Department of Pharmacology, Federal University of Paraná, Curitiba, PR, Brazil.
Department of Pharmacology, Federal University of Paraná, Curitiba, PR, Brazil.
Int Immunopharmacol. 2023 Oct;123:110745. doi: 10.1016/j.intimp.2023.110745. Epub 2023 Aug 2.
Sepsis is associated with several comorbidities in survivors, such as posttraumatic stress disorder (PTSD). This study investigated whether rats that survive sepsis develop the generalization of fear memory as a model of PTSD. Responses to interventions that target the endothelin-1 (ET-1)/cannabinoid system and glial activation in the initial stages of sepsis were evaluated. As a control, we evaluated hyperalgesia before fear conditioning. Sepsis was induced by cecal ligation and puncture (CLP) in Wistar rats. CLP-induced sepsis with one or three punctures resulted in fear generalization in the survivors 13 and 20 days after the CLP procedure, a process that was not associated with hyperalgesia. Septic animals were intracerebroventricularly treated with vehicle, the endothelin receptor A (ET) antagonist BQ123, the cannabinoid CB and CB receptor antagonists AM251 and AM630, respectively, and the glial blocker minocycline 4 h after CLP. The blockade of either CB or ET receptors increased the survival rate, but only the former reversed fear memory generalization. The endothelinergic system blockade is important for improving survival but not for fear memory. Treatment with the CB receptor antagonist or minocycline also reversed the generalization of fear memory but did not increase the survival rate that was associated with CLP. Minocycline treatment also reduced tumor necrosis factor-α levels in the hippocampus suggesting that neuroinflammation is important for the generalization of fear memory induced by CLP. The influence of CLP on the generalization of fear memory was not related to Arc protein expression, a regulator of synaptic plasticity, in the dorsal hippocampus.
败血症与幸存者的多种合并症有关，如创伤后应激障碍（PTSD）。本研究探讨了败血症存活大鼠是否会发展出恐惧记忆泛化，作为 PTSD 的模型。评估了针对败血症初始阶段内皮素-1（ET-1）/大麻素系统和神经胶质激活的干预措施的反应。作为对照，我们在恐惧条件之前评估了痛觉过敏。通过盲肠结扎和穿孔（CLP）在 Wistar 大鼠中诱导败血症。CLP 诱导的败血症，一次或三次穿孔，导致幸存者在 CLP 手术后 13 天和 20 天出现恐惧泛化，这一过程与痛觉过敏无关。在 CLP 后 4 小时，对败血症动物进行脑室内给予载体、内皮素受体 A（ET）拮抗剂 BQ123、大麻素 CB 和 CB 受体拮抗剂 AM251 和 AM630 以及神经胶质阻滞剂米诺环素治疗。阻断 CB 或 ET 受体均可提高存活率，但只有前者可逆转恐惧记忆泛化。内皮素能系统阻断对于提高存活率很重要，但对于恐惧记忆则不然。CB 受体拮抗剂或米诺环素治疗也可逆转恐惧记忆泛化，但不会增加与 CLP 相关的存活率。米诺环素治疗还降低了海马中的肿瘤坏死因子-α 水平，表明神经炎症对于 CLP 诱导的恐惧记忆泛化很重要。CLP 对恐惧记忆泛化的影响与背侧海马中的 Arc 蛋白表达无关，Arc 蛋白是突触可塑性的调节因子。
