Frick M A, Woodruff J L, Caudillo Y M, Pikel K E, Rehm J V, Maciejewska N, Grillo C A, Reagan L P, Fadel J R
Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina, USA.
Columbia VA Health Care System, Columbia, South Carolina, USA.
J Neurochem. 2025 Aug;169(8):e70175. doi: 10.1111/jnc.70175.
Neuroinflammation has emerged as a contributing mechanism in age-related cognitive decline (ARCD), Parkinson's disease (PD), obesity, sleep disorders, and autoimmune disorders. Orexin/hypocretin, a neuropeptide expressed in the lateral hypothalamus (LH), has well-established roles in homeostatic processes, such as energy metabolism, food intake, sleep, and wakefulness. Our laboratory and others have shown that orexin expression decreases with age, and this age-related orexin decline is exacerbated in disease states. Additionally, it has recently been shown that orexin possesses anti-inflammatory and neuroprotective properties. Based on these observations, we hypothesize that orexin is modulating neuroinflammation in brain regions that are critical in the development of ARCD. To test this hypothesis, we used lentiviral gene transfer to downregulate orexin expression in male and female young rats to mimic age-related orexin deficiency and examined neuroinflammatory responses to peripheral administration of lipopolysaccharide (LPS). We found a significant reduction of basal forebrain (BF) microglial complexity and plasma BDNF in both males and females following orexin downregulation. Notably, orexin downregulation blocked the capacity of the neuroinflammatory system to respond to LPS. These results demonstrate that neuroinflammatory responses are dependent on orexin signaling, and this system becomes dysfunctional in aging in a sex-dependent manner.
神经炎症已成为与年龄相关的认知衰退（ARCD）、帕金森病（PD）、肥胖、睡眠障碍和自身免疫性疾病的一种促成机制。食欲素/下丘脑泌素是一种在下丘脑外侧（LH）表达的神经肽，在能量代谢、食物摄入、睡眠和觉醒等稳态过程中具有既定作用。我们实验室和其他研究表明，食欲素表达随年龄增长而降低，且在疾病状态下，这种与年龄相关的食欲素下降会加剧。此外，最近有研究表明食欲素具有抗炎和神经保护特性。基于这些观察结果，我们推测食欲素正在调节对ARCD发展至关重要的脑区中的神经炎症。为了验证这一假设，我们使用慢病毒基因转移来下调雄性和雌性幼鼠的食欲素表达，以模拟与年龄相关的食欲素缺乏，并研究对脂多糖（LPS）外周给药的神经炎症反应。我们发现，食欲素下调后，雄性和雌性大鼠的基底前脑（BF）小胶质细胞复杂性和血浆脑源性神经营养因子（BDNF）均显著降低。值得注意的是，食欲素下调阻断了神经炎症系统对LPS的反应能力。这些结果表明，神经炎症反应依赖于食欲素信号传导，并且该系统在衰老过程中以性别依赖的方式功能失调。
