10 research outputs found
Sodium/myo-Inositol Transporters: Substrate Transport Requirements and Regional Brain Expression in the TgCRND8 Mouse Model of Amyloid Pathology
Inositol stereoisomers, myo- and scyllo-inositol, are known to enter the brain and are significantly elevated following oral administration. Elevations in brain inositol levels occur across a concentration gradient as a result of active transport from the periphery. There are two sodium/myo-inositol transporters (SMIT1, SMIT2) that may be responsible for regulating brain inositol levels. The goals of this study were to determine the effects of aging and Alzheimer's disease (AD)-like amyloid pathology on transporter expression, to compare regional expression and to analyze substrate requirements of the inositol transporters. QPCR was used to examine expression of the two transporters in the cortex, hippocampus and cerebellum of TgCRND8 mice, a mouse model of amyloid pathology, in comparison to non-transgenic littermates. In addition, we examined the structural features of inositol required for active transport, utilizing a cell-based competitive uptake assay. Disease pathology did not alter transporter expression in the cortex or hippocampus (p>0.005), with only minimal effects of aging observed in the cerebellum (SMIT1: F2,26 = 12.62; p = 0.0002; SMIT2: F2,26 = 8.71; p = 0.0015). Overall, brain SMIT1 levels were higher than SMIT2, however, regional differences were observed. For SMIT1, at 4 and 6 months cerebellar SMIT1 levels were significantly higher than cortical and hippocampal levels (p<0.05). For SMIT2, at all three ages both cortical and cerebellar SMIT2 levels were significantly higher than hippocampal levels (p<0.05) and at 4 and 6 months of age, cerebellar SMIT2 levels were also significantly higher than cortical levels (p<0.05). Inositol transporter levels are stably expressed as a function of age, and expression is unaltered with disease pathology in the TgCRND8 mouse. Given the fact that scyllo-inositol is currently in clinical trials for the treatment of AD, the stable expression of inositol transporters regardless of disease pathology is an important finding
Protocolo quimioterápico de baixa dose associado ao uso de ácido valproico como agente hipometilante em paciente com leucemia mieloide aguda em terceira recidiva : relato de caso
Characterization of Inositol Transporters as a Method for Drug Delivery to the Centra Nervous System
A challenge in the treatment of central nervous system (CNS) diseases is the transport of drug candidates into the brain. Inositol stereoisomers have show promise as therapeutic agents for CNS disorders. scyllo-Inositol was an effective prophylactic and therapeutic for Alzheimer’s disease (AD) in TgCRND8 mice, a model of AD. This suggests inositol stereoisomers have excellent CNS bioavailability. They enter the brain through inositol transporters, of which there are three: one hydrogen myo-inositol transporter (HMIT) and two sodium myo-inositol transporters (SMIT1, SMIT2). HYPOTHESIS: Given the high CNS bioavailability of inositol stereoisomers, it may be possible to use inositol transporters to shuttle other compounds into the CNS. OBJECTIVES: 1. To confirm the CNS bioavailability of the two main inositol stereoisomers, myo- and scyllo-inositol, in both TgCRND8 and wild-type mice. 2. To examine inositol transporter expression in the brains, as a function of time and disease pathology, in both groups. 3. To evaluate the flexibility of the inositol transporters for transporting compounds by determining the substrate structural features required for active transport. RESULTS: myo-Inositol and scyllo-inositol accumulated in the brain following oral administration. Disease pathology did not alter baseline inositol levels or uptake. Brain subregional transporter expression was unaltered as a function of age or disease pathology. In vitro cell culture experiments found HMIT inactive and therefore not a contender for drug transport. In contrast SMIT1 and SMIT2 were both active and competitive transport assays, revealed distinct criteria for active transport through each system. However, both were stringent in the substitutions to the structure of myo-inositol possible to maintain active transport. CONCLUSION: Active transport through the inositol transporters is very sensitive to changes in the structure of myo-inositol and only conservative changes are possible. Therefore, these transporters would not make effective shuttling systems for drug transport into the brain.Ph
Characterization of Inositol Transporters as a Method for Drug Delivery to the Centra Nervous System
