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European Neurology 03/2013; 69(6):344-345. · 1.81 Impact Factor
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ABSTRACT: Abstract
Alzheimer's disease (AD) is the most common cause of dementia, and its pathological hallmarks are senile plaques and neurofibrillary tangles in the brain, which eventually induce neuronal death. The prevailing hypothesis for the pathomechanism of AD is the amyloid cascade hypthesis: amyloid-β peptide (Aβ) deposition in the brain initiates a sequence of events leading to dementia.
The blood-brain barrier (BBB) is crucial for AD pathomechanism because the transport of Aβ across the BBB is regulated by the receptor for advanced glycation end products, low-density lipoprotein receptor-related proteins, and the P-glycoprotein. Many studies have elucidated that these transport proteins are impaired in AD patients.
Moreover, it is now widely recognized that most cases of AD show vascular pathology. Vascular risk factors such as diabetes mellitus, hypertension, hypercholesterolemia, and obesity are risk factors for AD. Recently, the vascular hypothesis for AD pathomechanism has been proposed; vascular risk factors first lead to BBB dysfunction and oligaemia and then induce Aβ deposition, toxic accumulates, and capillary hypoperfusion in the brain, ultimately leading to neuronal dysfunction.
Therapeutic strategies for Aβ clearance from the brain to blood across the BBB have been increasingly developed. The "peripheral sink" approaches are now challenged by anti-Aβ antibodies, the agents with high affinity to Aβ, and the modification of molecules that influence the Aβ transport across the BBB.
This review highlights the roles of the BBB in AD pathomechanism and its importance in designing therapeutic strategies.
Brain and nerve = Shinkei kenkyū no shinpo 02/2013; 65(2):145-51.
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ABSTRACT: The development of gene silencing therapies for neurological diseases has placed great importance on the delivery of short interfering RNA (siRNA) to the central nervous system (CNS). However, delivery of siRNA to neurons, glia and brain capillary endothelial cells (BCECs) has not been well established. This editorial describes different approaches that are being used to efficiently deliver siRNA to the CNS via intravenous, intracerebroventricular, or intranasal administration.
Expert Opinion on Drug Delivery 01/2013; · 4.90 Impact Factor
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ABSTRACT: Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract that is frequently accompanied by systemic complications. Neuropathologies have not been well investigated as extraintestinal manifestations of CD. We herein report the case of a 36-year-old man with CD who presented with progressive weakness and numbness. A neurological examination and the results of a nerve conduction study and a sural nerve biopsy led to a diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Plasma exchanges were initially effective; however, the effects gradually declined starting 10 days after the plasma exchange (PE). These results suggest that humoral factors may play an important role in CIDP associated with CD.
Internal Medicine 01/2013; 52(1):125-8. · 0.94 Impact Factor
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Muscle & Nerve 07/2012; 46(1):140-2. · 2.37 Impact Factor
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Takashi Hirai,
Mitsuhiro Enomoto,
Akira Machida,
Mariko Yamamoto,
Hiroya Kuwahara,
Mio Tajiri,
Yukihiko Hirai,
Shinichi Sotome,
Hidehiro Mizusawa,
Kenichi Shinomiya,
Atsushi Okawa, Takanori Yokota
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ABSTRACT: Gene therapy for neurological diseases requires efficient gene delivery to target tissues in the central and peripheral nervous systems. Although adeno-associated virus is one of the most promising vectors for clinical use against neurological diseases, it is difficult to get it across the blood-brain barrier. A clinically practical approach to using a vector based on adeno-associated virus to decrease the expression of a specific gene in both the central and the peripheral nervous system has yet to be established. Here, we analyzed whether upper lumbar intrathecal administration of a therapeutic vector incorporating adeno-associated virus and short-hairpin RNA against superoxide dismutase-1 bypassed the blood-brain barrier to target the spinal cord and dorsal root ganglia. The therapeutic vector effectively suppressed mRNA and protein expression of endogenous superoxide dismutase-1 in the lumbar spinal cord and dorsal root ganglia. Moreover, neither neurological side effects nor toxicity due to the incorporated short-hairpin RNA occurred after the injection. We propose that this approach could be developed into novel therapies for motor neuron diseases and chronic pain conditions, such as complex regional pain syndrome, through silencing of the genes responsible for pathologies in the spinal cord and dorsal root ganglia.
Human gene therapy methods. 05/2012; 23(2):119-27.
