Therapeutic Hypothermia Alleviates Hydrocephalus and Neurological Dysfunction Post Intraventricular Hemorrhage by Enhancing Drainage of Glymphatic‐Meningeal Lymphatic‐Deep Cervical Lymphatic System

AIMS: Intraventricular hemorrhage (IVH) has a high mortality and disability rate and poses significant clinical challenges, which often leads to hydrocephalus and neurological dysfunction. Emerging evidence implicates dysfunction of the glymphatic-meningeal lymphatic-deep cervical lymphatic system in the pathogenesis of post-IVH hydrocephalus. Therapeutic hypothermia (TH) holds promise for mitigating these sequelae. This study investigates the potential of TH to ameliorate IVH-induced hydrocephalus and neurological dysfunction, while elucidating its underlying mechanisms. METHODS: Rat models of IVH are established by intraventricular injection of autologous blood. TH, deep cervical lymph nodes (dCLNs) ligation, and intraperitoneal injection of AMPK inhibitor are used to intervene. RESULTS: In rat models of IVH, TH alleviates neurological dysfunction and attenuates hydrocephalus and pathology damage. TH protects physiological function and maintains normal structure of the glymphatic system. TH improves function and structure of the meningeal lymphatic system and promotes drainage of the deep cervical lymphatic system. TH upregulates RTN3, facilitates phosphorylation of AMPK, and suppresses ERS. All the above effects are reversed by ligation of dCLNs and AMPK inhibitor. CONCLUSION: TH alleviates hydrocephalus and neurological dysfunction post IVH by enhancing drainage of the glymphatic-meningeal lymphatic-deep cervical lymphatic system. The RTN3/AMPK/ERS pathway may be the proposed mechanism mediating this effect. TH is expected to become a novel therapeutic strategy for IVH.