Comparative Neuroanatomy Laboratory, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, Ponte Pietro Bucci 4B, Arcavacata di Rende, 87030 Cosenza, Italy.
Department of Health Sciences, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy; System and Applied Pharmacology@University Magna Grecia, 88100 Catanzaro, Italy.
Prog Neuropsychopharmacol Biol Psychiatry. 2024 Dec 20;135:111131. doi: 10.1016/j.pnpbp.2024.111131. Epub 2024 Aug 30.
Chromogranin A (CgA), a ∼ 49 kDa acidic secretory protein, is ubiquitously distributed in endocrine and neuroendocrine cells and neurons. As a propeptide, CgA is proteolytically cleaved to generate several peptides of biological importance, including pancreastatin (PST: hCgA), Vasostatin 1 (VS1: hCgA), and catestatin (CST: CgA ). VS1 represents the most conserved fragment of CgA. A 20 amino acid domain within VS1 (CgA 47-66) exhibits potent antimicrobial and anti-inflammatory activities. Autism is known to be associated with inflammation. Therefore, we seek to test the hypothesis that VS1 modulates autism behaviors by reducing inflammation in the hippocampus. Treatment of C57BL/6 (B6) and BTBR (a mouse model of idiopathic autism) mice with VS1 revealed the following: BTBR mice showed a significant decrease in chamber time in the presence of a stranger or a novel object. Treatment with VS1 significantly increased chamber time in both cases, underscoring a crucial role for VS1 in improving behavioral deficits in BTBR mice. In contrast to chamber time, sniffing time in BTBR mice in the presence of a stranger was less compared to B6 control mice. VS1 did not improve this latter parameter. Surprisingly, sniffing time in BTBR mice in the presence of a novel object was comparable with B6 mice. Proinflammatory cytokines such as IL-6 and IL-1b, as well as other inflammatory markers, were elevated in BTBR mice, which were dramatically reduced after supplementation with VS1. Interestingly, even Beclin-1/p62, pAKT/AKT, and p-p70-S6K/p70-S6K ratios were notably reduced by VS1. We conclude that VS1 plays a crucial role in restoring autistic spectrum disorders (ASD) plausibly by attenuating neuroinflammation.
嗜铬粒蛋白 A（CgA）是一种∼49kDa 的酸性分泌蛋白，广泛分布于内分泌和神经内分泌细胞和神经元中。作为前肽，CgA 经蛋白水解切割生成几种具有生物学重要性的肽，包括胰泌素（PST：hCgA）、Vasostatin 1（VS1：hCgA）和 Catestatin（CST：CgA）。VS1 代表 CgA 中最保守的片段。VS1 内的一个 20 个氨基酸结构域（CgA 47-66）具有强大的抗菌和抗炎活性。自闭症已知与炎症有关。因此，我们试图通过检测海马体炎症水平来验证 VS1 通过降低炎症来调节自闭症行为的假说。用 VS1 处理 C57BL/6（B6）和 BTBR（自闭症的一种自发性模型）小鼠，结果显示：BTBR 小鼠在有陌生人和新物体时，在箱体内的时间明显减少。VS1 治疗后，两种情况下箱体内时间均显著增加，这表明 VS1 对改善 BTBR 小鼠的行为缺陷具有重要作用。与箱体内时间相反，BTBR 小鼠在有陌生人和新物体时的嗅探时间与 B6 对照小鼠相比减少。VS1 不能改善这一参数。令人惊讶的是，BTBR 小鼠在有新物体时的嗅探时间与 B6 小鼠相当。BTBR 小鼠的促炎细胞因子如 IL-6 和 IL-1b 以及其他炎症标志物升高，而补充 VS1 后这些标志物显著降低。有趣的是，甚至 Beclin-1/p62、pAKT/AKT 和 p-p70-S6K/p70-S6K 比值也明显降低。我们得出结论，VS1 通过减轻神经炎症，在恢复自闭症谱系障碍（ASD）方面发挥着关键作用。
