Neuroprotective effects of memantine via enhancement of autophagy.

INTRODUCTION: Chemical intervention of autophagy has been investigated in clinical trials for various age-related conditions such as sarcopenia and neurodegeneration. However, at present, no autophagy inducer has been established as a disease-modifying agent against neurodegenerative diseases. METHODS: We screened a library consisting of 796 medicines clinically approved (in Japan) for autophagy enhancers as potential neurodegeneration therapeutics using HeLa cells stably expressing green fluorescent protein-microtubule-associated protein light chain 3 (GFP-LC3) followed by an analysis of the molecular mechanisms using various neuronal models. RESULTS: The primary screening identified 152 hits in a static cellular state. A widely available Alzheimer's disease drug, memantine, which antagonizes N-Methyl-d-aspartate receptor (NMDAR), was one of the hits. Memantine increased the levels of LC3-II in a dose-dependent and time-dependent manner, and upregulated autophagic flux. In addition, the pharmacological effects of memantine on autophagy were independent of mTORC1 activity and NMDAR activation. Furthermore, a VPS34 inhibitor suppressed the memantine-induced LC3-II upregulation, suggesting that memantine may affect VPS34 complex activity. Notably, intracellular Huntington's disease-specific aggregates of elongated huntingtin, a well-established autophagy substrate, were significantly decreased by memantine. In addition, memantine enhanced elimination of degraded mitochondrial in neurons derived from induced pluripotent stem cells of PARK2 or PARK6 patients, who exhibited defective PINK1/parkin-mediated mitophagy, suggests that memantine accelerated the clearance of damaged mitochondria. CONCLUSION: These findings indicate that memantine may be beneficial for the treatment of neurodegeneration characterized by the abnormal accumulation of autophagy or mitophagy substrates.

Quantitative evaluation of electroconvulsive therapy for Parkinson's disease with refractory psychiatric symptoms.

Patients with advanced-stage Parkinson's disease (PD) occasionally experience refractory depression or catatonic stupor. Electroconvulsive therapy (ECT) has been reported as a successful procedure for both severe psychosis and motor symptoms in patients with PD. Four patients with PD who were receiving ECT were quantitatively evaluated using the Unified PD Rating scale part III, Hoehn and Yahr scale, Barthel index, Neuropsychiatric Inventory, mini-mental state examination, Revised Hasegawa's Dementia scale, Beck's Depression Inventory, and Hamilton Rating Scale for Depression-17. We adopted the "half-age" method, which is an age-based stimulus-dosing method. The patients showed improvement in symptoms of psychosis and motor symptoms without any adverse effects. The interval of improvement after ECT varied among patients. Of note, a decrease in psychiatric symptoms successfully alleviated the burden of caregivers. ECT may be useful to treat parkinsonism with refractory psychosis, major depression, or catatonic stupor, within the limitations of the patients enrolled.

Vertebral artery dissection in patients with autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal cystic disease, and it is associated with various extrarenal manifestations, including vascular complications, such as intracranial aneurysms, and aortic root dilatation and aneurysms. However, intracranial arterial dissection has rarely been reported. We herein report the cases of 2 patients with ADPKD who developed a vertebral artery (VA) dissection. Dissection was also observed on the other side of the VA and in the internal carotid artery in the first and second patient, respectively. Both patients also had a history of hypertension, which is frequently accompanied by ADPKD, and their serum creatinine levels were normal. Our report supports the importance of considering ADPKD as one of the possible pathogenic factors in arterial dissection.

Transient hemiparesis due to a ruptured cerebral aneurysm in the prehospital setting.

A 67-year-old woman developed a sudden onset headache and left hemiparesis. Emergency medical technicians found that she was conscious, but had left hemiparesis. On arrival, she had an isolated headache without any neurological deficits, however, suddenly became comatose during a head CT examination, which demonstrated a subarachnoid haemorrhage. The head CT angiography on the second day revealed a cerebral aneurysm at the right middle cerebral artery, which was clipped on the same day. The patient demonstrated left haemiplegia and total aphasia after the operation, however, the neurological deficit gradually subsided and discharged on foot in 4 months without any deficits. Some patients with a subarachnoid haemorrhage may demonstrate transient neurological deficits, like those occurring during an ischaemic stroke, so emergency medical technicians and physicians should pay attention to treat such patients gently to avoid the re-rupture of a cerebral aneurysm, especially if the patient has headache symptoms.

Eosinophilic meningitis caused by primary angiitis of the central nervous system.

Eosinophilic meningitis is defined as the presence of 10 eosinophils/mm(3) in the cerebrospinal fluid (CSF) or eosinophils accounting for more than 10% of CSF leukocytes. A 76-year-old man who developed cognitive dysfunction and consciousness disturbance had eosinophilic meningitis (his CSF contained 19.0% eosinophils). Because the etiology was unknown, we performed a brain biopsy. The pathological findings showed inflammatory infiltration in the small-sized arteries of the meninges. The patient was ultimately diagnosed as having primary angiitis of the central nervous system (PACNS). Eosinophilic meningitis occurring in a patient with PACNS is extremely rare, and this is the first report of this condition in Japan.

Bilateral facial nerve palsy due to otitis media associated with myeloperoxidase-antineutrophil cytoplasmic antibody.

Otitis media (OM) is well known as a common feature of proteinase 3 antineutrophil cytoplasmic antibody (PR3-ANCA)-related Wegener granulomatosis, but is a very rare condition in myeloperoxidase ANCA (MPO-ANCA)-related vasculitis. In addition, there have been a few reports showing an association of MPO-ANCA-positive OM with cranial polyneuropathy. In this report, we describe 2 patients with bilateral facial nerve palsy due to MPO-ANCA-related OM. One patient also had bilateral trigeminal neuropathy, pachymeningitis and MPO-ANCA-related glomerulonephritis, whereas the other showed isolated bilateral facial nerve palsy with OM. In both the patients, treatment with prednisolone and immune-suppressant drugs resulted in an improvement of OM and cranial polyneuropathy. Physicians should be aware that MPO-ANCA-positive OM can cause bilateral facial nerve palsy.