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

• Published in: Nanotheranostics (Sydney, NSW) NSW), 2022, Vol.6 (2), p.126-142
• Main Authors: Hollinger, Kristen R, Sharma, Anjali, Tallon, Carolyn, Lovell, Lyndah, Thomas, Ajit G, Zhu, Xiaolei, Wiseman, Robyn, Wu, Ying, Kambhampati, Siva P, Liaw, Kevin, Sharma, Rishi, Rojas, Camilo, Rais, Rana, Kannan, Sujatha, Kannan, Rangaramanujam M, Slusher, Barbara S
• Format: Article
• Language: English
• Subjects: Animals; Cognition; Dendrimers - pharmacology; Disease Models, Animal; Mice; Microglia; Multiple Sclerosis - drug therapy; Research Paper
• ISSN: 2206-7418; 2206-7418
• DOI: 10.7150/ntno.63158

Cognitive impairment is a common aspect of multiple sclerosis (MS) for which there are no treatments. Reduced brain -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 -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. We attached 2-PMPA to hydroxyl polyamidoamine (PAMAM) dendrimers (D-2PMPA) using a click chemistry approach. Cy5-labelled-D-2PMPA was used to visualize selective glial uptake and . D-2PMPA was evaluated for anti-inflammatory effects in LPS-treated glial cultures. In experimental autoimmune encephalomyelitis (EAE)-immunized mice, D-2PMPA was dosed biweekly starting at disease onset and cognition was assessed using the Barnes maze, and GCPII activity was measured in CD11b+ hippocampal cells. D-2PMPA showed preferential uptake into microglia and robust anti-inflammatory activity, including elevations in NAAG, TGFβ, and mGluR3 in glial cultures. D-2PMPA significantly improved cognition in EAE mice, even though physical severity was unaffected. GCPII activity increased >20-fold in CD11b+ cells from EAE mice, which was significantly mitigated by D-2PMPA treatment. Hydroxyl dendrimers facilitate targeted drug delivery to activated microglia. These data support further development of D-2PMPA to attenuate elevated microglial GCPII activity and treat cognitive impairment in MS.