Intranasal Delivery: Effects on the Neuroimmune Axes and Treatment of Neuroinflammation

Abstract

This review highlights the pre-clinical and clinical work performed to use intranasal delivery of various compounds from growth factors to stem cells to reduce neuroimmune interactions. We introduce the concept of intranasal (IN) delivery and the variations of this delivery method based on the model used (i.e., rodents, non-human primates, and humans). We summarize the literature available on IN delivery of growth factors, vitamins and metabolites, cytokines, immunosuppressants, exosomes, and lastly stem cells. We focus on the improvement of neuroimmune interactions, such as the activation of resident central nervous system (CNS) immune cells, expression or release of cytokines, and detrimental effects of signaling processes. We highlight common diseases that are linked to dysregulations in neuroimmune interactions, such as Alzheimer’s disease, Parkinson’s disease, stroke, multiple sclerosis, and traumatic brain injury.

Current State and Future Directions of Intranasal Delivery Route for Central Nervous System Disorders: A Scientometric and Visualization Analysis

“…The red cluster (cluster 1) was the largest cluster with 85 keywords, and the primary keywords were Alzheimer’s-disease, intranasal insulin, Parkinson’s-disease, in vivo , neuroprotection, stroke, memory, oxidative stress, neuroinflammation, therapy, mouse model, and growth factor I ( Rehman et al, 2019 ; Rhea et al, 2020 ; Su et al, 2020 ). Based on the above results, we could summarize that this cluster mainly has publications that focus on intranasal drug delivery for treatment of neurodegenerative and other neurological disorders ( Benedict et al, 2004 ; Reger et al, 2005 ; Lochhead and Thorne, 2012 ).…”

“…Combining the specific location of four clusters from Figure 9A , it can be seen that, early research around the year 2012, “pathways and mechanisms of intranasal delivery (cluster 4)” had drawn much attention among investigators of this field. Afterward, “intranasal drug delivery for neurodegenerative, neuropsychiatric, and other neurological disorders (cluster 1 and cluster 3)” have progressively gained importance around 2015, and some areas remain the hotpots until today, for example, “neuroinflammation (AAY = 2017.90) ( Rhea et al, 2020 ),” “mesenchymal stem cell (AAY = 2017.62)” ( Aguilera et al, 2021 ; Vaes et al, 2021 ), and “mild cognitive impairment (AAY = 2016.85) ( Craft et al, 2012 ).” Also, it needs to be noted that keywords in “cluster 2: the study of nasal drug delivery systems” had the largest AAY compared with other clusters, and the keywords of “nanocarriers (AAY = 2018.22) ( Rehman et al, 2019 ),” “nanostructured lipid carriers (AAY = 2018.11) ( Agbo et al, 2021 ),” “loaded chitosan nanoparticles (AAY = 2017.52) ( Zhao et al, 2017 ),” and “PLGA nanoparticles (2017.41) ( Nanaki et al, 2020 )” were mainly found in the early years. These results indicate that the research focus of this field has shifted from “cluster 4: pathways and mechanisms of intranasal delivery” to “cluster 2: the study of nasal drug delivery systems, especially the nanostructured and nano-sized carrier systems” ( Ali et al, 2010 ; Battaglia et al, 2018 ; Pires et al, 2020 ).…”

TGR5 activation attenuates neuroinflammation via Pellino3 inhibition of caspase-8/NLRP3 after middle cerebral artery occlusion in rats

“…INT777 (6α-ethyl-23(S)-methyl-cholic acid; 6-EMCA) is a specific TGR5 agonist without farnesoid X receptor activity; research has shown that intracerebroventricular injection of INT777 significantly improves amyloid-beta (Aβ) 1–42-induced cognitive impairment [ 41 ]. There is growing evidence that intranasal administration is a viable route for delivery to the brain to treat neuroinflammation [ 23 ]. Indeed, the results of mass spectrometric analysis have shown that this route of administration is sufficient to provide an effective brain concentration of INT777 [ 42 ].…”

“…To ensure efficient delivery to the CNS, INT777 was administered intranasally 1 h after MCAO, as previously described [ 13 , 23 ], with some modifications. Specifically, rats received either saline (vehicle), INT777 (0.16 mg/kg), INT777 (0.48 mg/kg), or INT777 (1.44 mg/kg), administered as nose drops (5 μL/drop) over a period of 20 min, alternating drops every 2 min between the left and right nares.…”

Think Big, Start Small: How Nanomedicine Could Alleviate the Burden of Rare CNS Diseases

“…The second pathway involves the respiratory epithelium which, through the trigeminal nerve, will also allow agents to directly reach the brain tissue [ 47 ]. The intranasal route has been examined with success in a variety of neuroinflammation-related diseases, as recently thoroughly reviewed by Rhea et al [ 48 ].…”