Mușat Mădălina Iuliana, Ifrim-Predoi Ana-Maria, Mitran Smaranda Ioana, Osiac Eugen, Cătălin Bogdan
Experimental Research Centre for Normal and Pathological Aging, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania.
Department of Surgery, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania.
Int J Mol Sci. 2025 Apr 10;26(8):3558. doi: 10.3390/ijms26083558.
Non-alcoholic fatty liver disease (NAFLD) has been associated with depression and inadequate response to antidepressants. While ketamine has demonstrated efficacy in treating depression, its impact on pre-existing liver injury and depression remains unclear. This study aimed to evaluate the effects of ketamine treatment in a murine model of depression and liver damage, considering age-related differences. Young and aged male C57BL/6N mice were submitted to chronic unpredictable mild stress (CUMS) and methionine-choline-deficient (MCD) diet to induce depressive-like behavior and NAFLD. Behavioral testing (sucrose preference test, open field test, novel object recognition test, Crawley's sociability test) were used to assess ketamine's (50 mg/kg) effect on behavior. Hepatic ultrasonography was utilized to evaluate liver status. The cortical and hippocampal NeuN+, GFAP+, and Iba1+ signals were quantified for each animal. Ketamine administration proved effective in relieving anhedonia and anxiety-like behavior, regardless of liver damage. Although ketamine treatment did not improve memory in animals with liver damage, it enhanced sociability, particularly in aged subjects. The acute administration of ketamine did not affect the severity of liver injury, but seems to affect astrogliosis and neuronal loss. Although animal models of depression only replicate certain clinical features of the condition, they remain valuable for evaluating the complex and varied effects of ketamine. By applying such models, we could demonstrate ketamine's therapeutic versatility, and also indicate that responses to the treatment may differ across different age groups.
非酒精性脂肪性肝病（NAFLD）与抑郁症以及对抗抑郁药反应不足有关。虽然氯胺酮已证明对治疗抑郁症有效，但其对已存在的肝损伤和抑郁症的影响仍不清楚。本研究旨在评估氯胺酮治疗对抑郁症和肝损伤小鼠模型的影响，并考虑年龄相关差异。将年轻和老年雄性C57BL/6N小鼠置于慢性不可预测轻度应激（CUMS）和蛋氨酸-胆碱缺乏（MCD）饮食中，以诱导抑郁样行为和NAFLD。行为测试（蔗糖偏好测试、旷场测试、新物体识别测试、克劳利社交能力测试）用于评估氯胺酮（50 mg/kg）对行为的影响。利用肝脏超声评估肝脏状态。对每只动物的皮质和海马NeuN+、GFAP+和Iba1+信号进行定量。无论肝损伤情况如何，氯胺酮给药均被证明可有效缓解快感缺失和焦虑样行为。虽然氯胺酮治疗并未改善肝损伤动物的记忆力，但增强了社交能力，尤其是在老年受试者中。氯胺酮的急性给药并未影响肝损伤的严重程度，但似乎影响星形胶质细胞增生和神经元丢失。虽然抑郁症动物模型仅复制了该疾病的某些临床特征，但它们对于评估氯胺酮的复杂多样作用仍然很有价值。通过应用此类模型，我们可以证明氯胺酮的治疗多功能性，并且还表明不同年龄组对该治疗的反应可能不同。
