3- Bromopyruvate, a caloric restriction mimetic, exerts a mitohormetic effect to provide neuroprotection through activation of autophagy in rats during aging

In the present study, attempts have been made to evaluate the potential role of 3 Bromopyruvate (3-BP) a glycolytic inhibitor and a caloric restriction mimetic (CRM), to exert neuroprotection in rats during aging through modulation of autophagy. Young male rats (4 months), and naturally aged (22 months) male rats were supplemented with 3-BP (30 mg/kg b.w., orally) for 28 Daysdays. Concomitantly, oOur dataResults demonstrated decreased levela significant increase in the antioxidant biomarkers (ferric reducing antioxidant potential level, total thiol, superoxide dismutase and catalase activities) and decrease in the level of pro-oxidant biomarkers such as protein carbonyl after 3-BP supplementation in brain tissues. A significant increase in reactive oxygen species (ROS) was observed due to the mitohormetic effect of 3-BP supplementation in the treated rats. Furthermore, the 3-BP treatment also enhanced the activities of electron transport chain complexes I and IV in aged brain mitochondria thus proving its antioxidant potential at the level of mitochondria. Gene expression analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess the expression of autophagy, neuroprotective and aging marker genes. RT-PCR data revealed that 3-BP up-regulated the expression of autophagy markers genes (Beclin-1 and LC3 β), sirtuin-1, and neuronal marker gene (NSE), respectively in the aging brain. The results suggest that 3-BP induces a mitohormetic effect through the elevation of ROS which reinforces defensive mechanism(s) targeted at regulating autophagy. These findings suggest that consistently low-dose 3-BP may be beneficial for neuroprotection during aging and age-related disorders.

在本研究中，研究者们尝试评估3-溴丙酮酸（3-BP），一种糖酵解抑制剂和热量限制模拟剂（CRM），通过调节自噬作用，在老年大鼠中发挥神经保护作用的潜在作用。将年轻雄性大鼠（4个月大）和自然老化雄性大鼠（22个月大）分别以口服方式补充3-BP（30 mg/kg 体重，持续28天）。研究结果显示，在3-BP补充后，大脑组织中抗氧化生物标志物（如铁离子还原抗氧化能力、总硫醇、超氧化物歧化酶和过氧化氢酶活性）水平显著升高，而促氧化生物标志物（如蛋白质羰基）水平则有所下降。由于3-BP补充剂的线粒体激素效应，观察到处理组大鼠中活性氧（ROS）水平显著增加。此外，3-BP处理还增强了老年大脑线粒体中电子传递链复合物I和IV的活性，从而证实了其在线粒体水平上的抗氧化潜力。通过逆转录聚合酶链反应（RT-PCR）进行基因表达分析，以评估自噬、神经保护和衰老标志基因的表达。RT-PCR数据揭示，3-BP分别在老化大脑中上调了自噬标记基因（Beclin-1和LC3β）、Sirtuin-1以及神经元标记基因（NSE）的表达。这些结果表明，3-BP通过提高ROS水平，从而增强针对调节自噬的防御机制，诱导线粒体激素效应。这些发现表明，持续的低剂量3-BP可能对老年期神经保护和与年龄相关的疾病有益。