対称分岐型オリゴグリセロール三量体を用いた水溶性化研究

As a water-solubilizing fragment, branched glycerol trimer (BGL003) has been conjugated here with several lipophilic molecules to increase the hydrophilicity. Alkanethiols have been chemically modified by BGL003 to develop a lipophilic-thiolate-chemisorbed “Self-assembled Monolayers” (SAM) on metal surface in an aqueous solution. Octadecanethiol (ODT) which is used with organic solvent for depositing a molecular layer on the expensive metal surfaces. Herein, lipophilic thiols have been connected with BGL003 through succinyl residue and converted to a water-soluble derivative. The chemically modified octadecanethiol derivative has been applied for novel transition metal coating in water and the anticorrosive effect of metal piece was as high as with lipophilic thiol in organic solvent. Thus, an environmentally friendly coating method has been established from this project. Next, a couple of branched glycerol trimers with new apex were synthesized. Using N-acyl tyrosine methylamide as a smallest model of peptides and SN38 as an antineoplastic drug, the new BGL003 was connected with side chain of tyrosine and A-ring of SN38, respectively, via one additional linker molecule. Paclitaxel and docetaxel are also a chemotherapy medication and another new BGL003 has been conjugated with 3´-debenzoylated paclitaxel and 3´-de(tert-butyloxycarbonyl) docetaxel, respectively, without any linker molecule. I believe these BGL003 modified drugs will be more hydrophilic and increase absorption amount in the human body. The efficiency (in vitro and in vivo) of these modified drugs will be tested later on

Role of fractalkine-CX3CR1 pathway in seizure-induced microglial activation, neurodegeneration, and neuroblast production in the adult rat brain.

Temporal lobe seizures lead to an acute inflammatory response in the brain primarily characterized by activation of parenchymal microglial cells. Simultaneously, degeneration of pyramidal cells and interneurons is evident together with a seizure-induced increase in the production of new neurons within the dentate gyrus of the hippocampus. We have previously shown a negative correlation between the acute seizure-induced inflammation and the survival of newborn hippocampal neurons. Here, we aimed to evaluate the role of the fractalkine-CX3CR1 pathway for these acute events. Fractalkine is a chemokine expressed by both neurons and glia, while its receptor, CX3CR1 is primarily expressed on microglia. Electrically-induced partial status epilepticus (SE) was induced in adult rats through stereotaxically implanted electrodes in the hippocampus. Recombinant rat fractalkine or CX3CR1 antibody was infused intraventricularly during one week post-SE. A significant increase in the expression of CX3CR1, but not fractalkine, was observed in the dentate gyrus at one week. CX3CR1 antibody treatment resulted in a reduction in microglial activation, neurodegeneration, as well as neuroblast production. In contrast, fractalkine treatment had only minor effects. This study provides evidence for a role of the fractalkine-CX3CR1 signaling pathway in seizure-induced microglial activation and suggests that neuroblast production following seizures may partly occur as a result of microglial activation

Cytotoxicity, 2D-and 3D-QSAR Study of some Halogen Containing Hydroxy and Amino Substituted Aromatic Compounds

Abstract A set of 24 halogen containing hydroxy and amino substituted aromatic compounds were subjected to 2D-and 3D-QSAR studies. 3D-QSAR was studied at a 2.0 Ǻ 3D grid spacing using molecular interaction fields (MIFs) analysis. The best predictive models by MIFs gave the cross-validated correlation coefficient, Q 2 of 0.668 and squared correlation coefficient, R 2 of 0.979 and the models by MLR, PCR and PLSR methods for 2D-QSAR provided a highly significant squared correlation coefficient (

Neurodegenerative pathways as targets for acquired epilepsy therapy development

There is a growing body of clinical and experimental evidence that neurodegenerative diseases and epileptogenesis after an acquired brain insult may share common etiological mechanisms. Acquired epilepsy commonly develops as a comorbid condition in patients with neurodegenerative diseases such as Alzheimer's disease, although it is likely much under diagnosed in practice. Progressive neurodegeneration has also been described after traumatic brain injury, stroke, and other forms of brain insults. Moreover, recent evidence has shown that acquired epilepsy is often a progressive disorder that is associated with the development of drug resistance, cognitive decline, and worsening of other neuropsychiatric comorbidities. Therefore, new pharmacological therapies that target neurobiological pathways that underpin neurodegenerative diseases have potential to have both an anti-epileptogenic and disease-modifying effect on the seizures in patients with acquired epilepsy, and also mitigate the progressive neurocognitive and neuropsychiatric comorbidities. Here, we review the neurodegenerative pathways that are plausible targets for the development of novel therapies that could prevent the development or modify the progression of acquired epilepsy, and the supporting published experimental and clinical evidence

Alterations in Brain Inflammation, Synaptic Proteins, and Adult Hippocampal Neurogenesis during Epileptogenesis in Mice Lacking Synapsin2.

Synapsins are pre-synaptic vesicle-associated proteins linked to the pathogenesis of epilepsy through genetic association studies in humans. Deletion of synapsins causes an excitatory/inhibitory imbalance, exemplified by the epileptic phenotype of synapsin knockout mice. These mice develop handling-induced tonic-clonic seizures starting at the age of about 3 months. Hence, they provide an opportunity to study epileptogenic alterations in a temporally controlled manner. Here, we evaluated brain inflammation, synaptic protein expression, and adult hippocampal neurogenesis in the epileptogenic (1 and 2 months of age) and tonic-clonic (3.5-4 months) phase of synapsin 2 knockout mice using immunohistochemical and biochemical assays. In the epileptogenic phase, region-specific microglial activation was evident, accompanied by an increase in the chemokine receptor CX3CR1, interleukin-6, and tumor necrosis factor-α, and a decrease in chemokine keratinocyte chemoattractant/ growth-related oncogene. Both post-synaptic density-95 and gephyrin, scaffolding proteins at excitatory and inhibitory synapses, respectively, showed a significant up-regulation primarily in the cortex. Furthermore, we observed an increase in the inhibitory adhesion molecules neuroligin-2 and neurofascin and potassium chloride co-transporter KCC2. Decreased expression of γ-aminobutyric acid receptor-δ subunit and cholecystokinin was also evident. Surprisingly, hippocampal neurogenesis was reduced in the epileptogenic phase. Taken together, we report molecular alterations in brain inflammation and excitatory/inhibitory balance that could serve as potential targets for therapeutics and diagnostic biomarkers. In addition, the regional differences in brain inflammation and synaptic protein expression indicate an epileptogenic zone from where the generalized seizures in synapsin 2 knockout mice may be initiated or spread