and volume was positively correlated with disease duration. Conclusions: MR neurography and the measurement of peripheral nerve volume are useful for diagnosing and assessing CIDP. Muscle Nerve 55: 483–489, 2017

Magnetic resonance neurography for the evaluation of CIDP.

Introduction: To visualize peripheral nerves in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), we used MR imaging. We also quantified the volumes of the brachial and lumbar plexus and their nerve roots. Methods: Thirteen patients with CIDP and 12 healthy volunteers were enrolled. Whole‐body MR neurography based on diffusion‐weighted whole‐body imaging with background body signal suppression (DWIBS) was performed. Peripheral nerve volumes were calculated from serial axial MR images. Results: The peripheral nervous system was visualized with 3‐dimensional reconstruction. Volumes ranged from 8.7 to 49.5 cm3/m2 in the brachial plexus and nerve roots and from 10.2 to 53.5 cm3/m2 in the lumbar plexus and nerve roots. Patients with CIDP had significantly larger volumes than controls (P < 0.05), and volume was positively correlated with disease duration. Conclusions: MR neurography and the measurement of peripheral nerve volume are useful for diagnosing and assessing CIDP. Muscle Nerve 55: 483–489, 2017

Retrospective analysis of parkinsonian patients exhibiting normal 123I-MIBG cardiac uptake

BACKGROUND Although most patients with Parkinsons disease (PD) show decreased cardiac (123)I-metaiodobenzylguanidine (MIBG) uptake, some exhibit normal uptake. We evaluated the clinical characteristics of such patients. METHODS We enrolled 154 non-demented patients showing parkinsonism with normal cardiac MIBG uptake and had been clinically followed up during 29.9 ± 27.6 months. We defined the patients who did not fit the exclusion criteria for PD and demonstrated ≥ 30% reduction in the Unified Parkinsons Disease Rating Scale (UPDRS) motor score after anti-Parkinson agent administration as probable PD. We compared clinical characteristics and the cardiac MIBG heart-to-mediastinum (H/M) ratio between the probable PD group (N=37) and other groups (N=117). RESULTS The probable PD group showed significantly higher UPDRS motor scores and greater incidence of tremor/rigidity than those of other groups. In addition, they showed a significantly lower cardiac MIBG H/M ratio in the delayed phase (delayed, p<0.0001). Washout-rate (WR) was significantly higher in probable PD cases (p<0.0001). Among 16 probable PD patients undergoing serial cardiac MIBG scintigraphy, the delayed phase cardiac MIBG H/M ratio showed a significant decrease and WR significantly increased during follow-up periods. CONCLUSIONS An increase in WR and lower delayed phase cardiac MIBG uptake were found to be characteristics of such patients.

Neurotrophin levels in cerebrospinal fluid of adult patients with meningitis and encephalitis.

Background: The data on cerebrospinal fluid (CSF) levels of neurotrophins (NTs) in patients with meningoencephalitis are scarce, especially in adult patients. Methods: We measured CSF levels of NTs such as nerve growth factor (NGF), brain-derived neurotrophic factor, and neurotrophin-3 (NT-3) in adult patients with various meningitis (n = 10) and encephalitis (n = 10) in both acute phase and recovery phase and adult control subjects (n = 21) by the enzyme-linked immunosorbent assay for NTs. Results: Data show that NGF and NT-3 CSF levels were markedly elevated in the patient group in the acute phase compared with non-neurological controls (p < 0.001 and p < 0.05, respectively) and later returned to the levels of controls. Most intriguingly, we only recognized a significant correlation between NGF and NT-3 CSF levels in the patients in the acute phase. Conclusion: Such strong correlation of NGF and NT-3 CSF levels strongly suggests that in adult patients, some common regulatory mechanism(s) might be present among various kinds of NTs to cope with central nervous system infection.

