Deletion of Nox4 enhances remyelination following cuprizone-induced demyelination by increasing phagocytic capacity of microglia and macrophages in mice.

NOX4 is a major reactive oxygen species-producing enzyme that modulates cell stress responses. We here examined the effect of Nox4 deletion on demyelination-remyelination, the most common pathological change in the brain. We used a model of cuprizone (CPZ)-associated demyelination-remyelination in wild-type and Nox4-deficient (Nox4-/- ) mice. While the CPZ-induced demyelination in the corpus callosum after 4 weeks of CPZ intoxication was slightly less pronounced in Nox4-/- mice than that in wild-type mice, remyelination following CPZ withdrawal was significantly enhanced in Nox4-/- mice with an increased accumulation of IBA1-positive microglia/macrophages in the demyelinating corpus callosum. Consistently, locomotor function, as assessed by the beam walking test, was significantly better during the remyelination phase in Nox4-/- mice. Nox4 deletion did not affect autonomous growth of primary-culture oligodendrocyte precursor cells. Although Nox4 expression was higher in cultured macrophages than in microglia, Nox4-/- microglia and macrophages both showed enhanced phagocytic capacity of myelin debris and produced increased amounts of trophic factors upon phagocytosis. The expression of trophic factors was higher, in parallel with the accumulation of IBA1-positive cells, in the corpus callosum in Nox4-/- mice than that in wild-type mice. Nox4 deletion suppressed phagocytosis-induced increase in mitochondrial membrane potential, enhancing phagocytic capacity of macrophages. Treatment with culture medium of Nox4-/- macrophages engulfing myelin debris, but not that of Nox4-/- astrocytes, enhanced cell growth and expression of myelin-associated proteins in cultured oligodendrocyte precursor cells. Collectively, Nox4 deletion promoted remyelination after CPZ-induced demyelination by enhancing microglia/macrophage-mediated clearance of myelin debris and the production of trophic factors leading to oligodendrogenesis.

Wernicke-Korsakoff Syndrome in a Young Adult on Dialysis Who Showed Bilateral Ganglia Lesions.

A 30-year-old man admitted with renal dysfunction (serum creatinine, 8.19 mg/dL) was diagnosed with immunoglobulin A nephritis through a renal biopsy. He was treated with intravenous methylprednisolone pulse therapy and urgent hemodialysis, and eventually, he underwent maintenance hemodialysis. On day 108, he developed amnesia. Magnetic resonance imaging revealed bilateral basal ganglia lesions. Wernicke encephalopathy (WE) was diagnosed based on decreased serum thiamine concentration (12.8 µg/dL; reference range, 24-66 µg/dL). Thiamine replacement therapy was initiated, but the Wernicke-Korsakoff syndrome persisted. Careful monitoring of thiamine is required in patients undergoing dialysis. In addition, patients with WE may exhibit bilateral basal ganglia lesions.

PDGFRß-positive cell-mediated post-stroke remodeling of fibronectin and laminin α2 for tissue repair and functional recovery.

Post-stroke intra-infarct repair promotes peri-infarct neural reorganization leading to functional recovery. Herein, we examined the remodeling of extracellular matrix proteins (ECM) that constitute the intact basal membrane after permanent middle cerebral artery occlusion (pMCAO) in mice. Among ECM, collagen type IV remained localized on small vessel walls surrounding CD31-positive endothelial cells within infarct areas. Fibronectin was gradually deposited from peri-infarct areas to the ischemic core, in parallel with the accumulation of PDGFRß-positive cells. Cultured PDGFRß-positive pericytes produced fibronectin, which was enhanced by the treatment with PDGF-BB. Intra-infarct deposition of fibronectin was significantly attenuated in pericyte-deficient Pdgfrb+/-mice. Phagocytic activity of macrophages against myelin debris was significantly enhanced on fibronectin-coated dishes. In contrast, laminin α2, produced by GFAP- and aquaporin 4-positive astrocytes, accumulated strongly in the boundary of peri-infarct areas. Pericyte-conditioned medium increased the expression of laminin α2 in cultured astrocytes, partly through TGFß1. Laminin α2 increased the differentiation of oligodendrocyte precursor cells into oligodendrocytes and the expression of myelin-associated proteins. Peri-infarct deposition of laminin α2 was significantly reduced in Pdgfrb+/-mice, with attenuated oligodendrogenesis in peri-infarct areas. Collectively, intra-infarct PDGFRß-positive cells may orchestrate post-stroke remodeling of key ECM that create optimal environments promoting clearance of myelin debris and peri-infarct oligodendrogenesis.

Sideway Aspiration Technique for Thrombus in a Sharply Bifurcated Branch of a Large Vessel.

Objective: Standard thrombectomy techniques, including stent retrieval and a direct aspiration first pass technique, are not effective when the occluded vessel is narrow and sharply bifurcated from the main trunk. Here, we present a new and alternative method for patients with such anatomical features and describe two cases treated by this method. Case Presentations: Case 1 was a 66-year-old woman who presented with consciousness disturbance and left hemiparesis. MRA suggested a right middle cerebral artery occlusion. Case 2 was an 86-year-old man who presented with sudden onset of consciousness disturbance; MRA indicated occlusion of the basilar artery. Both cases were successfully treated by our new method. First, we navigated a microcatheter, microguidewire, and aspiration catheter into the patent and visible branch adjacent to the occluded branch. The aspiration catheter was then carefully pulled back with continuous mechanical aspiration. When reverse blood flow from the aspiration catheter was suspended, we slightly advanced the catheter and caught the thrombus. Complete recanalization was attained in the two cases treated with this technique, which was named as sideway aspiration technique (SAT). Conclusion: Although it warrants further study, SAT may be a potentially safe and effective method for thrombectomy in cases with thrombus in a sharply bifurcated branch.

