scholarly journals The Effects of Combined Therapy With Metformin and Hydroxypropyl-β-Cyclodextrin in a Mouse Model of Niemann-Pick Disease Type C1

2022 ◽  
Vol 12 ◽  
Author(s):  
Jiang Du ◽  
Xinlei Liu ◽  
Yan Zhang ◽  
Xiaojing Han ◽  
Chunya Ma ◽  
...  

Niemann–Pick disease type C1 (NPC1) is a neurodegenerative disorder characterized by lysosomal storage of free cholesterol. 2-Hydroxypropyl-β-cyclodextrin (HPβCD) is a cyclic oligosaccharide derivative that is being developed to treat NPC1. Recently, metformin was reported to be beneficial in various neurodegenerative diseases, such as Alzheimer’s and Huntington’s diseases. In this study, we examined the effects of combined treatment with HPβCD and metformin on Npc1−/− mice. Unfortunately, body weight and survival rates showed that cotreatment with metformin did not extend survival time and increase the body weight of HPβCD-treated Npc1−/− mice. However, cotreatment with metformin reduced inflammatory response and inhibited the proinflammatory cytokine release in the brain, liver and spleen of HPβCD-treated Npc1−/− mice. Furthermore, metformin did not reduce the free cholesterol levels in Npc1−/− brain tissue or fibroblasts. In conclusion, our results demonstrate that metformin does not show beneficial effects on body weight or survival time but reduced the inflammatory response in a mouse model of NPC1 when combined with HPβCD.

2014 ◽  
Vol 15 (4) ◽  
pp. 529-541 ◽  
Author(s):  
Kelly A. King ◽  
Sandra Gordon-Salant ◽  
Karen S. Pawlowski ◽  
Anna M. Taylor ◽  
Andrew J. Griffith ◽  
...  

2018 ◽  
Vol 19 (4) ◽  
pp. 972 ◽  
Author(s):  
Lynn Ebner ◽  
Anne Gläser ◽  
Anja Bräuer ◽  
Martin Witt ◽  
Andreas Wree ◽  
...  

Hippocampus ◽  
2011 ◽  
Vol 21 (2) ◽  
pp. 212-219 ◽  
Author(s):  
Su-ya Zhou ◽  
Shu-jun Xu ◽  
Ying-gang Yan ◽  
Hui-mei Yu ◽  
Shu-cai Ling ◽  
...  

2018 ◽  
Vol 63 (4) ◽  
pp. 870-880 ◽  
Author(s):  
Antony Cougnoux ◽  
Miyad Movassaghi ◽  
Jaqueline A. Picache ◽  
James R. Iben ◽  
Fatemeh Navid ◽  
...  

2019 ◽  
Vol 20 (5) ◽  
pp. 1152 ◽  
Author(s):  
Nushrat Yasmin ◽  
Yoichi Ishitsuka ◽  
Madoka Fukaura ◽  
Yusei Yamada ◽  
Shuichi Nakahara ◽  
...  

Niemann-Pick disease Type C (NPC) is a rare lysosomal storage disease characterized by the dysfunction of intracellular cholesterol trafficking with progressive neurodegeneration and hepatomegaly. We evaluated the potential of 6-O-α-maltosyl-β-cyclodextrin (G2-β-CD) as a drug candidate against NPC. The physicochemical properties of G2-β-CD as an injectable agent were assessed, and molecular interactions between G2-β-CD and free cholesterol were studied by solubility analysis and two-dimensional proton nuclear magnetic resonance spectroscopy. The efficacy of G2-β-CD against NPC was evaluated using Npc1 deficient Chinese hamster ovary (CHO) cells and Npc1 deficient mice. G2-β-CD in aqueous solution showed relatively low viscosity and surface activity; characteristics suitable for developing injectable formulations. G2-β-CD formed higher-order inclusion complexes with free cholesterol. G2-β-CD attenuated dysfunction of intercellular cholesterol trafficking and lysosome volume in Npc1 deficient CHO cells in a concentration dependent manner. Weekly subcutaneous injections of G2-β-CD (2.9 mmol/kg) ameliorated abnormal cholesterol metabolism, hepatocytomegaly, and elevated serum transaminases in Npc1 deficient mice. In addition, a single cerebroventricular injection of G2-β-CD (21.4 μmol/kg) prevented Purkinje cell loss in the cerebellum, body weight loss, and motor dysfunction in Npc1 deficient mice. In summary, G2-β-CD possesses characteristics favorable for injectable formulations and has therapeutic potential against in vitro and in vivo NPC models.


2019 ◽  
Vol 11 (506) ◽  
pp. eaat3738 ◽  
Author(s):  
Lluis Samaranch ◽  
Azucena Pérez-Cañamás ◽  
Beatriz Soto-Huelin ◽  
Vivek Sudhakar ◽  
Jerónimo Jurado-Arjona ◽  
...  

Niemann-Pick disease type A (NPD-A) is a lysosomal storage disorder characterized by neurodegeneration and early death. It is caused by loss-of-function mutations in the gene encoding for acid sphingomyelinase (ASM), which hydrolyzes sphingomyelin into ceramide. Here, we evaluated the safety of cerebellomedullary (CM) cistern injection of adeno-associated viral vector serotype 9 encoding human ASM (AAV9-hASM) in nonhuman primates (NHP). We also evaluated its therapeutic benefit in a mouse model of the disease (ASM-KO mice). We found that CM injection in NHP resulted in widespread transgene expression within brain and spinal cord cells without signs of toxicity. CM injection in the ASM-KO mouse model resulted in hASM expression in cerebrospinal fluid and in different brain areas without triggering an inflammatory response. In contrast, direct cerebellar injection of AAV9-hASM triggered immune response. We also identified a minimally effective therapeutic dose for CM injection of AAV9-hASM in mice. Two months after administration, the treatment prevented motor and memory impairment, sphingomyelin (SM) accumulation, lysosomal enlargement, and neuronal death in ASM-KO mice. ASM activity was also detected in plasma from AAV9-hASM CM-injected ASM-KO mice, along with reduced SM amount and decreased inflammation in the liver. Our results support CM injection for future AAV9-based clinical trials in NPD-A as well as other lysosomal storage brain disorders.


2009 ◽  
Vol 36 (2) ◽  
pp. 242-251 ◽  
Author(s):  
David Smith ◽  
Kerri-Lee Wallom ◽  
Ian M. Williams ◽  
Mylvaganam Jeyakumar ◽  
Frances M. Platt

2008 ◽  
Vol 268 (1-2) ◽  
pp. 108-116 ◽  
Author(s):  
Zhuo Luan ◽  
Yoshiaki Saito ◽  
Hajime Miyata ◽  
Eisaku Ohama ◽  
Haruaki Ninomiya ◽  
...  

Cornea ◽  
2011 ◽  
Vol 30 (7) ◽  
pp. 796-803 ◽  
Author(s):  
Marine Hovakimyan ◽  
Oliver Stachs ◽  
Maria Reichard ◽  
Hermann Mascher ◽  
Jan Lukas ◽  
...  

2018 ◽  
Vol 123 (2) ◽  
pp. S47
Author(s):  
Stefanie Flunkert ◽  
Ewald Auer ◽  
Roland Rabl ◽  
Tina Loeffler ◽  
Joerg Neddens ◽  
...  

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