Intranasal Salvinorin A Improves Long-term Neurological Function via Immunomodulation in a Mouse Ischemic Stroke Model

Abstract

Salvinorin A (SA), a highly selective kappa opioid receptor agonist, has been shown to reduce brain infarct volume and improve neurological function after ischemic stroke. However, the underlying mechanisms have not been fully understood yet. Therefore, we explored whether SA provides neuroprotective effects by regulating the immune response after ischemic stroke both in the central nervous system (CNS) and peripheral circulation. In this study, adult male mice were subjected to transient Middle Cerebral Artery Occlusion (tMCAO) and then were treated intranasally with SA (50 μg/kg) or with the vehicle dimethyl sulfoxide (DMSO). Multiple behavioral tests were used to evaluate neurofunction. Flow cytometry and immunofluorescence staining were used to evaluate the infiltration of peripheral immune cells into the brain. The tracer cadaverine and endogenous immunoglobulin G (IgG) extravasation were used to detect blood brain barrier leakage. We observed that SA intranasal administration after ischemic stroke decreased the expression of pro-inflammatory factors in the brain. SA promoted the polarization of microglia/macrophages into a transitional phenotype and decreased the pro-inflammatory phenotype in the brain after tMCAO. Interestingly, SA treatment scarcely altered the number of peripheral immune cells but decreased the macrophage and neutrophil infiltration into the brain at 24 h after tMCAO. Furthermore, SA treatment also preserved BBB integrity, reduced long-term brain atrophy and white matter injury, as well as improved the long-term neurofunctional outcome in mice. In this study, intranasal administration of SA improved long-term neurological function via immuno-modulation and by preserving blood–brain barrier integrity in a mouse ischemic stroke model, suggesting that SA could potentially serve as an alternative treatment strategy for ischemic stroke. Graphic Abstract

Research progress in brain-targeted nasal drug delivery

“…Brain stroke BDNF (Zhou et al, 2023), Valsartan (Sabry et al, 2023), Salvinorin A (Misilimu et al, 2022), etc.…”

Microglia at the blood brain barrier in health and disease

“…Notably, deletion of Arg1+ microglia promotes neuroinflammation in stroke models ( Li et al, 2022 ), emphasizing the importance of reducing neuroinflammation and balancing microglia activation in recovery. Intranasal treatment of salvinorin A, a highly selective non-opioid kappa opioid receptor agonist, reduced neuroinflammation and BBB permeability in transient MCAO mice ( Misilimu et al, 2022 ). Animals sacrificed 5 days after transient MCAO and treatment with salvinorin A demonstrated increased density of microglia near the infarction in the cortex and corpus striatum but with fewer microglia expressing CD16, a marker for pro-inflammatory microglia/macrophages in the cortex ( Misilimu et al, 2022 ).…”

“…Intranasal treatment of salvinorin A, a highly selective non-opioid kappa opioid receptor agonist, reduced neuroinflammation and BBB permeability in transient MCAO mice ( Misilimu et al, 2022 ). Animals sacrificed 5 days after transient MCAO and treatment with salvinorin A demonstrated increased density of microglia near the infarction in the cortex and corpus striatum but with fewer microglia expressing CD16, a marker for pro-inflammatory microglia/macrophages in the cortex ( Misilimu et al, 2022 ). These findings suggest that dampening pro-inflammatory microglial activation is beneficial for restoring BBB integrity and may improve recovery following stroke ( Xing et al, 2018 ; Chen et al, 2022 ; Kuo et al, 2023 ; Liao et al, 2023 ).…”

Editorial: Therapeutic relevance and mechanisms of neuro-immune communication in brain injury

“…Neuroinflammation can exacerbate both acute and secondary injury and lead to adverse long-term outcomes in brain injury. Based on the inflammatory signaling pathway, neuroscientists have found many drugs for the treatment of brain injury in animal studies, such as salvinorin A (a highly selective kappa opioid receptor agonist) (Misilimu et al, 2022 ), morphine (Rahimi et al, 2021 ), ACT001 (a sesquiterpene lactone derivative) (Cai et al, 2022 ), febuxostat (Wang et al, 2022 ), ethyl pyruvate (Shi et al, 2015 ), and amantadine (Leclerc et al, 2021 ). Traditional Chinese medicine formulas and natural extracts have been confirmed to be neuroprotective by regulating the neuroinflammatory response.…”