Khalid Iqra, Saleem Uzma, Ahmad Bashir, Hawwal Mohammed F, Mothana Ramzi A
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan.
Welsh School of Pharmacy, University of Wales, Cardiff, United Kingdom.
Saudi Pharm J. 2024 Apr;32(4):101994. doi: 10.1016/j.jsps.2024.101994. Epub 2024 Feb 15.
Schizophrenia, a global mental health disorder affecting approximately 1 % of the population, is characterized by neurotransmitter dysregulation, particularly dopamine, serotonin, and glutamate. Current antipsychotic therapies, despite their efficacy, are accompanied by adverse effects, which has motivated researchers to investigate more secure substitutes. This study examines the potential antipsychotic effects of esculetin, a natural coumarin derivative recognized for its wide-ranging pharmacological activities (anti-inflammatory, antioxidant, anti-pathogenic, anticancer, and neuroprotective), in animal model of schizophrenia induced by ketamine. In order to induce disease, acute and chronic ketamine administration was performed on Swiss albino mice, supplemented with esculetin (as the test substance) and clozapine (as the reference standard). Behavioral studies and biochemical assays were performed to evaluate positive, negative, and cognitive symptoms of schizophrenia, as well as antioxidant and oxidant levels in various brain regions. Esculetin demonstrated significant improvements in behavioral symptoms, attenuated oxidative stress and neuroinflammation, and modulated neurotransmitter levels. Afterwards, ELISA was performed to evaluate levels of schizophrenia biomarkers AChE, BDNF. Moreover, proinflammatory cytokines (IL-6 and TNF-α) and NF-κB were also determined. Histopathological parameters of under study brain parts i.e., hippocampus, cortex and striata were also assessed. Esculetin and clozapine significantly (*** < 0.0001) altered ketamine induced behavioral symptoms and attenuated ketamine induced oxidative stress and neuroinflammation. Additionally, esculetin significantly (*** < 0.0001) altered neurotransmitter (dopamine, serotonin, glutamate) levels. ELISA analysis depicts ketamine reduced BDNF levels in hippocampus, cortex and striata while esculetin significantly (*** < 0.0001) increased BDNF levels in under study three parts of brain. Histopathological changes were seen in test groups. The findings of this study indicate that esculetin may have therapeutic potential in the treatment of schizophrenia induced by ketamine. As a result, esculetin may have the potential to be utilized as a treatment for schizophrenia.
精神分裂症是一种影响全球约1%人口的精神健康障碍，其特征是神经递质失调，尤其是多巴胺、血清素和谷氨酸。目前的抗精神病药物疗法尽管有效，但会伴有不良反应，这促使研究人员去研究更安全的替代药物。本研究在氯胺酮诱导的精神分裂症动物模型中，考察了七叶亭（一种因其广泛药理活性而闻名的天然香豆素衍生物，具有抗炎、抗氧化、抗病原体、抗癌和神经保护作用）的潜在抗精神病作用。为了诱发疾病，对瑞士白化小鼠进行急性和慢性氯胺酮给药，并补充七叶亭（作为受试物质）和氯氮平（作为参考标准品）。进行行为学研究和生化分析，以评估精神分裂症的阳性、阴性和认知症状，以及不同脑区的抗氧化和氧化水平。七叶亭在行为症状方面有显著改善，减轻了氧化应激和神经炎症，并调节了神经递质水平。之后，进行酶联免疫吸附测定（ELISA）以评估精神分裂症生物标志物乙酰胆碱酯酶（AChE）、脑源性神经营养因子（BDNF）的水平。此外，还测定了促炎细胞因子（白细胞介素-6和肿瘤坏死因子-α）和核因子-κB。还评估了所研究脑区（即海马体、皮层和纹状体）的组织病理学参数。七叶亭和氯氮平显著（<0.0001）改变了氯胺酮诱导的行为症状，并减轻了氯胺酮诱导的氧化应激和神经炎症。此外，七叶亭显著（<0.0001）改变了神经递质（多巴胺、血清素、谷氨酸）水平。ELISA分析表明，氯胺酮降低了海马体、皮层和纹状体中的BDNF水平，而七叶亭显著（***<0.0001）提高了所研究的三个脑区中的BDNF水平。在试验组中观察到了组织病理学变化。本研究结果表明，七叶亭在治疗氯胺酮诱导的精神分裂症方面可能具有治疗潜力。因此，七叶亭可能有潜力被用作精神分裂症的一种治疗药物。
