College of Pharmacy, Department of Pharmacology and Toxicology, King Saud University, Riyadh, Saudi Arabia.
College of Pharmacy, Department of Pharmacology and Toxicology, King Saud University, Riyadh, Saudi Arabia.
Pharmacol Biochem Behav. 2020 Dec;199:173057. doi: 10.1016/j.pbb.2020.173057. Epub 2020 Oct 15.
Little is known about genetic and epigenetic alterations in autism spectrum disorder. Moreover, the efficiency of DNA repair in autism must be improved to correct these alterations. We examined whether 3-aminobenzamide (3-AB) could reverse these alterations. We conducted experiments to clarify the molecular mechanism underlying these ameliorations. An assessment of genetic and epigenetic alterations by a modified comet assay showed elevated levels of oxidative DNA strand breaks and DNA hypermethylation in BTBR TItpr3/J (BTBR) mice used as a model of autism. Oxidative DNA strand breaks and DNA methylation were further quantified fluorometrically, and the results showed similar changes. Conversely, 3-AB treated BTBR mice showed a significant reduction in these alterations compared with untreated mice. The expressions of 43 genes involved in DNA repair were altered in BTBR mice. RT Profiler PCR Array revealed significantly altered expression of seven genes, which was confirmed by RT-PCR analyses. 3-AB treatment relieved these disturbances and significantly improved Ogg1 and Rad1 up-regulation. Moreover, autism-like behaviors were also mitigated in BTBR animals by 3-AB treatment without alterations in locomotor activities. The simultaneous effects of reduced DNA damage and DNA methylation levels as well as the regulation of repair gene expression indicate the potential of 3-AB as a therapeutic agent to decrease the levels of DNA damage and DNA methylation in autistic patients. The current data may help in the development of therapies that ultimately provide a better quality of life for individuals suffering from autism.
关于自闭症谱系障碍中的遗传和表观遗传改变知之甚少。此外，必须提高自闭症患者的 DNA 修复效率，以纠正这些改变。我们研究了 3-氨基苯甲酰胺（3-AB）是否可以逆转这些改变。我们进行了实验以阐明这些改善的潜在分子机制。通过改良彗星试验评估遗传和表观遗传改变表明，BTBR TItpr3/J（BTBR）小鼠（用于自闭症模型）的氧化 DNA 链断裂和 DNA 超甲基化水平升高。通过荧光定量法进一步定量了氧化 DNA 链断裂和 DNA 甲基化，结果显示出相似的变化。相反，与未处理的小鼠相比，3-AB 处理的 BTBR 小鼠这些改变明显减少。BTBR 小鼠中涉及 DNA 修复的 43 个基因的表达发生改变。RT Profiler PCR 阵列显示 7 个基因的表达显著改变，通过 RT-PCR 分析得到了证实。3-AB 处理缓解了这些干扰，并显著改善了 Ogg1 和 Rad1 的上调。此外，3-AB 处理还减轻了 BTBR 动物的自闭症样行为，而运动活性没有改变。减少 DNA 损伤和 DNA 甲基化水平以及调节修复基因表达的同时作用表明 3-AB 作为一种治疗剂具有降低自闭症患者 DNA 损伤和 DNA 甲基化水平的潜力。目前的数据可能有助于开发最终为自闭症患者提供更好生活质量的治疗方法。
