(1482) Intranasal and ICV Administration of Metabolic Glycoengineered NSCs After Cardiac Arrest

Introduction: Out-of-Hospital Cardiac Arrest (CA) affects over 350,000 people every year. While stem cell therapy shows promise for treating ischemic brain injury, its effectiveness is limited post-transplantation. Metabolic glycoengineering (MGE) enhances cell viability and neuronal differentiation in vivo by incorporating sugar analogs into the cell surface, thereby significantly improving the therapeutic effects of transplanted human neural stem cells (NSCs). This report compared the optimal delivery routes of MGE-NSCs on ischemic brain injury post-CA. We hypothesize that intracerebroventricular (ICV) and intranasal (IN) administrated MGE-NSCs improved neurological recovery at different post-CA recovery stages.

Methods: MGE-NSC therapies were randomly selected with ICV or IN administration 3 h after resuscitation in rats with 9min- or 11min-asphyxial CA. Neurological deficit scores (NDS), and neurobehavior tests were compared 3 d and 4 w after CA. Cresyl Violet staining was utilized to measure neuron ischemia. Tracking of transplanted MGE-NSCs was evaluated by immunofluorescence staining.

Results: ICV administration displayed superior early recovery outcomes over the IN route, with better NDSs post-CA and more transplanted MGE-NSCs targeted cortex and hippocampus. Conversely, IN administration showed late-stage superiority over ICV-NSCs, with better locomotion and reduced anxiety-/depression-related behaviors after 4 weeks with more MGE-NSCs surviving in the IN group and spread to further regions (cerebellum, brainstem) by week 4. Both ICV- and IN-delivered MGE-NSCs promoted cell differentiation, angiogenesis, and synaptic plasticity. IN-NSCs were as effective as or more than ICV-NSCs in these histological measurements.

Conclusions: Our study showcased the remarkable advantages of administering MGE-NSCs through ICV in short-term effects and intranasal routes in long-term effects after CA-induced ischemic brain injury, which underscore the versatility and efficacy of MGE-NSC therapy in enhancing recovery following CA, highlighting the potential of tailored treatment approaches for different phases of post-resuscitation care.
This work was partially supported by R01NS125232 and R01NS110387 from NINDS, and 2024-MSCRFD-6401 from Maryland Stem Cell Research Fund (All to X Jia).