Application of electroshock therapy in improvement of depression by regulating blood-brain barrier and inflammatory factors

Abstract

The invention discloses application of electroshock therapy in improvement of depression by regulating blood brain barrier and inflammatory factors, and relates to the technical field of nerve regulation. The invention discloses application of an electroshock treatment device in preparation of a medicine or a medical preparation for improving depression. The medicine or the medical preparation is used for improving depression by adjusting blood-brain barrier permeability of a subject. The regulation of the permeability of the blood-brain barrier comprises a close connection structure for repairing the blood-brain barrier; the repair is realized by up-regulating the expression of a tight junction protein, and the tight junction protein is selected from at least one of ZO-1, occuldin or claudin-5. The invention systematically discloses a brand new mechanism for treating and improving depression by electroshock, namely, a continuous path for reversing peripheral immune activation, repairing blood-brain barrier injury and relieving central nervous inflammation plays a role; the mechanism chain is clear, and innovative explanation is provided for the curative effect of ECT.

Description

Technical Field

[0001] This invention relates to the field of neuromodulation technology, and more particularly to the application of electroconvulsive therapy in improving depression by modulating the blood-brain barrier and inflammatory factors. Background Technology

[0002] Depression is a common and highly disabling mental disorder with a complex pathogenesis involving abnormalities in multiple systems, including genetics, neurobiochemistry, endocrine function, and immune inflammation. Although existing antidepressants (such as SSRIs and SNRIs) and psychotherapy are effective for some patients, problems such as delayed onset of action, insufficient efficacy, and side effects persist, leading to a significant proportion of patients developing treatment-resistant depression. Therefore, exploring more effective and well-defined physical therapy methods is of great importance.

[0003] Electroconvulsive therapy (ECT) is currently recognized as one of the most effective physical interventions for severe and treatment-resistant depression. However, its exact neurobiological mechanisms remain unclear, which limits its precise clinical application and public acceptance to some extent. Traditional hypotheses mainly revolve around the regulatory effects of ECT on monoamine neurotransmitters, the hypothalamic-pituitary-adrenal axis, and neural plasticity, but these mechanisms have not fully explained its rapid and powerful antidepressant effects.

[0004] In recent years, the immune-inflammatory hypothesis has provided a new perspective for understanding the pathophysiological mechanisms of depression. Studies have shown that patients with malignant depression (MDD) exhibit significant peripheral and central immune-inflammatory activation, manifested as elevated levels of pro-inflammatory cytokines and microglial activation. The blood-brain barrier (BBB), as a crucial interface separating the peripheral circulation from the central nervous system, is considered a key link in the intrusion of peripheral inflammatory signals into the central nervous system, triggering neuroinflammation. Previous studies have suggested that stress can lead to increased BBB permeability, but its role in depression, particularly as a key target for ECT intervention, has not yet been systematically elucidated.

[0005] Currently, existing technologies remain in the gaps regarding whether and how ECT exerts its therapeutic effect by regulating the entire peripheral immune-BBB-central inflammation pathway. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of the prior art and propose the application of electroconvulsive therapy in improving depression by modulating the blood-brain barrier and inflammatory factors.

[0007] To achieve the above objectives, the present invention adopts the following technical solution: The use of an electroconvulsive therapy device in the preparation of a drug or medical agent for improving depression, wherein the drug or medical agent improves depression by modulating the permeability of the blood-brain barrier in a subject.

[0008] Preferably, the regulation of blood-brain barrier permeability includes repairing the tight junction structure of the blood-brain barrier.

[0009] Preferably, the repair is achieved by upregulating the expression of tight junction proteins, which are selected from at least one of ZO-1, occludin, or claudin-5.

[0010] The use of an electroconvulsive therapy device in the preparation of a drug or medical agent for improving depression, wherein the drug or medical agent improves depression by modulating the level of inflammatory factors in a subject.

[0011] Preferably, the regulation of inflammatory factor levels includes reducing the level of at least one of the pro-inflammatory cytokines TNF-α, IL-1β, or IL-6.

[0012] Preferably, the regulation of inflammatory factor levels includes increasing the level of the anti-inflammatory cytokine IL-10.

