Continuous vagus nerve stimulation exerts beneficial effects on rats with experimentally induced Parkinson's disease: Evidence suggesting involvement of a vagal afferent pathway.

BACKGROUND: Vagus nerve stimulation (VNS) exerts neuroprotective and anti-inflammatory effects in preclinical models of central nervous system disorders, including Parkinson's disease (PD). VNS setting applied for experimental models is limited into single-time or intermittent short-duration stimulation. We developed a VNS device which could deliver continuous stimulation for rats. To date, the effects of vagal afferent- or efferent-selective stimulation on PD using continuous electrical stimulation remains to be determined. OBJECTIVE: To investigate the effects of continuous and selective stimulation of vagal afferent or efferent fiber on Parkinsonian rats. METHODS: Rats were divided into 5 group: intact VNS, afferent VNS (left VNS in the presence of left caudal vagotomy), efferent VNS (left VNS in the presence of left rostral vagotomy), sham, vagotomy. Rats underwent the implantation of cuff-electrode on left vagus nerve and 6-hydroxydopamine administration into the left striatum simultaneously. Electrical stimulation was delivered just after 6-OHDA administration and continued for 14 days. In afferent VNS and efferent VNS group, the vagus nerve was dissected at distal or proximal portion of cuff-electrode to imitate the selective stimulation of afferent or efferent vagal fiber respectively. RESULTS: Intact VNS and afferent VNS reduced the behavioral impairments in cylinder test and methamphetamine-induced rotation test, which were accompanied by reduced inflammatory glial cells in substantia nigra with the increased density of the rate limiting enzyme in locus coeruleus. In contrast, efferent VNS did not exert any therapeutic effects. CONCLUSION: Continuous VNS promoted neuroprotective and anti-inflammatory effect in experimental PD, highlighting the crucial role of the afferent vagal pathway in mediating these therapeutic outcomes.

Synergistic therapeutic effects of intracerebral transplantation of human modified bone marrow-derived stromal cells (SB623) and voluntary exercise with running wheel in a rat model of ischemic stroke.

BACKGROUND: Mesenchymal stromal cell (MSC) transplantation therapy is a promising therapy for stroke patients. In parallel, rehabilitation with physical exercise could ameliorate stroke-induced neurological impairment. In this study, we aimed to clarify whether combination therapy of intracerebral transplantation of human modified bone marrow-derived MSCs, SB623 cells, and voluntary exercise with running wheel (RW) could exert synergistic therapeutic effects on a rat model of ischemic stroke. METHODS: Wistar rats received right transient middle cerebral artery occlusion (MCAO). Voluntary exercise (Ex) groups were trained in a cage with RW from day 7 before MCAO. SB623 cells (4.0 × 105 cells/5 µl) were stereotactically injected into the right striatum at day 1 after MCAO. Behavioral tests were performed at day 1, 7, and 14 after MCAO using the modified Neurological Severity Score (mNSS) and cylinder test. Rats were euthanized at day 15 after MCAO for mRNA level evaluation of ischemic infarct area, endogenous neurogenesis, angiogenesis, and expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). The rats were randomly assigned to one of the four groups: vehicle, Ex, SB623, and SB623 + Ex groups. RESULTS: SB623 + Ex group achieved significant neurological recovery in mNSS compared to the vehicle group (p < 0.05). The cerebral infarct area of SB623 + Ex group was significantly decreased compared to those in all other groups (p < 0.05). The number of BrdU/Doublecortin (Dcx) double-positive cells in the subventricular zone (SVZ) and the dentate gyrus (DG), the laminin-positive area in the ischemic boundary zone (IBZ), and the mRNA level of BDNF and VEGF in SB623 + Ex group were significantly increased compared to those in all other groups (p < 0.05). CONCLUSIONS: This study suggests that combination therapy of intracerebral transplantation SB623 cells and voluntary exercise with RW achieves robust neurological recovery and synergistically promotes endogenous neurogenesis and angiogenesis after cerebral ischemia, possibly through a mechanism involving the up-regulation of BDNF and VEGF.

Transplantation of modified human bone marrow-derived stromal cells affords therapeutic effects on cerebral ischemia in rats.

