Current therapies for reducing raised intracranial pressure (ICP) under conditions such as idiopathic intracranial hypertension or hydrocephalus have limited efficacy and tolerability. Thus, there is a pressing need to identify alternative drugs. Glucagon-like peptide-1 receptor (GLP-1R) agonists are used to treat diabetes and promote weight loss but have also been shown to affect fluid homeostasis in the kidney. We investigated whether exendin-4, a GLP-1R agonist, is able to modulate cerebrospinal fluid (CSF) secretion at the choroid plexus and subsequently reduce ICP in rats. We used tissue sections and cell cultures to demonstrate expression of GLP-1R in the choroid plexus and its activation by exendin-4, an effect blocked by the GLP-1R antagonist exendin 9-39. Acute treatment with exendin-4 reduced Na⁺- and K⁺-dependent adenosine triphosphatase activity, a key regulator of CSF secretion, in cell cultures. Finally, we demonstrated that administration of exendin-4 to female rats with raised ICP (hydrocephalic) resulted in a GLP-1R–mediated reduction in ICP. These findings suggest that GLP-1R agonists can reduce ICP in rodents. Repurposing existing GLP-1R agonist drugs may be a useful therapeutic strategy for treating raised ICP.

目前在特发性颅内高压或脑积水等情况下降低颅内压（ICP）升高的疗法的疗效和耐受性有限。因此，迫切需要寻找替代药物。胰高血糖素样肽 1 受体 (GLP-1R) 激动剂用于治疗糖尿病和促进减肥，但也被证明会影响肾脏的液体稳态。我们研究了 GLP-1R 激动剂 exendin-4 是否能够调节脉络丛的脑脊液 (CSF) 分泌，从而降低大鼠的 ICP。我们使用组织切片和细胞培养物来证明 GLP-1R 在脉络丛中的表达及其被 exendin-4 的激活，而 exendin-4 的激活作用被 GLP-1R 拮抗剂 exendin 9-39 阻断。Exendin-4 的急性处理可降低细胞培养物中 Na ⁺和 K ⁺依赖性三磷酸腺苷酶的活性，腺苷三磷酸酶是脑脊液分泌的关键调节因子。最后，我们证明，对 ICP 升高（脑积水）的雌性大鼠施用 exendin-4 会导致 GLP-1R 介导的 ICP 降低。这些发现表明 GLP-1R 激动剂可以降低啮齿动物的 ICP。重新利用现有的 GLP-1R 激动剂药物可能是治疗 ICP 升高的有效治疗策略。