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ABSTRACT: Schwann cells exhibit a high degree of plasticity in adult peripheral nerves after mechanical injury; they have, therefore, been implicated in promoting nerve regeneration. However, Schwann cell behavior after ischemic injury has not yet been elucidated. To determine how Schwann cell plasticity may contribute to recovery from ischemic neuropathy, we used a rat model in which ischemia was induced in the tibial nerve by a 5-hour occlusion of the supplying arteries. Proliferation of immature Schwann cells that emerged in the injured nerve was evaluated by double immunostaining for the p75 neurotrophin receptor and proliferating cell nuclear antigen. The number of proliferating cell nuclear antigen/p75 neurotrophin receptor double-positive cells increased significantly in 1 to 2 weeks after ischemia and subsequently decreased by 4 weeks. During this time, the postmitotic Schwann cells differentiated into mature cells, as demonstrated with bromodeoxyuridine incorporation, which facilitated axon guidance and subsequent axon remyelination. These results suggest the emergence and proliferation of immature Schwann cells that contribute to nerve regeneration after ischemic injury. The manipulation of this population of proliferating immature Schwann cells may be a useful strategy for treating ischemic peripheral neuropathy.
Journal of Neuropathology and Experimental Neurology 05/2012; 71(6):511-9. · 4.26 Impact Factor
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ABSTRACT: Progressive accumulation of specific misfolded protein is a defining feature of amyotrophic lateral sclerosis (ALS), similarly seen in Alzheimer disease, Parkinson disease, Huntington disease and Creutzfeldt-Jakob disease. The intercellular transfer of inclusions made of tau, α-synuclein and huntingtin has been demonstrated, revealing the existence of mechanisms reminiscent of those by which prions spread through the nervous system. Evidence for such a prion-like propagation mechanism has now spread to the major misfolded proteins, superoxide dismutase 1 (SOD1) and the 43 kDa transactive response DNA binding protein (TDP-43), implicated in ALS. The focus in this review is on what is known about ALS progression in terms of clinical as well as molecular aspects. Furthermore, the concept of 'propagation' is dissected into contiguous and non-contiguous types, and this concept is expanded to the severity of the focal symptom as well as its regional spread which can be explained by cell to cell propagation in the local neuron pool.
Journal of neurology, neurosurgery, and psychiatry 04/2012; 83(7):739-45. · 4.87 Impact Factor
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ABSTRACT: Spinal epidural abscess (SEA) is a rare infection complicated in patients who have some risk factors such as injection-drug use, diabetes mellitus, and several illnesses. However, no case of SEA associated with abortion has been reported. Here we report a case of SEA in a 30-year-old woman after dilation and curettage for incomplete abortion. The diagnosis of SEA was done by MRI and pus was drained after the cervical discectomy. Bacteroides fragilis group was cultured from the aspirated pus sample. The patient responded to surgical drainage and antibiotics.
Journal of global infectious diseases 04/2012; 4(2):132-4.
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Therapeutic delivery 04/2012; 3(4):417-20.
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Azusa Uchida,
Hiroki Sasaguri,
Nobuyuki Kimura,
Mio Tajiri,
Takuya Ohkubo,
Fumiko Ono,
Fumika Sakaue,
Kazuaki Kanai,
Takashi Hirai,
Tatsuhiko Sano, [......],
Kyohei Sakaki,
Mitsuhiro Enomoto,
Yukihiko Hirai,
Jiro Kumagai,
Yasuhiro Yasutomi,
Hideki Mochizuki,
Satoshi Kuwabara,
Toshiki Uchihara,
Hidehiro Mizusawa, Takanori Yokota
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ABSTRACT: Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to α-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and phosphorylation of transactive response deoxyribonucleic acid-binding protein 43 occurred after degeneration had begun. In contrast, similarly prepared rat models expressed transactive response deoxyribonucleic acid-binding protein 43 only in the nucleus of motoneurons. There is thus a species difference in transactive response deoxyribonucleic acid-binding protein 43 pathology, and our monkey model recapitulates amyotrophic lateral sclerosis pathology to a greater extent than rodent models, providing a valuable tool for studying the pathogenesis of sporadic amyotrophic lateral sclerosis.
Brain 03/2012; 135(Pt 3):833-46. · 9.46 Impact Factor
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ABSTRACT: Using clinical information, it was investigated whether lesions in sporadic amyotrophic lateral sclerosis (sALS) spread contiguously from an onset site to the another regions in domino-like manner as hypothesized by prion-like propagation of pathogenic proteins. First, the data from medical records of 53 sALS patients with bulbar or lower limb onset showed that the symptom has noncontiguously spread from the bulbar region to the lower limbs or vice versa, skipping the upper limbs, in 18.9% of the patients. Second, in 18 patients with upper limb onset, correlation between the local progression speed of symptom severity in the onset limb and the interval from onset to involvement of the second region (lower limb) was investigated. The symptom severity was assessed by a score on "dressing and hygene", the subscale of the revised ALS functional rating scale. The two parameters should be positively correlated, if the lesion propagates contiguously from an initially affected motoneuron to the neighbouring ones within the same motoneuron pool (local progression) and then propagates to the another motoneuron pools (regional spread). However, the statistically significant correlation was not found, suggesting that there may be the different mechanisms between local progression and regional spread of ALS lesions.