Differentiation of cancer from atrial fibrillation in patients with acute multifocal stroke

OBJECTIVE Acute multifocal embolic infarction (AMEI) is conventionally caused by etiologies such as cardioembolism due to atrial fibrillation (Af), but can also be caused by serious underlying diseases such as cancer. We characterized cancer-related AMEI and identified useful indicators for cancer-associated strokes. METHODS A retrospective analysis was performed on 35 patients with Af-related AMEI and 35 patients with cancer-related AMEI selected from 1235 consecutive patients with acute infarcts. All patients received diffusion-weighted magnetic resonance (MR) imaging. Cerebral MR angiography, carotid and cardiac ultrasonography, electrocardiogram-monitoring and whole body computed tomography were also performed on these patients. D-dimer levels were evaluated on admission, and were measured during the sub-acute phase in 19 of the patients with Af and 27 of the patients with cancer. RESULTS Acute phase D-dimer levels were significantly higher in patients with cancer than in patients with Af alone. The cut-off D-dimer value to identify cancer-associated infarcts was 2.0μg/mL. D-dimer levels during the sub-acute phase remained elevated in the cancer patients. CONCLUSIONS We may differentiate cancer-associated AMEI from Af using a D-dimer level≥2.0μg/mL, which does not decrease during the sub-acute phase.

Usefulness of combining 123I-FP-CIT-SPECT striatal asymmetry index and cardiac 123I-metaiodobenzylguanidine scintigraphy examinations for diagnosis of parkinsonisms

BACKGROUND Although single-photon emission computerized tomography of the dopamine transporter (DAT-SPECT) is useful for diagnosing parkinsonian syndrome, its applicability toward the early phase of Parkinsons disease remains unknown. METHODS We enrolled 32 patients showing parkinsonism with normal cardiac 123I-metaiodobenzylguanidine (MIBG) uptake and abnormal DAT-SPECT findings among 84 consecutive patients with parkinsonism. We divided these patients into two groups (group 1: Parkinsons disease, group 2: corticobasal degeneration, progressive supranuclear palsy, multiple system atrophy), and compared their clinical characteristics, specific binding ratios, and striatal asymmetry indexes on DAT-SPECT examinations. RESULTS The striatal asymmetry indexes were significantly lower in group 1 than in group 2 (p<0.05), but there were no differences in the specific binding ratios between the two groups. CONCLUSION The combined use of striatal asymmetry index on DAT-SPECT and cardiac MIBG scintigraphy might offer useful clues for the differential diagnosis of the early phase Parkinsons disease from other parkinsonian syndromes.

Histone deacetylase inhibitor attenuates neurotoxicity of clioquinol in PC12 cells

Clioquinol is considered to be a causative agent of subacute myelo-optico neuropathy (SMON), although the pathogenesis of SMON is yet to be elucidated. We have previously shown that clioquinol inhibits nerve growth factor (NGF)-induced Trk autophosphorylation in PC12 cells transformed with human Trk cDNA. To explore the further mechanism of neuronal damage by clioquinol, we evaluated the acetylation status of histones in PC12 cells. Clioquinol reduced the level of histone acetylation, and the histone deacetylase (HDAC) inhibitor Trichostatin A upregulated acetylated histones and prevented the neuronal cell damage caused by clioquinol. In addition, treatment with HDAC inhibitor decreased neurite retraction and restored the inhibition of NGF-induced Trk autophosphorylation by clioquinol. Thus, clioquinol induced neuronal cell death via deacetylation of histones, and HDAC inhibitor alleviates the neurotoxicity of clioquinol. Clioquinol is now used as a potential medicine for malignancies and neurodegenerative diseases. Therefore, HDAC inhibitors can be used as a candidate medicine for the prevention of its side effects on neuronal cells.

Targeting of aquaporin 4 into lipid rafts and its biological significance

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system and is considered to be caused by the binding of NMO-IgG to aquaporin 4 (AQP4) on astrocytes, which initiates complement-dependent cytotoxicity. AQP4 has two isoforms, i.e., M1 and M23. AQP4 is considered to form heterotetramers containing both isoforms in vivo. Most of the previous studies were performed using either one of the isoforms expressing cell lines. In this study, we generated a fluorescent epitope-tagged AQP4 M1 and M23 co-expressing astrocyte cell line and examined the subcellular targeting of AQP4. In this cell line, AQP4 was targeted mostly to membrane lipid rafts fraction evidenced by sucrose density gradient ultracentrifugation followed by Western blotting with anti-AQP4 antibody. Cholesterol depletion with methyl-β-cyclodextrin or simvastatin resulted in the dislocation (relocation) of AQP4 from lipid rafts to non-rafts fraction of the membrane and AQP4 was not internalized intracellularly. This change in the localization of AQP4 on membrane significantly reduced complement-dependent cytotoxic effects of NMO-IgG obtained from patients with NMO without affecting AQP4 orthogonal arrays. Thus, these data strongly suggest that the targeting of AQP4 in the lipid rafts is closely related to the pathogenic effects of NMO-IgG.