Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
World-Class Research Center "Digital Biodesign and Personalized Healthcare", IM Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia.
Curr Neuropharmacol. 2022;20(10):1908-1924. doi: 10.2174/1570159X20666220302101854.
In view of the significant role of HS in brain functioning, it is proposed that HS may also possess protective effects against adverse effects of neurotoxicants. Therefore, the objective of the present review is to discuss the neuroprotective effects of HS against toxicity of a wide spectrum of endogenous and exogenous agents involved in the pathogenesis of neurological diseases as etiological factors or key players in disease pathogenesis. Generally, the existing data demonstrate that HS possesses neuroprotective effects upon exposure to endogenous (amyloid β, glucose, and advanced-glycation end-products, homocysteine, lipopolysaccharide, and ammonia) and exogenous (alcohol, formaldehyde, acrylonitrile, metals, 6-hydroxydopamine, as well as 1-methyl-4-phenyl- 1,2,3,6- tetrahydropyridine (MPTP) and its metabolite 1-methyl-4-phenyl pyridine ion (MPP)) neurotoxicants. On the one hand, neuroprotective effects are mediated by S-sulfhydration of key regulators of antioxidant (Sirt1, Nrf2) and inflammatory response (NF-κB), resulting in the modulation of the downstream signaling, such as SIRT1/TORC1/CREB/BDNF-TrkB, Nrf2/ARE/HO-1, or other pathways. On the other hand, HS appears to possess a direct detoxicative effect by binding endogenous (ROS, AGEs, Aβ) and exogenous (MeHg) neurotoxicants, thus reducing their toxicity. Moreover, the alteration of HS metabolism through the inhibition of HS-synthetizing enzymes in the brain (CBS, 3-MST) may be considered a significant mechanism of neurotoxicity. Taken together, the existing data indicate that the modulation of cerebral HS metabolism may be used as a neuroprotective strategy to counteract neurotoxicity of a wide spectrum of endogenous and exogenous neurotoxicants associated with neurodegeneration (Alzheimer's and Parkinson's disease), fetal alcohol syndrome, hepatic encephalopathy, environmental neurotoxicant exposure, etc. In this particular case, modulation of HS-synthetizing enzymes or the use of HS-releasing drugs should be considered as the potential tools, although the particular efficiency and safety of such interventions are to be addressed in further studies.
鉴于 HS 在大脑功能中的重要作用，有人提出 HS 可能对神经毒性物质的有害影响也具有保护作用。因此，本综述的目的是讨论 HS 对广泛的内源性和外源性神经毒性物质（作为神经退行性疾病发病机制的病因因素或关键参与者）毒性的神经保护作用。一般来说，现有数据表明，HS 具有暴露于内源性（淀粉样β、葡萄糖和晚期糖基化终产物、同型半胱氨酸、脂多糖和氨）和外源性（酒精、甲醛、丙烯腈、金属、6-羟多巴胺以及 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）及其代谢物 1-甲基-4-苯基吡啶离子（MPP））神经毒性物质时的神经保护作用。一方面，神经保护作用是通过抗氧化剂（Sirt1、Nrf2）和炎症反应（NF-κB）关键调节剂的 S-硫醇化介导的，从而调节下游信号，如 SIRT1/TORC1/CREB/BDNF-TrkB、Nrf2/ARE/HO-1 或其他途径。另一方面，HS 似乎通过与内源性（ROS、AGEs、Aβ）和外源性（MeHg）神经毒性物质结合而具有直接解毒作用，从而降低其毒性。此外，通过抑制大脑中 HS 合成酶（CBS、3-MST）改变 HS 代谢可能是一种重要的神经毒性机制。总之，现有数据表明，调节大脑 HS 代谢可以作为一种神经保护策略，以对抗与神经退行性变（阿尔茨海默病和帕金森病）、胎儿酒精综合征、肝性脑病、环境神经毒性物质暴露等相关的广泛内源性和外源性神经毒性物质的神经毒性。在这种特殊情况下，应考虑调节 HS 合成酶或使用释放 HS 的药物作为潜在工具，尽管需要进一步研究来确定此类干预措施的特定效率和安全性。
