Dendrimer-2PMPA selectively blocks upregulated microglial GCPII activity and improves cognition in a mouse model of multiple sclerosis

Nanotheranostics

article

Kristen R. Hollinger¹  Anjali Sharma²  Carolyn Tallon¹  Lyndah Lovell¹  Ajit G. Thomas¹  Xiaolei Zhu¹  Robyn Wiseman⁵  Ying Wu¹  Siva P. Kambhampati²  Kevin Liaw²  Rishi Sharma²  Camilo Rojas¹  Rana Rais¹  Sujatha Kannan²  Rangaramanujam M. Kannan²  Barbara S. Slusher¹ 

[1] Johns Hopkins Drug Discovery, Johns Hopkins University;Center for Nanomedicine, Department of Ophthalmology, Johns Hopkins University;Department of Neurology, Johns Hopkins University;Department of Psychiatry and Behavioral Sciences, Johns Hopkins University;Department of Pharmacology and Molecular Sciences, Johns Hopkins University;Department of Chemical and Biomolecular Engineering, Johns Hopkins University;Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University;Kennedy Krieger Institute, Johns Hopkins University;Department of Neuroscience, Johns Hopkins University;Department of Medicine, Johns Hopkins University

关键词: multiple sclerosis;    cognitive impairment;    dendrimer;    GCPII;    NAAG;   

DOI  :  10.7150/ntno.63158

学科分类：大气科学

来源: Ivyspring International Publisher

【 摘 要 】

Cognitive impairment is a common aspect of multiple sclerosis (MS) for which there are no treatments. Reduced brain N-acetylaspartylglutamate (NAAG) levels are linked to impaired cognition in various neurological diseases, including MS. NAAG levels are regulated by glutamate carboxypeptidase II (GCPII), which hydrolyzes the neuropeptide to N-acetyl-aspartate and glutamate. GCPII activity is upregulated multifold in microglia following neuroinflammation. Although several GCPII inhibitors, such as 2-PMPA, elevate brain NAAG levels and restore cognitive function in preclinical studies when given at high systemic doses or via direct brain injection, none are clinically available due to poor bioavailability and limited brain penetration. Hydroxyl-dendrimers have been successfully used to selectively deliver drugs to activated glia.

【 授权许可】

CC BY-NC