Rinshō shinkeigaku = Clinical neurology. 01/2012; 52(11):1059-61.
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ABSTRACT: We report the case of a 50-year-old man with subacute onset of bilateral visual field loss and visual acuity loss. His visual acuity was 0.07 OD/0.09 OS and Goldmann perimetry showed central scotomas. The optic fundi were normal bilaterally. Magnetic resonance imaging (MRI) showed hyperintensity in the right optic nerve on T(2) weighted imaging and swelling of the optic chiasm with slight enhancement of the bilateral optic nerves and the optic chiasm on gadolinium-enhanced imaging. Since sensory disturbance in the left hand and leg was noted in addition to the visual problem, multiple sclerosis (MS) was suspected initially. The patient was treated with intravenous methylprednisolone (1,000 mg/day), plasma exchange therapy, and immunosuppressant therapy. However, his visual disturbance did not improve. He had a history of deafness and family history of visual disturbance, because of which we performed an analysis of mitochondrial DNA. G11778A point mutation was found, and a diagnosis of Leber's hereditary optic neuropathy (LHON) was made. Although gadolinium contrast enhancement and swelling of the optic nerve are rare, this case shows that these findings are not in conflict with LHON. The present case also suggests that mitochondrial dysfunction may trigger the onset of MS-like extraocular symptoms in patients with LHON.
Rinshō shinkeigaku = Clinical neurology. 01/2012; 52(2):102-5.
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Nihon Naika Gakkai Zasshi 12/2011; 100(12):3618-21.
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Journal of Neurology 10/2011; 259(5):977-9. · 3.47 Impact Factor
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ABSTRACT: The brain capillary endothelial cell (BCEC) is a major functional component of the blood-brain barrier and is an underlying factor in the pathophysiology of various diseases, including brain ischemia, multiple sclerosis, and neurodegenerative disorders. We examined gene silencing in BCECs by using endogenous lipoprotein to introduce short-interfering RNA (siRNA) in vivo. A cholesterol-conjugated 21/23-mer siRNA targeting organic anion transporter 3 (OAT3) mRNA (Chol-siOAT3) was intravenously injected into mice after its incorporation into extracted endogenous lipoproteins. Chol-siOAT3 was not delivered to neurons or glia, but was successfully delivered into BCECs and resulted in a significant reduction of OAT3 mRNA levels when injected after its incorporation into high-density lipoprotein (HDL). Efficient delivery was not achieved, however, when Chol-siOAT3 was injected without any lipoproteins, or after its incorporation into low-density lipoprotein (LDL). Investigations in apolipoprotein E (ApoE)-deficient and LDL receptor (LDLR)-deficient mice revealed that the uptake of HDL-containing Chol-siOAT3 was mainly mediated by ApoE and LDLR in mice. These findings indicate that siRNA can be delivered into BCECs in vivo by using endogenous lipoprotein, which could make this strategy useful as a new gene silencing therapy for diseases involving BCECs.
Molecular Therapy 09/2011; 19(12):2213-21. · 6.87 Impact Factor
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Journal of Neurology 06/2011; 258(12):2293-5. · 3.47 Impact Factor
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Journal of Neurology 05/2011; 258(12):2288-90. · 3.47 Impact Factor
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Rheumatology International 03/2011; 32(4):1105-7. · 1.88 Impact Factor
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ABSTRACT: Systemic injections of AAV vectors generally transduce to the liver more effectively than to cardiac and skeletal muscles. The short hairpin RNA (shRNA)-expressing AAV9 (shRNA-AAV9) can also reduce target gene expression in the liver, but not enough in cardiac or skeletal muscles. Higher doses of shRNA-AAV9 required for inhibiting target genes in cardiac and skeletal muscles often results in shRNA-related toxicity including microRNA oversaturation that can induce fetal liver failure. In this study, we injected high-dose shRNA-AAV9 to neonates and efficiently silenced genes in cardiac and skeletal muscles without inducing liver toxicity. This is because AAV is most likely diluted or degraded in the liver than in cardiac or skeletal muscle during cell division after birth. We report that this systemically injected shRNA-AAV method does not induce any major side effects, such as liver dysfunction, and the dose of shRNA-AAV is sufficient for gene silencing in skeletal and cardiac muscle tissues. This novel method may be useful for generating gene knockdown in skeletal and cardiac mouse tissues, thus providing mouse models useful for analyzing diseases caused by loss-of-function of target genes.
Biochemical and Biophysical Research Communications 02/2011; 405(2):204-9. · 2.48 Impact Factor