AIMS: SB623 cells are human bone marrow stromal cells transfected with Notch1 intracellular domain. In this study, we examined potential regenerative mechanisms underlying stereotaxic transplantation of SB623 cells in rats with experimental acute ischemic stroke. METHODS: We prepared control group, empty capsule (EC) group, SB623 cell group (SB623), and encapsulated SB623 cell (eSB623) group. Transient middle cerebral artery occlusion (MCAO) was performed on day 0, and 24 h after MCAO, stroke rats received transplantation into the envisioned ischemic penumbra. Modified neurological severity score (mNSS) was evaluated, and histological evaluations were performed. RESULTS: In the mNSS, SB623 and eSB623 groups showed significant improvement compared to the other groups. Histological analysis revealed that the infarction area in SB623 and eSB623 groups was reduced. In the eSB623 group, robust cell viability and neurogenesis were detected in the subventricular zone that increased significantly compared to all other groups. CONCLUSION: SB623 cells with or without encapsulation showed therapeutic effects on ischemic stroke. Encapsulated SB623 cells showed enhanced neurogenesis and increased viability inside the capsules. This study reveals the mechanism of secretory function of transplanted SB623 cells, but not cell-cell interaction as primarily mediating the cells' functional benefits in ischemic stroke.

A Pediatric Case of Cauda Equina Dermoid Cyst Resected by Minimally Invasive Unilateral Hemilaminectomy.

A 3-year-old boy had difficulty sitting up and walking for several months. Magnetic resonance imaging (MRI) revealed an intradural tumor at the L3-4 level. The tumor was successfully resected by unilateral hemilaminectomy and diagnosed as dermoid cyst. The patient had an uneventful postoperative course without pain, and MRI found no recurrence after surgery. A small bone defect remained that might be favorably reconstructed with autologous and artificial bone. Hemilaminectomy allowed us to resect the cauda equina dermoid cyst with minimal invasiveness. Pediatric patients require follow-up as they are more likely to experience spinal deformity or instability after surgery.

Growth Curves for Intracranial Volume and Two-dimensional Parameters for Japanese Children without Cranial Abnormality: Toward Treatment of Craniosynostosis.

In the management of patients with craniosynostosis, it is important to understand growth curve of the normal cranium. Although three-dimensional (3D) computed tomography (CT) images taken in thin slices are easily available nowadays, data on the growth curves of intracranial volume (ICV), cranial length, cranial width, and cranial height in the normal cranium are mainly based on older studies using radiography, and there are insufficient reports using CT images especially taken in thin slices. The purpose of this study was to establish growth curves in the normal cranium of Japanese children using thin-slice images. Cranial images of 106 subjects (57 males, 49 females; aged 0-83 months) without significant cranial abnormalities were retrospectively analyzed. Using thin-slice CT images, the ICV and two-dimensional parameters such as cranial length, cranial width, and cranial height were measured by iPlan, followed by generating growth curves and calculating cephalic index (CI). ICV calculated from thin-slice CT images was compared with that obtained by substituting two-dimensional parameters into Mackinnon formula. The ICV growth curves for males and females were similar in shape. As with the ICV, the two-dimensional parameters increased most rapidly in the first year after birth. There was no significant difference in CI between the sexes or among any age groups. ICV calculated from thin-slice 3D CT images was 60% of that obtained from Mackinnon formula. These data will enable us to compare these specific measurements in craniosynostosis patients directly with those of normal children, which will hopefully help in managing these patients.

Vagus Nerve Stimulation with Mild Stimulation Intensity Exerts Anti-Inflammatory and Neuroprotective Effects in Parkinson's Disease Model Rats.

BACKGROUND: The major surgical treatment for Parkinson's disease (PD) is deep brain stimulation (DBS), but a less invasive treatment is desired. Vagus nerve stimulation (VNS) is a relatively safe treatment without cerebral invasiveness. In this study, we developed a wireless controllable electrical stimulator to examine the efficacy of VNS on PD model rats. METHODS: Adult female Sprague-Dawley rats underwent placement of a cuff-type electrode and stimulator on the vagus nerve. Following which, 6-hydroxydopamine (6-OHDA) was administered into the left striatum to prepare a PD model. VNS was started immediately after 6-OHDA administration and continued for 14 days. We evaluated the therapeutic effects of VNS with behavioral and immunohistochemical outcome assays under different stimulation intensity (0.1, 0.25, 0.5 and 1 mA). RESULTS: VNS with 0.25-0.5 mA intensity remarkably improved behavioral impairment, preserved dopamine neurons, reduced inflammatory glial cells, and increased noradrenergic neurons. On the other hand, VNS with 0.1 mA and 1 mA intensity did not display significant therapeutic efficacy. CONCLUSIONS: VNS with 0.25-0.5 mA intensity has anti-inflammatory and neuroprotective effects on PD model rats induced by 6-OHDA administration. In addition, we were able to confirm the practicality and effectiveness of the new experimental device.

Spinal Cord Diffuse Midline Glioma, H3K27M- mutant Effectively Treated with Bevacizumab: A Report of Two Cases.

