Intranasal Lithium Chloride Nanoparticles Inhibit Inflammatory Pyroptosis in Brains and Ameliorate Memory Loss and Depression Behavior in 5xFAD mice

This study compares the changes in lithium concentrations in the brain and blood following the administration of intranasal or oral lithium chloride (LiCl) dissolved in either Ryanodex Formulation Vehicle (RFV) or water, as well as the therapeutic effectiveness and side effects of intranasal versus oral lithium chloride (LiCl) in RFV, and their mechanisms for inhibiting inflammation and pyroptosis in 5xFAD Alzheimers Disease (AD) mice brains. In comparison to oral LiCl in RFV, intranasal LiCl in RFV decreased lithium blood concentrations but increased brain concentrations and duration, resulting in a significantly higher brain/blood lithium concentration ratio than intranasal LiCl in water or oral LiCl in RFV in young adult mice. Intranasal LiCl in RFV robustly protects both memory loss and depressive behavior in both young and old 5xFAD mice, with no side effects or thyroid/kidney toxicity. In fact, intranasal LiCl in RFV protects against age-dependent kidney function impairment in 5xFAD mice. This lithium mediated neuroprotection was associated with its potent effects on the inhibition of InsP3R-1 Ca2+ channel receptor increase, ameliorating pathological inflammation and activation of the pyroptosis pathway, and the associated loss of synapse proteins. Intranasal LiCl in RFV could become an effective and potent inhibitor of pathological inflammation/pyroptosis in the CNS and treat both dementia and depression with no or minimal side effects/organ toxicity, particular in AD.