A challenge in the treatment of central nervous system (CNS) diseases is the transport of drug candidates into the brain. Inositol stereoisomers have show promise as therapeutic agents for CNS disorders. scyllo-Inositol was an effective prophylactic and therapeutic for Alzheimer’s disease (AD) in TgCRND8 mice, a model of AD. This suggests inositol stereoisomers have excellent CNS bioavailability. They enter the brain through inositol transporters, of which there are three: one hydrogen myo-inositol transporter (HMIT) and two sodium myo-inositol transporters (SMIT1, SMIT2). HYPOTHESIS: Given the high CNS bioavailability of inositol stereoisomers, it may be possible to use inositol transporters to shuttle other compounds into the CNS. OBJECTIVES: 1. To confirm the CNS bioavailability of the two main inositol stereoisomers, myo- and scyllo-inositol, in both TgCRND8 and wild-type mice. 2. To examine inositol transporter expression in the brains, as a function of time and disease pathology, in both groups. 3. To evaluate the flexibility of the inositol transporters for transporting compounds by determining the substrate structural features required for active transport. RESULTS: myo-Inositol and scyllo-inositol accumulated in the brain following oral administration. Disease pathology did not alter baseline inositol levels or uptake. Brain subregional transporter expression was unaltered as a function of age or disease pathology. In vitro cell culture experiments found HMIT inactive and therefore not a contender for drug transport. In contrast SMIT1 and SMIT2 were both active and competitive transport assays, revealed distinct criteria for active transport through each system. However, both were stringent in the substitutions to the structure of myo-inositol possible to maintain active transport. CONCLUSION: Active transport through the inositol transporters is very sensitive to changes in the structure of myo-inositol and only conservative changes are possible. Therefore, these transporters would not make effective shuttling systems for drug transport into the brain.Ph
In vivo uptake of β-amyloid by non-plaque associated microglia
The role of microglia in β-amyloid (Aβ) deposition or clearance in the Alzheimer's disease (AD) brain remains unclear. Previous in vivo studies have focused primarily on the association of microglia with Aβ-positive parenchymal plaques, but have given little consideration to the possible interaction between Aβ and non-plaque associated microglia. Further, it is not known if microglia play a direct role in mediating Aβ uptake following anti-aggregant treatment. We report here the identification of Aβ-positive processes throughout the cortex and hippocampus of TgCRND8 mice expressing the human Swedish (KM670/671NL) and Indiana (V717F) amyloid precursor protein mutations, which localized to ionized calcium binding protein-1-positive resident microglia that were not associated with extracellular plaques. Oral administration of 1-deoxy-1-fluoro-scyllo-inositol, a scyllo-inositol analogue, to TgCRND8 mice improved spatial memory impairments and suppressed amyloid pathology in a dose-dependent manner. Further, treatment with 1-deoxy-1- fluoro-scyllo-inositol significantly increased hippocampal intra-microglial Aβ levels without stimulating microglial proliferation or peripheral macrophage recruitment. These results reveal a novel, beneficial role for non-plaque associated microglia in the regulation of cerebral Aβ levels in a mouse model of AD
Luminescent Rhenium and Ruthenium Complexes of an Amphoteric Poly(amidoamine) Functionalized with 1,10-Phenanthroline
A new amphoteric copolymer, <b>PhenISA</b>, has
been obtained
by copolymerization of 4-(4′-aminobutyl)-1,10-phenanthroline
(BAP) with 2-methylpiperazine and bisÂ(acrylamido)Âacetic acid (BAC)
(6% of phenanthroline-containing repeating units). The copolymer showed
excellent solubility in water, where it self-aggregated to give clear
nanoparticle suspensions (hydrodynamic diameter = 21 ± 2 nm,
by dynamic light scattering (DLS) analysis). The phenanthroline pendants
of the polymer stably coordinated either ReÂ(CO)<sub>3</sub><sup>+</sup> or RuÂ(phen)<sub>2</sub><sup>2+</sup> fragments, affording luminescent <b>Re-PhenISA</b>, <b>Re-Py-PhenISA</b>, and <b>Ru-PhenISA</b> polymer complexes, emitting from triplet metal-to-ligand charge
transfer (<sup>3</sup>MLCT) excited states (with λ<sub>em</sub> = 608, 571, and 614 nm, respectively, and photoluminescence quantum
yields Φ<sub>em</sub> = 0.7%, 4.8%, and 4.1%, in aerated water
solution, respectively). DLS analyses indicated that the polymer complexes
maintained the nanosize of <b>PhenISA</b>. All the complexes
were stable under physiological conditions (pH 7.4, 0.15 M NaCl) in
the presence of an excess of the ubiquitous competitor cysteine. In
vitro viability assays showed no toxicity of <b>Re-Py-PhenISA</b> and <b>Ru-PhenISA</b> complexes, at concentrations in the
range of 0.5–50 μM (calculated on the metal-containing
unit), toward HEK-293 (human embryonic kidney) cells. A preliminary
investigation of internalization in HEK-293 cells, by means of fluorescence
confocal microscopy, showed that <b>Ru-PhenISA</b> enters cells
via an endocytic pathway and, subsequently, homogeneously diffuse
within the cytoplasm across the vesicle membranes