"Diffuse midline glioma (DMG), H3K27M-mutant" was newly classified in the revised World Health Organization (WHO) 2016 classification of central nervous system tumors. Spinal cord DMG, H3K27M-mutant is relatively rare, with poor prognosis, and there are no effective treatment protocols. In this study, we report two cases of spinal cord DMG, H3K27M-mutant treated with bevacizumab. The two patients were women in their 40s who initially presented with sensory impairment. MRI showed spinal intramedullary tumors, and each patient underwent laminectomy/laminoplasty and biopsy of the tumors. Histological examination initially suggested low-grade astrocytoma in case 1 and glioblastoma in case 2. Upon further immunohistochemical examination in case 1 and molecular examination in case 2, however, both cases were diagnosed as DMG, H3K27M-mutant. Case 1 was treated with radiation therapy and temozolomide (TMZ) chemotherapy, which induced a transient improvement of symptoms; 3 months after surgery, however, the patient's symptoms rapidly deteriorated. MRI showed tumor enlargement with edema to the medulla. Triweekly administration of bevacizumab improved her symptoms for the following 12 months. Case 2 was treated with bevacizumab from the beginning because of acute deterioration of breathing. After bevacizumab administration, both cases showed tumor regression on MRI and drastic improvement of symptoms within a few days. Although spinal cord DMG, H3K27M-mutant has an aggressive clinical course and poor prognosis, bevacizumab administration may offer the significant clinical benefit of alleviating edema, which improves patient's capacity for activities of daily life.

Long-Term Continuous Cervical Spinal Cord Stimulation Exerts Neuroprotective Effects in Experimental Parkinson's Disease.

BACKGROUND: Spinal cord stimulation (SCS) exerts neuroprotective effects in animal models of Parkinson's disease (PD). Conventional stimulation techniques entail limited stimulation time and restricted movement of animals, warranting the need for optimizing the SCS regimen to address the progressive nature of the disease and to improve its clinical translation to PD patients. OBJECTIVE: Recognizing the limitations of conventional stimulation, we now investigated the effects of continuous SCS in freely moving parkinsonian rats. METHODS: We developed a small device that could deliver continuous SCS. At the start of the experiment, thirty female Sprague-Dawley rats received the dopamine (DA)-depleting neurotoxin, 6-hydroxydopamine, into the right striatum. The SCS device was fixed below the shoulder area of the back of the animal, and a line from this device was passed under the skin to an electrode that was then implanted epidurally over the dorsal column. The rats were divided into three groups: control, 8-h stimulation, and 24-h stimulation, and behaviorally tested then euthanized for immunohistochemical analysis. RESULTS: The 8- and 24-h stimulation groups displayed significant behavioral improvement compared to the control group. Both SCS-stimulated groups exhibited significantly preserved tyrosine hydroxylase (TH)-positive fibers and neurons in the striatum and substantia nigra pars compacta (SNc), respectively, compared to the control group. Notably, the 24-h stimulation group showed significantly pronounced preservation of the striatal TH-positive fibers compared to the 8-h stimulation group. Moreover, the 24-h group demonstrated significantly reduced number of microglia in the striatum and SNc and increased laminin-positive area of the cerebral cortex compared to the control group. CONCLUSIONS: This study demonstrated the behavioral and histological benefits of continuous SCS in a time-dependent manner in freely moving PD animals, possibly mediated by anti-inflammatory and angiogenic mechanisms.

Cell therapy for central nervous system disorders: Current obstacles to progress.

Cell therapy for disorders of the central nervous system has progressed to a new level of clinical application. Various clinical studies are underway for Parkinson's disease, stroke, traumatic brain injury, and various other neurological diseases. Recent biotechnological developments in cell therapy have taken advantage of the technology of induced pluripotent stem (iPS) cells. The advent of iPS cells has provided a robust stem cell donor source for neurorestoration via transplantation. Additionally, iPS cells have served as a platform for the discovery of therapeutics drugs, allowing breakthroughs in our understanding of the pathology and treatment of neurological diseases. Despite these recent advances in iPS, adult tissue-derived mesenchymal stem cells remain the widely used donor for cell transplantation. Mesenchymal stem cells are easily isolated and amplified toward the cells' unique trophic factor-secretion property. In this review article, the milestone achievements of cell therapy for central nervous system disorders, with equal consideration on the present translational obstacles for clinic application, are described.

Lithium counteracts depressive behavior and augments the treatment effect of selective serotonin reuptake inhibitor in treatment-resistant depressed rats.

