Kensuke Iwasa

Bio: Kensuke Iwasa is an academic researcher from Saitama Medical University. The author has contributed to research in topics: Multiple sclerosis & Neuroinflammation. The author has an hindex of 5, co-authored 10 publications receiving 65 citations.

Protective and therapeutic role of 2-carba-cyclic phosphatidic acid in demyelinating disease.

Abstract: Multiple sclerosis is a neuroinflammatory demyelinating and neurodegenerative disease of the central nervous system characterized by recurrent and progressive demyelination/remyelination cycles, neuroinflammation, oligodendrocyte loss, demyelination, and axonal degeneration. Cyclic phosphatidic acid (cPA) is a natural phospholipid mediator with a unique cyclic phosphate ring structure at the sn-2 and sn-3 positions of the glycerol backbone. We reported earlier that cPA elicits a neurotrophin-like action and protects hippocampal neurons from ischemia-induced delayed neuronal death. We designed, chemically synthesized, and metabolically stabilized derivatives of cPA: 2-carba-cPA (2ccPA), a synthesized compound in which one of the phosphate oxygen molecules is replaced with a methylene group at the sn-2 position. In the present study, we investigated whether 2ccPA exerts protective effects in oligodendrocytes and suppresses pathology in the two most common mouse models of multiple sclerosis. To evaluate whether 2ccPA has potential beneficial effects on the pathology of multiple sclerosis, we investigated the effects of 2ccPA on oligodendrocyte cell death in vitro and administrated 2ccPA to mouse models of experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination. We demonstrated that 2ccPA suppressed the CoCl2-induced increase in the Bax/Bcl-2 protein expression ratio and phosphorylation levels of p38MAPK and JNK protein. 2ccPA treatment reduced cuprizone-induced demyelination, microglial activation, NLRP3 inflammasome, and motor dysfunction. Furthermore, 2ccPA treatment reduced autoreactive T cells and macrophages, spinal cord injury, and pathological scores in EAE, the autoimmune multiple sclerosis mouse model. We demonstrated that 2ccPA protected oligodendrocytes via suppression of the mitochondrial apoptosis pathway. Also, we found beneficial effects of 2ccPA in the multiperiod of cuprizone-induced demyelination and the pathology of EAE. These data indicate that 2ccPA may be a promising compound for the development of new drugs to treat demyelinating disease and ameliorate the symptoms of multiple sclerosis.

Prostaglandin F2α FP receptor inhibitor reduces demyelination and motor dysfunction in a cuprizone-induced multiple sclerosis mouse model

Abstract: Previously, we have demonstrated that prostamide/PGF synthase, which catalyzes the reduction of prostaglandin (PG) H2 to PGF2α, is constitutively expressed in myelin sheaths and cultured oligodendrocytes, suggesting that PGF2α has functional significance in myelin-forming oligodendrocytes. To investigate the effects of PGF2α/FP receptor signaling on demyelination, we administrated FP receptor agonist and antagonist to cuprizone-exposed mice, a model of multiple sclerosis. Mice were fed a diet containing 0.2% cuprizone for 5 weeks, which induces severe demyelination, glial activation, proinflammatory cytokine expression, and motor dysfunction. Administration of the FP receptor antagonist AL-8810 attenuated cuprizone-induced demyelination, glial activation, and TNFα expression in the corpus callosum, and also improved the motor function. These data suggest that during cuprizone-induced demyelination, PGF2α/FP receptor signaling contributes to glial activation, neuroinflammation, and demyelination, resulting in motor dysfunction. Thus, FP receptor inhibition may be a useful symptomatic treatment in multiple sclerosis.

The role of inflammation in the development of epilepsy

Abstract: Epilepsy, a neurological disease characterized by recurrent seizures, is often associated with a history of previous lesions in the nervous system. Impaired regulation of the activation and resolution of inflammatory cells and molecules in the injured neuronal tissue is a critical factor to the development of epilepsy. However, it is still unclear as to how that unbalanced regulation of inflammation contributes to epilepsy. Therefore, one of the goals in epilepsy research is to identify and elucidate the interconnected inflammatory pathways in systemic and neurological disorders that may further develop epilepsy progression. In this paper, inflammatory molecules, in neurological and systemic disorders (rheumatoid arthritis, Crohn’s, Type I Diabetes, etc.) that could contribute to epilepsy development, are reviewed. Understanding the neurobiology of inflammation in epileptogenesis will contribute to the development of new biomarkers for better screening of patients at risk for epilepsy and new therapeutic targets for both prophylaxis and treatment of epilepsy.

