Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India.
Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India.
Neuropeptides. 2022 Dec;96:102296. doi: 10.1016/j.npep.2022.102296. Epub 2022 Oct 20.
Autism is a neuropsychiatric disorder characterized by a neurotransmitter imbalance that impairs neurodevelopment processes. Autism development is marked by communication difficulties, poor socio-emotional health, and cognitive impairment. Insulin-like growth factor-1 (IGF-1) and glucagon-like growth factor-1 (GLP-1) are responsible for regular neuronal growth and homeostasis. Autism progression has been linked to dysregulation of IGF-1/GLP-1 signalling. 4-hydroxyisoleucine (HI), a pharmacologically active amino acid produced from Trigonella foenum graecum, works as an insulin mimic and has neuroprotective properties. The GLP-1 analogue liraglutide (LRG) was employed in our investigation to compare the efficacy of 4-HI in autism prevention. The current study explores the protective effects of 4-HI 50 and 100 mg/kg orally on IGF-1/GLP-1 signalling activation in a PPA-induced experimental model of autism. Propionic acid (PPA) injections to rats by intracerebroventricular (ICV) route for the first 11 days of the experiment resulted in autism-like neurobehavioral, neurochemical, gross morphological, and histopathological abnormalities. In addition, we investigated the dose-dependent neuroprotective effects of 4-HI on the levels of several neurotransmitters and neuroinflammatory cytokines in rat brain homogenate and blood plasma. Neuronal apoptotic and anti-oxidant cellular markers were also studied in blood plasma and brain homogenate samples. Furthermore, the luxol fast blue (LFB) staining results demonstrated significant demyelination in the brains of PPA-induced rats reversed by 4-HI treatment. Rats were assessed for spontaneous locomotor impairments, neuromuscular coordination, stress-like behaviour, learning, and memory to assess neurobehavioral abnormalities. The administration of 4-HI and LRG significantly reversed the behavioural, gross and histological abnormalities in the PPA-treated rat brains. After treatment with 4-HI and LRG, LFB-stained photomicrographs of PPA-treated rats' brains demonstrated the recovery of white matter loss. Our findings indicate that 4-HI protects neurons in rats with autism by enhancing the IGF-1 and GLP-1 protein levels.
自闭症是一种神经精神疾病，其特征是神经递质失衡，损害神经发育过程。自闭症的发展表现为沟通困难、社会情感健康不良和认知障碍。胰岛素样生长因子-1（IGF-1）和胰高血糖素样肽-1（GLP-1）负责神经元的正常生长和内稳。自闭症的发展与 IGF-1/GLP-1 信号的失调有关。4-羟基异亮氨酸（HI）是从三叶草属植物中产生的一种具有药理活性的氨基酸，可作为胰岛素模拟物，具有神经保护特性。我们的研究中使用了 GLP-1 类似物利拉鲁肽（LRG）来比较 4-HI 在自闭症预防中的功效。本研究探讨了 4-HI 50 和 100mg/kg 口服对 PPA 诱导的自闭症实验模型中 IGF-1/GLP-1 信号激活的保护作用。通过脑室内（ICV）途径向大鼠注射丙酸（PPA），在实验的前 11 天导致自闭症样神经行为、神经化学、大体形态和组织病理学异常。此外，我们还研究了 4-HI 对大鼠脑匀浆和血浆中几种神经递质和神经炎症细胞因子水平的剂量依赖性神经保护作用。还研究了血浆和脑匀浆样本中神经元凋亡和抗氧化细胞标志物。此外，洛索夫快速蓝（LFB）染色结果表明，PPA 诱导的大鼠大脑中的脱髓鞘显著逆转，逆转由 4-HI 处理。通过评估大鼠的自发运动障碍、神经肌肉协调、应激样行为、学习和记忆，评估神经行为异常。4-HI 和 LRG 的给药显著逆转了 PPA 处理大鼠大脑中的行为、大体和组织学异常。用 4-HI 和 LRG 处理后，PPA 处理大鼠大脑 LFB 染色的照片显示白质损失得到恢复。我们的研究结果表明，4-HI 通过增强 IGF-1 和 GLP-1 蛋白水平来保护自闭症大鼠的神经元。