[0013] An electroconvulsive therapy system for improving depression, the system comprising: An electroconvulsive therapy (ECT) device used to generate electrical stimulation pulses; The control unit is configured to control parameters of the electrical stimulation pulses to achieve the application described above; the parameters include voltage, frequency, and treatment duration.

[0014] Preferably, the system further includes a monitoring module for monitoring biomarkers related to blood-brain barrier function or inflammation levels during or after treatment.

[0015] Preferably, the biomarkers include the concentration of inflammatory factors in peripheral blood or protein biomarkers related to the integrity of the blood-brain barrier.

[0016] The beneficial effects of this invention are as follows: 1. This invention systematically reveals a novel mechanism by which electroconvulsive therapy (ECT) improves depression, namely, by acting through a continuous pathway of reversing peripheral immune activation, repairing blood-brain barrier damage, and reducing central nervous system inflammation; this mechanism chain is clear and provides an innovative explanation for the efficacy of ECT.

[0017] 2. This invention clarifies that the blood-brain barrier is a key and modifiable target connecting peripheral and central inflammation, which provides direction for the future development of new antidepressant therapies (such as drugs targeting BBB protection) and also provides theoretical support for the precise application of ECT. For example, patients who may respond well to ECT can be screened by monitoring peripheral inflammatory markers or BBB integrity-related biomarkers.

[0018] 3. Based on bioinformatics analysis of the GEO database, this invention discovered a population phenomenon of peripheral inflammation activation in MDD patients; verified the existence of the peripheral-BBB-central chain and the reversal effect of ECT using the CUMS animal model; and directly confirmed the mechanism by which peripheral inflammatory signals amplify central inflammation using cell co-culture experiments.

[0019] 4. The immune inflammation and BBB pathways revealed in this invention are often overlooked in traditional drug treatments; ECT treatment targeting this pathway provides an effective treatment option with complementary mechanisms for patients with treatment-resistant depression who are not sensitive to drugs, and has important clinical value. Attached Figure Description

[0020] Figure 1 This is a diagram showing the animal experimental results of this invention; Figure 2 This is the principal component analysis diagram of the present invention; Figure 3 This is a volcano diagram of differentially expressed genes in this invention; Figure 4 Venn diagram for differentially expressed gene overlap analysis in this invention; Figure 5 This is a bubble diagram of KEGG pathway enrichment analysis in this invention. Figure 6 This is an electron microscope image of the results of this invention; Figure 7 This is a diagram illustrating the experimental mechanism of the present invention. Detailed Implementation

[0021] The technical solution of the present invention will be further described in detail below with reference to specific embodiments.

[0022] Example 1: Application of electroconvulsive therapy in a mouse model of depression like Figure 1-7 As shown, this embodiment uses C57BL / 6 mice to simulate the treatment process for human depression. All experimental procedures complied with animal ethics guidelines.

[0023] Animal model establishment: Eight-week-old male C57BL / 6 mice were randomly divided into three groups: control group (CON), depression model group (CUMS), and electroconvulsive therapy group (CUMS+ECS), with 10 mice in each group.

[0024] The CUMS group and the CUMS+ECS group underwent chronic unpredictable mild stress (CUMS) modeling for 6 weeks, including random stressors such as water deprivation, food deprivation, tilted cages, and damp bedding. The CON group received no stress treatment.

[0025] Electroconvulsive therapy intervention: After modeling, the CUMS+ECS group received electroconvulsive therapy (ECS) with the following parameters: bidirectional rectangular wave, frequency 100 Hz, current intensity 75 mA, wave width 0.5 ms, and duration 1.0 s. This was administered once daily for 10 consecutive days. ECS was applied to the mouse head via specialized electrodes to simulate clinical ECT. The CON and CUMS groups received sham treatment (the same procedure but without electrical stimulation).

[0026] Behavioral assessment: After treatment, behavioral tests will be conducted: Sugar water preference experiment: In assessing anhedonia, the sugar water preference rate in the CUMS group was significantly lower than that in the CON group (p<0.01), while the preference rate in the CUMS+ECS group recovered to a level close to that of the CON group.