Marine omega-3 (n-3) phospholipids: A comprehensive review of their properties, sources, bioavailability, and relation to brain health.

Abstract: For several decades, there has been considerable interest in marine-derived long chain n-3 fatty acids (n-3 LCPUFAs) due to their outstanding health benefits. n-3 LCPUFAs can be found in nature either in triglycerides (TAGs) or in phospholipid (PL) form. From brain health point of view, PL n-3 is more bioavailable and potent compared to n-3 in TAG form, as only PL n-3 is able to cross the blood-brain barrier and can be involved in brain biochemical reactions. However, PL n-3 has been ignored in the fish oil industry and frequently removed as an impurity during degumming processes. As a result, PL products derived from marine sources are very limited compared to TAG products. Commercially, PLs are being used in pharmaceutical industries as drug carriers, in food manufacturing as emulsifiers and in cosmetic industries as skin care agents, but most of the PLs used in these applications are produced from vegetable sources that contain less (without EPA, DPA, and DHA) or sometimes no n-3 LCPUFAs. This review provides a comprehensive account of the properties, structures, and major sources of marine PLs, and provides focussed discussion of their relationship to brain health. Epidemiological, laboratory, and clinical studies on n-3 LCPUFAs enriched PLs using different model systems in relation to brain and mental health that have been published over the past few years are discussed in detail.

Quantitative proteomics of acutely-isolated mouse microglia identifies novel immune Alzheimer's disease-related proteins.

Abstract: Microglia are innate immune cells of the brain that perform phagocytic and inflammatory functions in disease conditions. Transcriptomic studies of acutely-isolated microglia have provided novel insights into their molecular and functional diversity in homeostatic and neurodegenerative disease states. State-of-the-art mass spectrometry methods can comprehensively characterize proteomic alterations in microglia in neurodegenerative disorders, potentially providing novel functionally relevant molecular insights that are not provided by transcriptomics. However, comprehensive proteomic profiling of adult primary microglia in neurodegenerative disease conditions has not been performed. We performed quantitative mass spectrometry based proteomic analyses of purified CD11b+ acutely-isolated microglia from adult (6 mo) mice in normal, acute neuroinflammatory (LPS-treatment) and chronic neurodegenerative states (5xFAD model of Alzheimer’s disease [AD]). Differential expression analyses were performed to characterize specific microglial proteomic changes in 5xFAD mice and identify overlap with LPS-induced pro-inflammatory changes. Our results were also contrasted with existing proteomic data from wild-type mouse microglia and from existing microglial transcriptomic data from wild-type and 5xFAD mice. Neuropathological validation studies of select proteins were performed in human AD and 5xFAD brains. Of 4133 proteins identified, 187 microglial proteins were differentially expressed in the 5xFAD mouse model of AD pathology, including proteins with previously known (Apoe, Clu and Htra1) as well as previously unreported relevance to AD biology (Cotl1 and Hexb). Proteins upregulated in 5xFAD microglia shared significant overlap with pro-inflammatory changes observed in LPS-treated mice. Several proteins increased in human AD brain were also upregulated by 5xFAD microglia (Aβ peptide, Apoe, Htra1, Cotl1 and Clu). Cotl1 was identified as a novel microglia-specific marker with increased expression and strong association with AD neuropathology. Apoe protein was also detected within plaque-associated microglia in which Apoe and Aβ were highly co-localized, suggesting a role for Apoe in phagocytic clearance of Aβ. We report a comprehensive proteomic study of adult mouse microglia derived from acute neuroinflammation and AD models, representing a valuable resource to the neuroscience research community. We highlight shared and unique microglial proteomic changes in acute neuroinflammation aging and AD mouse models and identify novel roles for microglial proteins in human neurodegeneration.

The Role of Diet in Multiple Sclerosis: Mechanistic Connections and Current Evidence

Abstract: This review seeks to examine current research related to the role of diet in multiple sclerosis (MS). Recent research in preclinical models, epidemiologic studies, and limited prospectively followed cohorts provide preliminary evidence that dietary factors influence MS incidence, disease course, and symptomatology. Current evidence for the effects of fatty acids, fruits and vegetables, whole grains, dairy, and salt are reviewed. Dietary patterns including overall diet quality, caloric restriction, McDougall diet, Paleolithic diet, and Mediterranean diet are discussed. Hypotheses regarding potential mechanistic connections underlying observed effects are also presented. Several individual dietary components and patterns demonstrate potential for significant impact in MS. Definitive answers regarding the ability of diet to act as a disease modifier in MS will ultimately require large-scale clinical trials. Continued prospective studies and clinical trials to further advance this line of research are warranted.