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Background: Subarachnoid hemorrhage (SAH) serves as a disease characterized by high incidence rate, which is exceedingly prevalent and severe. Presently, there is no unambiguous or efficacious intervention for the neurological impairment following SAH. Administering multi-targeted neuroprotective agents to reduce oxidative stress (OS) and neuroinflammation caused by early brain injury (EBI) has been demonstrated to improve neurological function and prognosis following SAH. Edaravone dexborneol (EDB), a novel multi targeted neuroprotective medication, combines four parts edaravone (EDA) with 1 part (+)-borneol in proportion. Clinical trials conducted in China have revealed during 2 days of acute ischemic stroke (AIS), early administration of EDB leads to improved therapeutic outcomes compared to treatment in EDA monotherapy. Currently, there is no clear evidence that EDB can effectively treat SAH, therefore, our study aims to investigate its potential therapeutic effects and mechanisms on EBI after SAH. Method: We used the intravascular threading method to establish a mouse model of SAH to explore whether EDA and EDB could produce anti-OS and anti-apoptosis effects. Behavioral assessment of mice was conducted using the balance beam experiment and the modified Garcia scoring system. Neuronal damage due to OS and Keap1/Nrf2 signaling pathway were detected through techniques of immunofluorescence, Western blotting, spectrophotometry. The group of EDA and EDB were injected intraperitoneally for 72 h after SAH. Results: The experiment results indicated that EDB lead to remarkably positive results by significantly enhancing neurological function, reducing blood-brain barrier (BBB) injury, and effectively inhibiting neuronal apoptosis after SAH. Further examination indicated EDB significantly reduced the expression of Keap1 and increased the expression of Nrf2, and it inhibited MDA, and enhanced SOD activity after SAH. These outcomes surpassed the effectiveness observed in EDA monotherapy. However, the application of ML385 reversed the anti-OS effects of EDB and EDA. Conclusion: Our experimental findings indicated that EDB could activate Keap1/Nrf2 signaling pathway to reduce OS damage, thereby protecting neurological function and enhancing behavioral abilities after SAH. These outcomes could facilitate the creation of new approaches for the clinical management of SAH.

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Spontaneous subarachnoid hemorrhage (SAH) accounts for approximately 5% of all cases of stroke. SAH is correlated with elevated rates of mortality and disability. Despite significant advancements in comprehending the pathogenesis and surgical management, efficacious clinical interventions remain restricted, and the prognosis is yet to be enhanced. MicroRNAs play a crucial role in various pathological processes in organisms. Revealing these regulatory processes is conducive to the development of new treatment methods. MicroRNA-124 is highly expressed in the nervous system and has significant research value for SAH. This study aims to explore the role of miR-124 in the early post-SAH period on neural function and verify whether it is involved in the pathological and physiological processes of SAH. In this study, we used methods such as comparing the expression levels of miR-124 in cerebrospinal fluid, establishing a rat SAH model, and a mouse embryonic primary neuron hemoglobin stimulation model to verify the downstream proteins of miR-124 in SAH. Through transfection techniques, we adjusted the expression of this small RNA in Vitro and in Vivo models using miR-124 inhibitor and mimic in the primary neuron hemoglobin stimulation model and rat SAH model, and observed the phenotype. Finally, by consulting the literature and verifying in Vivo and in Vitro methods, AK4 and downstream molecule ATF3 were identified as downstream targets of miR-124.

Asunto(s)

MicroARNs , Fármacos Neuroprotectores , Hemorragia Subaracnoidea , Ratas , Animales , Ratones , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Hemorragia Subaracnoidea/genética , MicroARNs/genética , MicroARNs/metabolismo , Hemoglobinas

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Subarachnoid hemorrhage (SAH) triggers a cascade of events that lead to early brain injury (EBI), which contributes to poor outcomes and appears within 3 days after SAH initiation. EBI involves multiple process including neuronal death, blood-brain barrier (BBB) injury and inflammation response. Microglia are cluster of immune cells originating in the brain which respond to SAH by changing their states and releasing inflammatory molecules through various signaling pathways. M0, M1, M2 are three states of microglia represent resting state, promoting inflammation state, and anti-inflammation state respectively, which can be modulated by pharmacological strategies. AIM OF THE STUDY: After identified potential active ingredients and targets of Sanhua Decoction (SHD) for SAH, we selected aloe-emodin (AE) as a potential ingredient modulating microglia activation states. MATERIALS AND METHODS: Molecular mechanisms, targets and pathways of SHD were reveal by network pharmacology technique. The effects of AE on SAH were evaluated in vivo by assessing neurological deficits, neuronal apoptosis and BBB integrity in a mouse SAH model. Furthermore, BV-2 cells were used to examine the effects of AE on microglial polarization. The influence of AE on microglia transformation was measured by Iba-1, TNF-α, CD68, Arg-1 and CD206 staining. The signal pathways of neuronal apoptosis and microglia polarization was measured by Western blot. RESULTS: Network pharmacology identified potential active ingredients and targets of SHD for SAH. And AE is one of the active ingredients. We also confirmed that AE via NF-κB and PKA/CREB pathway inhibited the microglia activation and promoted transformation from M1 phenotype to M2 at EBI stage after SAH. CONCLUSIONS: AE, as one ingredient of SHD, can alleviate the inflammatory response and protecting neurons from SAH-induced injury. AE has potential value for treating SAH-induced nerve injury and is expected to be applied in clinical practice.

Asunto(s)

Aloe , Lesiones Encefálicas , Emodina , Hemorragia Subaracnoidea , Ratones , Animales , Microglía , Emodina/farmacología , Emodina/uso terapéutico , Enfermedades Neuroinflamatorias , Hemorragia Subaracnoidea/tratamiento farmacológico , Hemorragia Subaracnoidea/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , FN-kappa B/metabolismo , Lesiones Encefálicas/metabolismo

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Introduction: Intracranial stents are of paramount importance in managing cerebrovascular disorders. Nevertheless, the currently employed drug-eluting stents, although effective in decreasing in-stent restenosis, might impede the re-endothelialization process within blood vessels, potentially leading to prolonged thrombosis development and restenosis over time. Methods: This study aims to construct a multifunctional bioactive coating to enhance the biocompatibility of the stents. Salvianolic acid B (SALB), a bioactive compound extracted from Salvia miltiorrhiza, exhibits potential for improving cardiovascular health. We utilized dopamine as the base and adhered chitosan-coated SALB microspheres onto nickel-titanium alloy flat plates, resulting in a multifunctional drug coating. Results: By encapsulating SALB within chitosan, the release period of SALB was effectively prolonged, as evidenced by the in vitro drug release curve showing sustained release over 28 days. The interaction between the drug coating and blood was examined through experiments on water contact angle, clotting time, and protein adsorption. Cellular experiments showed that the drug coating stimulates the proliferation, adhesion, and migration of human umbilical vein endothelial cells. Discussion: These findings indicate its potential to promote re-endothelialization. In addition, the bioactive coating effectively suppressed smooth muscle cells proliferation, adhesion, and migration, potentially reducing the occurrence of neointimal hyperplasia and restenosis. These findings emphasize the exceptional biocompatibility of the newly developed bioactive coating and demonstrate its potential clinical application as an innovative strategy to improve stent therapy efficacy. Thus, this coating holds great promise for the treatment of cerebrovascular disease.