Time- and region-specific effects of intranasal insulin on oxidative stress parameters in the rat brain

Understanding how intranasal insulin affects brain signaling and metabolism is essential for elucidating its therapeutic potential in neurodegenerative disorders with underlying metabolic dysfunction, such as Alzheimer’s disease (AD). Oxidative stress, which increases with aging, has been observed in both AD and type 2 diabetes, indicating a potential link between oxidative stress, brain insulin resistance and cognitive impairment. This study aimed to investigate the effect of intranasal insulin on the redox potential in a brain region- and time- dependent manner. Male Wistar rats received 2 IU of regular insulin intranasally and were sacrificed 3, 7.5, 15, 30, 60, and 120 minutes after administration. Six animals served as intact control. Redox homeostasis was assessed by measuring lipid peroxidation, total reductive capacity, concentrations of free thiol groups and low-molecular-weight thiols, and superoxide dismutase activity in plasma, nasal epithelia, and brain regions. The results were correlated with insulin signaling analyses from the same samples. Intranasal insulin induced rapid but highly heterogeneous redox responses. The most pronounced alterations occurred in nasal epithelia, where respiratory and olfactory regions exhibited distinct and opposing redox profiles. In the brain, redox responses varied markedly across regions, with the most prominent alterations involving thiol parameters in the cortices, hippocampus, hypothalamus, olfactory bulb, and cerebellum. Plasma redox parameters remained largely unchanged, supporting the predominantly central action of intranasally delivered insulin. Correlation analyses revealed associations between oxidative stress markers and insulin signaling parameters, suggesting complex interactions between metabolic signaling pathways and redox regulation. These findings demonstrate that intranasal insulin modulates redox homeostasis in a rapid, region-specific, and time-dependent manner, highlighting the importance of spatial and temporal factors in insulin-mediated regulation of brain oxidative balance.

阐明鼻内胰岛素在伴代谢功能异常的神经退行性疾病（如阿尔茨海默病，AD）中的治疗潜力，需先明确其对大脑信号传导与代谢的调控作用。随衰老进程加剧的氧化应激已在阿尔茨海默病与2型糖尿病中被观测到，提示氧化应激、脑胰岛素抵抗与认知损伤之间存在潜在关联。本研究旨在探究鼻内胰岛素以脑区特异性与时间依赖性方式对氧化还原电位的调控作用。雄性Wistar大鼠经鼻给予2 IU常规胰岛素，分别于给药后3、7.5、15、30、60及120分钟处死取材；另设6只大鼠作为空白对照组。通过检测血浆、鼻上皮及各脑区的脂质过氧化水平、总还原能力、游离巯基与低分子量巯基浓度，以及超氧化物歧化酶活性，评估其氧化还原稳态状态，并将检测结果与同一样本的胰岛素信号通路分析结果进行关联。实验结果显示，鼻内胰岛素可诱导快速但具有高度异质性的氧化还原应答反应。其中鼻上皮的变化最为显著，其呼吸区与嗅觉区呈现出截然不同且方向相反的氧化还原特征。在大脑中，不同脑区的氧化还原应答差异显著，大脑皮层、海马体、下丘脑、嗅球及小脑的巯基相关参数变化最为突出。血浆氧化还原参数基本未发生明显变化，佐证了经鼻给药的胰岛素主要发挥中枢调控作用。相关性分析显示，氧化应激标志物与胰岛素信号通路参数之间存在关联，提示代谢信号通路与氧化还原调控之间存在复杂的相互作用。本研究结果证实，鼻内胰岛素可通过快速、脑区特异性且时间依赖性的方式调控氧化还原稳态，凸显了时空因素在胰岛素介导的大脑氧化平衡调控中的重要意义。