Intranasal salvinorin A improves neurological outcome in rhesus monkey ischemic stroke model using autologous blood clot

Wu, Longfei; Wu, Di; Chen, Jian; Chen, Chunhua; Yao, Tianqi; He, Xiaoduo; Ma, Ying; Zhi, Xiao; Liu, Renyu; Ji, Xunming

doi:10.1177/0271678x20938137

Cited by 15 publications

(19 citation statements)

References 34 publications

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“…Consistent with results from nonhuman animal research, many human trials have shown Salvinorin A inhalation produced no significant changes in heart rate, blood pressure, O 2 saturation and core temperature suggesting a safe physiological profile of SA (Johnson et al 2011;Mendelson et al 2011). A recent study demonstrating that intranasal SA improves neurological outcome in a rhesus monkey autologous clot ischemic stroke model is very encouraging (Wu et al 2020). Further studies are needed to evaluate mechanisms that were not investigated in the past and also the role of SA treatment in immune-regulation after ischemic stroke.…”

Section: Introductionsupporting

confidence: 56%

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

Misilimu

Chen

et al. 2021

J Neuroimmune Pharmacol

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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

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Section: Introductionsupporting

confidence: 56%

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

Misilimu

Chen

et al. 2021

J Neuroimmune Pharmacol

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“…Based on cerebral angiography at 3 h post ischemia, we only included 3 monkeys with a still occluded M1-segment of MCA. Blood samples were drawn from the saphenous vein at baseline and 3 h after stroke onset ( Wang et al, 2016 ; Wu et al, 2021 ). MRI scanning was performed on a Magnetom Trio MRI Scanner (3.0 T; Siemens AG, Siemens Medical Solutions, Erlangen, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…MRI scanning was performed on a Magnetom Trio MRI Scanner (3.0 T; Siemens AG, Siemens Medical Solutions, Erlangen, Germany). MRI sequences and parameters were reported in our previous study ( Wang et al, 2016 ; Wu et al, 2021 ). Based on recent reports, DWI images obtained 1 day after ischemia were defined as “originally abnormal region” ( Nagaraja et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

Dysregulation of Principal Circulating miRNAs in Non-human Primates Following Ischemic Stroke

et al. 2021

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Despite the recent interest in plasma microRNA (miRNA) biomarkers in acute ischemic stroke patients, there is limited knowledge about the miRNAs directly related to stroke itself due to the multiple complications in patients, which has hindered the research progress of biomarkers and therapeutic targets of ischemic stroke. Therefore, in this study, we compared the differentially expressed miRNA profiles in the plasma of three rhesus monkeys pre- and post-cerebral ischemia. After cerebral ischemia, Rfam sequence category revealed increased ribosomic RNA (rRNA) and decreased transfer RNAs (tRNAs) in plasma. Of the 2049 miRNAs detected after cerebral ischemia, 36 were upregulated, and 76 were downregulated (fold change ≥2.0, P < 0.05). For example, mml-miR-191-5p, miR-421, miR-409-5p, and let-7g-5p were found to be significantly overexpressed, whereas mml-miR-128a-5p_R − 2, miR-431_R − 1, and let-7g-3p_1ss22CT were significantly downregulated. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that these differentially expressed miRNAs were implicated in the regulation of ubiquitin-mediated proteolysis and signaling pathways in cancer, glioma, chronic myeloid leukemia, and chemokine signaling. miRNA clustering analysis showed that mml-let-7g-5p and let-7g-3p_1ss22CT, which share three target genes [RB1-inducible coiled-coil 1 (RB1CC1), G-protein subunit γ 5 (GNG5), and chemokine (C-X-C motif) receptor 4 (CXCR4)], belong to one cluster, were altered in opposite directions following ischemia. These data suggest that circulating mml-let-7g may serve as a therapeutic target for ischemic stroke.

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“…Furthermore, the rats with forebrain ischaemia had a significant amelioration of motor and cognitive functions following salvinorin A treatment [190]. More recently, acute intranasal administration of salvinorin A (25 µg/kg) in a stroke rhesus monkey model highlighted its therapeutic potential for stroke rescue as the drug significantly decreased the brain infarct volume and improved neurological outcomes, neuroprotective effects that were maintained for 28 days after the procedure [191].…”

Section: Neuroprotectionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Salvinorin A and Salvia divinorum: Clinical and Forensic Aspects

et al. 2021

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Salvia divinorum Epling and Játiva is a perennial mint from the Lamiaceae family, endemic to Mexico, predominantly from the state of Oaxaca. Due to its psychoactive properties, S. divinorum had been used for centuries by Mazatecans for divinatory, religious, and medicinal purposes. In recent years, its use for recreational purposes, especially among adolescents and young adults, has progressively increased. The main bioactive compound underlying the hallucinogenic effects, salvinorin A, is a non-nitrogenous diterpenoid with high affinity and selectivity for the k-opioid receptor. The aim of this work is to comprehensively review and discuss the toxicokinetics and toxicodynamics of S. divinorum and salvinorin A, highlighting their psychological, physiological, and toxic effects. Potential therapeutic applications and forensic aspects are also covered in this review. The leaves of S. divinorum can be chewed, drunk as an infusion, smoked, or vaporised. Absorption of salvinorin A occurs through the oral mucosa or the respiratory tract, being rapidly broken down in the gastrointestinal system to its major inactive metabolite, salvinorin B, when swallowed. Salvinorin A is rapidly distributed, with accumulation in the brain, and quickly eliminated. Its pharmacokinetic parameters parallel well with the short-lived psychoactive and physiological effects. No reports on toxicity or serious adverse outcomes were found. A variety of therapeutic applications have been proposed for S. divinorum which includes the treatment of chronic pain, gastrointestinal and mood disorders, neurological diseases, and treatment of drug dependence. Notwithstanding, there is still limited knowledge regarding the pharmacology and toxicology features of S. divinorum and salvinorin A, and this is needed due to its widespread use. Additionally, the clinical acceptance of salvinorin A has been hampered, especially due to the psychotropic side effects and misuse, turning the scientific community to the development of analogues with better pharmacological profiles.

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Intranasal salvinorin A improves neurological outcome in rhesus monkey ischemic stroke model using autologous blood clot

Cited by 15 publications

References 34 publications

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

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

Dysregulation of Principal Circulating miRNAs in Non-human Primates Following Ischemic Stroke

Pharmacokinetics and Pharmacodynamics of Salvinorin A and Salvia divinorum: Clinical and Forensic Aspects

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