Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia; Clinical Laboratory Science Section, Institute of Medical Science Technology, Universiti Kuala Lumpur, Kajang, Selangor Darul Ehsan 43000, Malaysia.
Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia.
Biomed Pharmacother. 2024 Jun;175:116729. doi: 10.1016/j.biopha.2024.116729. Epub 2024 May 21.
Type 2 diabetes (T2D) with depression causes severe cognitive impairments. The devastating conditions will further compromise the overall quality of life. The overconsumption of high-fat and high-sucrose (HFS) diet is one of the modifiable risk factors for T2D, depression, and cognitive impairments. Thus, it is essential to identify effective therapeutic strategies to overcome the cognitive impairments in T2D with depression. We proposed environmental enrichment (EE) which encompasses social, cognitive, and physical components as the alternative treatment for such impairments. We also investigated the potential neuroprotective properties of the antidiabetic drug metformin. This study aimed to investigate the effects of EE and metformin interventions on hippocampal neuronal death, and hippocampal-dependent memory impairment in T2D rats under stress.
Thirty-two male rats (200-250 g) were divided into four groups: C group (standard diet + conventional cage), DS group [HFS-induced T2D + restraint stress (RS)], DSE group [HFS-induced T2D + RS + EE] and DSEM group [HFS + RS + EE + metformin]. Serum corticosterone (CORT) was measured to evaluate stress levels. The serum Free Oxygen Radicals Testing (FORT) and Free Oxygen Radicals Defence Test (FORD) were measured to evaluate the systemic oxidative status (OS). Serum brain-derived neurotrophic factor (BDNF) and T-maze tasks were performed to evaluate cognitive functions. Rats were humanely sacrificed to collect brains for histological, morphometric, and hippocampal gene expression studies.
The CORT and the serum FORT levels in the DSE and DSEM groups were lower than in the DS group. Meanwhile, the serum BDNF, T-maze scores, histological, and morphometric analysis were improved in the DSE and DSEM groups than in the DS group. These findings supported that EE and the combined interventions of EE and metformin had neuroprotective properties. The hippocampal gene expression analysis revealed that the DSE and DSEM groups showed improved regulation of BDNF-TrkB signalling pathways, including the BDNF/TrkB binding, PI3K - Akt pathway, Ras-MAPK pathway, PLCγ-Ca2+ pathway, and CREB transcription.
EE and the combined interventions of EE and metformin improved hippocampal neuron survival and hippocampal-dependent memory in T2D rats under stress by enhancing gene expression regulation of neurogenesis and synaptic plasticity.
患有抑郁症的 2 型糖尿病（T2D）会导致严重的认知障碍。这些灾难性的情况将进一步降低整体生活质量。过度摄入高脂肪和高蔗糖（HFS）饮食是 T2D、抑郁症和认知障碍的可改变的危险因素之一。因此，确定有效的治疗策略来克服 T2D 伴发的认知障碍非常重要。我们提出环境丰富（EE），它包含社会、认知和身体成分，作为治疗这种障碍的替代方法。我们还研究了抗糖尿病药物二甲双胍的潜在神经保护特性。本研究旨在探讨 EE 和二甲双胍干预对压力下 T2D 大鼠海马神经元死亡和海马依赖性记忆损伤的影响。
32 只雄性大鼠（200-250g）分为四组：C 组（标准饮食+常规笼）、DS 组[HFS 诱导的 T2D+束缚应激（RS）]、DSE 组[HFS 诱导的 T2D+RS+EE]和 DSEM 组[HFS+RS+EE+二甲双胍]。测量血清皮质酮（CORT）评估应激水平。测量血清游离氧自由基测试（FORT）和游离氧自由基防御测试（FORD）评估系统氧化状态（OS）。进行血清脑源性神经营养因子（BDNF）和 T 迷宫任务评估认知功能。人道处死大鼠收集大脑进行组织学、形态计量学和海马基因表达研究。
DSE 和 DSEM 组的 CORT 和血清 FORT 水平低于 DS 组。同时，DSE 和 DSEM 组的血清 BDNF、T 迷宫评分、组织学和形态计量学分析均优于 DS 组。这些发现支持 EE 和 EE 联合干预具有神经保护作用。海马基因表达分析显示，DSE 和 DSEM 组改善了 BDNF-TrkB 信号通路的调节，包括 BDNF/TrkB 结合、PI3K-Akt 通路、Ras-MAPK 通路、PLCγ-Ca2+通路和 CREB 转录。
EE 和 EE 联合干预通过增强神经发生和突触可塑性的基因表达调节，改善了应激下 T2D 大鼠的海马神经元存活和海马依赖性记忆。