Low-dose sodium-glucose cotransporter 2 inhibitor ameliorates ischemic brain injury in mice through pericyte protection without glucose-lowering effects.

Antidiabetic sodium-glucose cotransporter 2 (SGLT2) inhibitors have attracted attention for their cardiorenal-protective properties beyond their glucose-lowering effect. However, their benefits in ischemic stroke remain controversial. Here we show the effects of luseogliflozin, a selective SGLT2 inhibitor, in acute ischemic stroke, using a permanent middle cerebral artery occlusion (pMCAO) model in non-diabetic mice. Pretreatment with low-dose luseogliflozin, which does not affect blood glucose levels, significantly attenuated infarct volume, blood-brain barrier disruption, and motor dysfunction after pMCAO. SGLT2 was expressed predominantly in brain pericytes and was upregulated in peri- and intra-infarct areas. Notably, luseogliflozin pretreatment reduced pericyte loss in ischemic areas. In cultured pericytes, luseogliflozin activated AMP-activated protein kinase α and increased mitochondrial transcription factor A expression and number of mitochondria, conferring resistance to oxygen-glucose deprivation. Collectively, pre-stroke inhibition of SGLT2 induces ischemic tolerance in brain pericytes independent of the glucose-lowering effect, contributing to the attenuation of ischemic brain injury.

Meningitis retention syndrome associated with complicated mild encephalitis/encephalopathy with reversible splenial lesion in a young adult patient: a case report.

Meningitis retention syndrome (MRS), comprising aseptic meningitis and urinary retention, is a self-limiting disease that resolves within a few weeks. Refractory urinary retention and encephalitic syndromes are rare. A 32-year-old man presented with acute fever and headache followed by acute urinary retention (UT). Neurological examination revealed meningeal irritation, UT, constipation and ataxic gait. The cerebrospinal fluid showed mononuclear leukocytosis, and the etiological examination was negative. We suspected MRS. However, magnetic resonance imaging demonstrated an abnormally intense lesion in the splenium of the corpus callosum (SCC). He also developed delirium on day 4 of hospitalization. We diagnosed the patient with MRS associated with mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). While his delirium and constipation improved, and the SCC lesion disappeared, UT was refractory and required 6 months to complete recovery. Our case suggests that severe MRS can exhibit refractory UT and may associate with MERS.

Fluctuations in Moyamoya Vasculopathy Associated with Basedow Disease Depending on Thyroid Hormone Status.

A 31-year-old woman presented with sudden onset of weakness in her left upper limb. Magnetic resonance imaging revealed acute cerebral infarctions in the right frontal and parietal lobes. Magnetic resonance angiography showed stenosis in the proximal portions of the bilateral middle cerebral arteries and terminal portions of the bilateral internal carotid arteries. The patient also complained of thyrotoxic symptoms, such as tachycardia, goiter, and fine finger tremor. She was diagnosed with acute ischemic stroke due to moyamoya vasculopathy (MMV) associated with Basedow disease. The patient's thyroid hormone status normalized and intracranial artery stenosis gradually improved. However, after 6 months, she developed transient left hemiparesis during the 7th week of gestation. Her thyroid function deteriorated, and MMV progressed. Then, MMV improved again with the normalization of her thyroid function. This case shows that MMV associated with Basedow disease could worsen or improve depending on the thyroid hormone status.

Late-onset ornithine transcarbamylase deficiency: a rare cause of recurrent abnormal behavior in adults.

BACKGROUND: Ornithine transcarbamylase is an enzyme of the urea cycle, which produces urea from ammonia. Although ornithine transcarbamylase deficiency mainly occurs as a severe neonatal-onset disease, a late-onset form that could become symptomatic from infancy to adulthood is also known. CASE PRESENTATION: A 34-year-old man presented with sudden onset of abnormal behavior, lethargy, and hyperammonemia (108 µmol/L). He had recently increased daily protein intake, which suggested urea cycle disorder. After initiation of protein-restricted diet and treatment with arginine and sodium phenylbutyrate, his symptoms resolved, along with a decrease in the ammonia level. An R40H(c.119G > A) mutation in the OTC gene was identified. CONCLUSION: Awareness of adult onset ornithine transcarbamylase deficiency in a patient with acute psychiatric symptoms due to hyperammonemia is important.

Reocclusion of the treated vessel due to endothelial injury after mechanical thrombectomy in a patient with acute ischaemic stroke.

A 92-year-old woman developed sudden consciousness disturbance, global aphasia and right hemiparesis. She had atrial fibrillation and cardioembolic stroke was diagnosed. Tissue plasminogen activator was administered, and endovascular treatment was initiated. The left middle cerebral artery was occluded and complete recanalisation was achieved after direct aspiration first-pass technique. However, MRI immediately after treatment showed reocclusion. Endovascular treatment was repeated and complete recanalisation was achieved. There was no evidence of cerebral artery dissection, but angiography soon after the second procedure revealed early reocclusion. Ozagrel, an antiplatelet agent, was administered intravenously and prevented reocclusion. Endothelial injury was speculated to have occurred during the first mechanical thrombectomy, leading to recurrent occlusion. Though the patient continued to have right hemiparesis, she recovered from her consciousness disturbance and aphasia after re-treatment.

Association between stroke-like episodes and neuronal hyperexcitability in MELAS with m.3243A>G: A case report.

•The pathophysiology of the stroke-like episodes of MELAS has not completely been elucidated.•Here we report a case of stroke-like episodes, successfully treated with levetiracetam.•Neuronal hyperexcitability can be the underlying mechanism of stroke-like episodes in MELAS.