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While the intranasal administration of drugs to the brain has been gaining both research attention and regulatory success over the past several years, key fundamental and translational challenges remain to fully leveraging the promise of this drug delivery pathway for improving the treatment of various neurological and psychiatric illnesses. In response, this review highlights the current state of understanding of the nose-to-brain drug delivery pathway and how both biological and clinical barriers to drug transport using the pathway can been addressed, as illustrated by demonstrations of how currently approved intranasal sprays leverage these pathways to enable the design of successful therapies. Moving forward, aiming to better exploit the understanding of this fundamental pathway, we also outline the development of nanoparticle systems that show improvement in delivering approved drugs to the brain and how engineered nanoparticle formulations could aid in breakthroughs in terms of delivering emerging drugs and therapeutics while avoiding systemic adverse effects. Graphical abstract

Background Bipolar Disorder (BD) is associated with a decrease in cellular resilience. Despite the half a century old discovery of lithium's efficacy for the treatment of BD, its exact mechanisms remain elusive. Accumulating data suggest that lithium's cytoprotective properties involve the modulation of several UPR proteins, such as GRP78. Mesencephalic astrocyte‐derived neurotrophic factor (MANF) is an endoplasmic reticulum resident protein that regulates proteostasis through directly interacting with GRP78. The purpose of this study was to determine whether lithium increases MANF expression using cellular and rodent models and, if so, to elucidate the cellular mechanisms of action. Procedure Mouse striatal neuroblasts were treated with PBS, lithium, or lithium + Activator Protein‐1 (AP‐1) inhibitor for 24–72 hours. Once cells were harvested, mRNA was extracted. In vivo experiments included, intraperitoneal injections of lithium or saline to male Sprague Dawley rats twice daily for 14 consecutive days. Following drug treatment, brain tissue was isolated, and mRNA was extracted from various regions. MANF gene expression was measured using RT‐qPCR. Results In vitro studies showed lithium‐treated cells displayed a significant increase in MANF mRNA expression compared to controls. In contrast, cells treated with lithium and AP‐1 inhibitor showed no increase in expression. Similarly, in vivo studies revealed that lithium‐treated rats compared to controls had a significant increase in MANF expression in the PFC and striatum. Conclusion Taken together, these data suggest that lithium's therapeutic mechanism involves the maintenance of ER homeostasis via increased MANF gene expression mediated by the AP‐1 transcription factor.

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