Stroke, a severe public health issue, looms over human health like the Sword of Damocles. Annually, it ruthlessly claims the lives of approximately 5.5 million people and leaves 13.7 million with disabilities. Among its types, ischemic stroke (IS) stands out due to the formation of blood clots within vessels, obstructing blood supply to the brain. Despite continuous medical efforts in prevention and treatment, including thrombolysis and mechanical thrombectomy, the risks of hemorrhage and ischemia-reperfusion (I/R) injury remain significant obstacles to patient recovery, imposing heavy medical and economic burdens on society. The search for new treatment strategies is urgent.
In recent years, the role of immune-inflammatory cascades in IS development has gained prominence in medical research. The blood-brain barrier (BBB) typically isolates the brain from the body's immune system, granting it immune privilege. However, IS disrupts the BBB, allowing peripheral immune cells to infiltrate damaged areas, triggering innate and adaptive immune responses. CD4+ T cells, crucial in the adaptive immune system, play a significant role in post-stroke immune reactions.
Against this backdrop, a groundbreaking study from Beijing University of Chinese Medicine has made waves in the medical community. The research focuses on Huang-Lian-Jie-Du Decoction (HLJDT), a traditional Chinese medicine formula composed of four herbs: Huang Lian, Huang Qin, Huang Bo, and Zhi Zi. Known for its anti-inflammatory and detoxifying effects, previous studies have shown HLJDT significantly reduces infarct volume and inhibits inflammatory factor release due to BBB disruption. Network pharmacology has revealed its mechanism involves regulating PI3K/AKT and MAPK signaling pathways to intervene in ischemic injury. However, how HLJDT modulates the interaction between peripheral immunity and the central nervous system to inhibit T cell infiltration remained unknown. A recent study titled "Huang-Lian-Jie-Du Decoction inhibits CD4+ T cell infiltration into CNS in MCAO rats by regulating BBB" has unveiled this mystery.
Researchers conducted a series of rigorous experiments using a rat model. The results were astonishing: HLJDT demonstrated strong therapeutic potential. In terms of neurological function improvement, there were no significant differences in Garcia scores among the groups before treatment. However, the model group showed a significant decline in scores three days post-reperfusion, indicating severe neurological impairment. HLJDT, particularly at medium and high doses, significantly improved neurological function, comparable to the FTY720 group. Although the low-dose group showed lesser effects, it still indicated a positive trend. TTC staining visually showed normal tissue in deep red and infarcted tissue in white. The infarct volumes in the FTY720 and HLJDT groups were significantly reduced, with medium and high doses showing the most pronounced effects, comparable to FTY720 in improving brain infarction.
At the pathological level, the sham-operated group exhibited healthy neurons with orderly arrangement. In contrast, the model group showed severe ischemia-reperfusion injury, with swollen neuronal cell bodies, pyknotic nuclei, vacuolated cytoplasm, and severe perivascular edema. While the low-dose HLJDT group showed limited improvement, the medium and high-dose groups, along with the FTY720 group, reduced nuclear pyknosis and fragmentation, restored nuclear size and shape, decreased cell membrane rupture, and reduced perivascular fluid accumulation. Nissl staining further confirmed their role in mitigating neuronal damage.
In regulating inflammatory factors, HE staining revealed tightly arranged endothelial cells and few inflammatory cells in the sham-operated group's brain tissue. The model group showed widespread infiltration of inflammatory cells, while the FTY720 and HLJDT groups significantly reduced perivascular inflammatory cells. CD4+ T lymphocyte detection clearly indicated that HLJDT lowered pro-inflammatory factors like IFN-γ from Th1 cells and IL-17A from Th17 cells, enhancing anti-inflammatory factors and balancing CD4+ T cell immune responses.
Moreover, HLJDT demonstrated immune-regulatory effects on peripheral blood, normalizing T cell counts. Immunofluorescence staining and statistical analysis confirmed its ability to reduce peripheral T lymphocyte infiltration into the central nervous system, particularly CD4+ T cells, which comprise 30-60% of T cells and are crucial in immune regulation.
At the microscopic level, transmission electron microscopy revealed intact tight junctions in the sham-operated group, while the model group showed disrupted junctions and widened endothelial cell gaps. Treatment with FTY720 and HLJDT initiated the repair of tight junctions, reducing cell membrane distances and enhancing connections. Western blot results also indicated that HLJDT upregulated tight junction proteins like occludin and adherens junction protein e-cadherin, promoting BBB repair.
In conclusion, this innovative study from Beijing University of Chinese Medicine has, for the first time, demonstrated that HLJDT, through its anti-inflammatory, BBB-repairing, and immune-balancing effects, provides comprehensive neuroprotection in MCAO rats via dual mechanisms. This breakthrough offers a promising new avenue for stroke treatment, highlighting the potential of traditional Chinese medicine in modern medical practice. As we look to the future, there is hope that Huang-Lian-Jie-Du Decoction will make significant strides in clinical stroke treatment, bringing new hope to countless patients.
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