Wistar Kyoto (WKY) rats are a useful animal model of treatment-resistant depression. Lithium is effective for treating recurrent mood disorders or treatment-resistant depression, and lithium augmentation treatment is also useful for treatment-resistant depression. However, the treatment effect of lithium on the depressive behavior of WKY rats remains poorly understood, and whether lithium augments the treatment effect of antidepressants in WKY rats is also unknown. In this study, we evaluated the treatment effect of lithium in WKY rats. We also sought to determine if lithium treatment augments the treatment effect of fluoxetine. Lithium was administered for 15 consecutive days and fluoxetine was administered 23.5, 5, and 1 h before the forced swim test (FST) day 2, based on previous studies. Lithium treatment counteracted depressive behavior in the FST and increased hippocampal neurogenesis. Additionally, co-administration of lithium and fluoxetine augmented the treatment effect observed in the FST and in hippocampal neurogenesis in WKY rats, although fluoxetine monotherapy showed no treatment effect. Lithium prevented an increase in body weight, similar to its effect in human patients. These results are consistent with those of lithium augmentation treatment for human patients with treatment-resistant depression. They suggest that WKY rats are a promising animal model for treatment-resistant depression. However, lithium treatment has various side effects. A new treatment with the same anti-depressive effect as fluoxetine + lithium treatment and fewer side effects compared with lithium would be desirable for patients with treatment-resistant depression.

Cerebral Infarction Arising from Takotsubo Cardiomyopathy: Case Report and Literature Review.

Although most patients with takotsubo cardiomyopathy have a favorable outcome, complications are not uncommon. Recent studies have reported an increase in incidence of cardioembolic complications; however, the association between takotsubo cardiomyopathy and stroke, in particular thromboembolic cerebral infarction, remains unclear. We reported a 44-year-old woman who had a cerebral infarction resulting from takotsubo cardiomyopathy. She had felt chest discomfort a few days prior to infarction, and later developed left hemiparesis. Head magnetic resonance imaging (MRI) revealed acute infarction in the right insular cortex and occlusion of the right middle cerebral artery at the M2 segment. Echocardiogram revealed a takotsubo-like shape in the motion of the left ventricular wall, and coronary angiography showed neither coronary stenosis nor occlusion. Cerebral infarction resulting from takotsubo cardiomyopathy was diagnosed and treatment with anticoagulant was started. MRI on the eighth day after hospitalization showed recanalization of the right middle cerebral artery and no new ischemic lesions. The findings of the 19 previously published cases who had cerebral infarction resulting from takotsubo cardiomyopathy were also reviewed and showed the median interval between takotsubo cardiomyopathy and cerebral infarction was approximately 1 week and cardiac thrombus was detected in 9 of 19 patients. We revealed that thromboembolic events occurred later than other complications of takotsubo cardiomyopathy and longer observation might be required due to possible cardiogenic cerebral infarction. Anticoagulant therapy is recommended for patients with takotsubo cardiomyopathy with cardiac thrombus or a large area of akinetic left ventricle.

[Multiple brain abscesses in the territory of the vertebral-basilar artery resulting from an infected aortic arch graft].

A 62-year-old man with high fever and in a state of disorientation was transferred to our hospital. One year before this transfer, he had undergone total arch replacement surgery for thoracic aortic dissection. On admission to our hospital, head MRI revealed multiple brain abscesses in the territory of the vertebral-basilar artery, and chest CT showed gas around the aortic graft, in particular, at the origin of the left subclavian artery. We diagnosed him with brain abscesses in the left vertebral-basilar artery resulting from an infected aortic graft. We immediately began administration of intravenous antibiotics. Although his blood, urine, and cerebrospinal fluid cultures were negative, fortunately, the brain abscesses and ectopic gas disappeared. Since reports of only antibiotic use for treating brain abscesses due to aortic graft infection are rare, the appropriate duration of antibiotic administration has not been established yet. Therefore, careful observation is required in this case.

Quality control and monitoring for the isolation process of mesenchymal stem cells and their differentiation into osteoblasts.

We developed a method of quality control and monitoring for the isolation of mesenchymal stem cells (MSCs) from bone marrow and their differentiation into osteoblasts. After dividing the cell culture process into five groups based on cell types such as MSCs and osteoblasts, we used microarray analysis to select genes with expression profiles characteristic of each group and quantitative polymerase chain reaction for confirming the expression profiles of these genes. Comparing multiple gene expression profiles per cell from quantitative polymerase chain reaction permitted us to distinguish (1) different groups of cell culture including MSCs and osteoblasts; (2) MSCs that had differentiated cells other than osteoblasts such as chondroblasts, adipocytes, or skin-derived fibroblasts; and (3) desirable MSCs from undesirable MSCs occurring under different culture conditions. These findings suggest that it is possible to standardize MSCs and osteoblasts on the basis of multiple gene expression profiles and to check the quality of these cells. We believe that our methods can be applied to cells cultured for transplants.