[0027] Open field test: assessing anxiety-like behavior, the CUMS group showed reduced activity time in the central region, while the CUMS+ECS group showed partial reversal.

[0028] Tail suspension test: assessing despair behavior, the immobility time was prolonged in the CUMS group and shortened in the CUMS+ECS group.

[0029] The results confirmed that the CUMS model was successful and that ECS intervention effectively improved depressive-like behaviors.

[0030] Blood-brain barrier and inflammatory marker monitoring: After behavioral testing, the mice were euthanized, and peripheral blood and hippocampal tissue were collected.

[0031] Blood-brain barrier assessment: Transmission electron microscopy revealed the following ultrastructure of the blood-brain barrier in the hippocampus: the CUMS group showed shortened tight junction structures, faded electron-dense regions, and widened intercellular spaces, indicating increased permeability; the CUMS+ECS group showed improved tight junction continuity and reduced damage.

[0032] PCR detection of tight junction protein genes (ZO-1, occludin, claudin-5): expression was downregulated in the CUMS group and upregulated in the CUMS+ECS group.

[0033] Inflammatory factor level detection: Peripheral blood ELISA detection: The CUMS group showed increased levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and decreased levels of anti-inflammatory cytokines (IL-10); the CUMS+ECS group reversed this change.

[0034] Hippocampal transcriptome sequencing: CUMS group showed enrichment of inflammatory pathways (such as cytokine signaling pathways and TLR pathways), and normalization of key gene expression after ECS intervention.

[0035] Flow cytometry analysis of peripheral blood macrophage activity showed increased activation in the CUMS group and decreased activation in the CUMS+ECS group.

[0036] Mechanism verification: Peripheral inflammation was simulated through a macrophage-microglia co-incubation experiment. The results showed that peripheral inflammatory factors could activate microglia, and this effect was weakened after ECS intervention, confirming that the chain of peripheral inflammation amplifying central inflammation through the blood-brain barrier was blocked by ECS.

[0037] in conclusion: This embodiment demonstrates that electroconvulsive therapy (ECT) effectively improves depressive-like behaviors by modulating blood-brain barrier permeability and inflammatory factor levels. This method can be translated into clinical applications; for example, during ECT treatment in patients with depression, imaging techniques can be used to assess changes in blood-brain barrier function, and hematological tests can be used to monitor inflammatory markers, providing a basis for optimizing and individualizing treatment plans.

[0038] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. The application of an electroconvulsive therapy device in the preparation of drugs or medical agents for improving depression, characterized in that, The drug or medical preparation improves depression by modulating the permeability of the blood-brain barrier in the subject.

2. The application according to claim 1, characterized in that, The regulation of blood-brain barrier permeability includes repairing the tight junction structures of the blood-brain barrier.

3. The application according to claim 2, characterized in that, The repair is achieved by upregulating the expression of tight junction proteins selected from at least one of ZO-1, occludin, or claudin-5.

4. The application of an electroconvulsive therapy device in the preparation of drugs or medical agents for improving depression, characterized in that, The drug or medical agent improves depression by modulating the level of inflammatory factors in the subject.

5. The application according to claim 4, characterized in that, The regulation of inflammatory factor levels includes reducing the level of at least one of the pro-inflammatory cytokines TNF-α, IL-1β, or IL-6.

6. The application according to claim 5, characterized in that, The regulation of inflammatory factor levels includes increasing the level of the anti-inflammatory cytokine IL-10.

7. An electroconvulsive therapy system for improving depression, characterized in that, The system includes: An electroconvulsive therapy (ECT) device used to generate electrical stimulation pulses; A control unit is configured to control parameters of the electrical stimulation pulses to achieve the application as described in any one of claims 1-6; the parameters include voltage, frequency, and treatment duration.

8. The system according to claim 7, characterized in that, The system also includes a monitoring module for monitoring biomarkers related to blood-brain barrier function or inflammation levels during or after treatment.

9. The system according to claim 7, characterized in that, The biomarkers include the concentration of inflammatory factors in peripheral blood or protein markers related to the integrity of the blood-brain barrier.

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