Intracerebral Distribution of CAG Repeat-Binding Small Molecule Visualized by Whole-Brain Imaging

Understanding the pharmacokinetics of drug candidates of interest in the brain and evaluating drug delivery to the brain are important for developing drugs targeting the brain. Previously, we demonstrated that a CAG repeat-binding small molecule, naphthyridine-azaquinolone (NA), resulted in repeat contraction in mouse models of dentatorubral–pallidoluysian atrophy and Huntington’s disease caused by aberrant expansion of CAG repeats. However, the intracerebral distribution and drug deliverability of NA remain unclear. Here, we report three-dimensional whole-brain imaging of an externally administered small molecule using tissue clearing and light sheet fluorescence microscopy (LSFM). We designed and synthesized an Alexa594-labeled NA derivative with a primary amine for whole-brain imaging (NA-Alexa594-NH2), revealing the intracerebral distribution of NA-Alexa594-NH2 after intraparenchymal and intracerebroventricular administrations by whole-brain imaging combined with tissue clearing and LSFM. We also clarified that intranasally administered NA-Alexa594-NH2 was delivered into the brain via multiple nose-to-brain pathways by tracking the time-dependent change in the intracerebral distribution. Whole-brain imaging of small molecules by tissue clearing and LSFM is useful for elucidating not only the intracerebral distribution but also the drug delivery pathways into the brain

Varied doses of Juzen-taiho-to, Hochu-ekki-to, Shofu-san, Oren-gedoku-to and prednisolone influence ear thickness from repeated painting with mite antigen solution in NC/Nga mice

<p><b>Copyright information:</b></p><p>Taken from "Kampo Medicines for Mite Antigen-Induced Allergic Dermatitis in NC/Nga Mice"</p><p>Evidence-based Complementary and Alternative Medicine 2005;2(2):191-199.</p><p>Published online 23 Mar 2005</p><p>PMCID:PMC1142189.</p><p>© The Author (2005). Published by Oxford University Press. All rights reserved.</p> Ear thickness was measured immediately before, and 1, 4 and 24 h after each antigen application. Results after the first and the second antigen applications were omitted because increased ear thickness and drug effects were negligible. Each value represents the mean ± SEM of 5–8 mice. < 0.05, < 0.01 for Kampo medicine-administered groups by multiple comparison test, < 0.05, < 0.01 for prednisolone-administered group by -test

Application of Juzen-taiho-to, Hochu-ekki-to, Shofu-san, Oren-gedoku-to and prednisolone initiates histological changes in ear tissues of NC/Nga mice treated repeatedly with mite antigen

<p><b>Copyright information:</b></p><p>Taken from "Kampo Medicines for Mite Antigen-Induced Allergic Dermatitis in NC/Nga Mice"</p><p>Evidence-based Complementary and Alternative Medicine 2005;2(2):191-199.</p><p>Published online 23 Mar 2005</p><p>PMCID:PMC1142189.</p><p>© The Author (2005). Published by Oxford University Press. All rights reserved.</p> Mouse ears were separated 24 h after the fifth antigen application. Tissue sections were stained with hematoxylin–eosin. () no antigen; () control; () Juzen-taiho-to 100 mg/kg; () Juzen-taiho-to 300 mg/kg; () Hochu-ekki-to 100 mg/kg; () Hochu-ekki-to 300 mg/kg; () Shofu-san 100 mg/kg; () Shofu-san 300 mg/kg; () Oren-gedoku-to 100 mg/kg; () Oren-gedoku-to 300 mg/kg; () prednisolone 3 mg/kg

Mixed results of Juzen-taiho-to, Hochu-ekki-to, Shofu-san, Oren-gedoku-to and prednisolone administration on serum total IgE levels in NC/Nga mice repeatedly treated with mite antigen

<p><b>Copyright information:</b></p><p>Taken from "Kampo Medicines for Mite Antigen-Induced Allergic Dermatitis in NC/Nga Mice"</p><p>Evidence-based Complementary and Alternative Medicine 2005;2(2):191-199.</p><p>Published online 23 Mar 2005</p><p>PMCID:PMC1142189.</p><p>© The Author (2005). Published by Oxford University Press. All rights reserved.</p> Serum samples were obtained 24 h after each antigen application and serum IgE was quantified by enzyme-linked immunosorbent assay. Each value indicates the mean ± SEM of 5–8 mice. < 0.05, < 0.01 for Kampo medicine-administered groups by multiple comparison test; < 0.01 for prednisolone-administered group by -test