Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran.
Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran.
Toxicol Appl Pharmacol. 2021 Jul 15;423:115558. doi: 10.1016/j.taap.2021.115558. Epub 2021 May 4.
Studies argue in favor of hydrogen sulfide (HS) as the next potent therapeutic agent for neurodegenerative diseases. In present study, we investigated the effect of long term treatment with NaHS (as donor of HS) on induction and progress of the 6-hydroxydopamine (6-OHDA) -induced Parkinsonism in rat.
The 6-OHDA was injected into medial forebrain bundle of right hemisphere by stereotaxic surgery. Behavioral tests and treatments were carried out to eight weeks after the toxin. Immunohistochemistry and western blotting were carried out to evaluate the survival of tyrosine hydroxylase (TH) -positive neurons in substantia nigra (SN) and also expression of glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP), the markers of endoplasmic reticulum (ER) stress, in striatum and SN.
Eight weeks assessment of the behavioral symptoms showed that NaHS especially at dose of 100 μmol/kg attenuates remarkably induction of the Parkinsonism and prevents its progress. NaHS also increased the survival of TH- positive neurons and suppressed 6-OHDA- induced overexpression of GRP78 and CHOP. Blockade of ATP-sensitive potassium (K-ATP) channels with glibenclamide (Glib) prevented markedly the effect of NaHS on both the induction phase and survival of TH- positive neurons. But Glib did not affect the preventing effect of NaHS on the progress phase and its suppressing effect on the overexpression of ER stress markers.
HS attenuates induction of the 6-OHDA- induced Parkinsonism and also increases the survival of dopaminergic neurons through activation of K-ATP channels. HS also prevents progress of the Parkinsonism probably through suppression of ER stress.
有研究认为硫化氢（HS）可能成为治疗神经退行性疾病的新一代有效药物。本研究旨在探讨长期给予硫氢化钠（HS 的供体）对大鼠 6-羟多巴胺（6-OHDA）诱导帕金森病发病和进展的影响。
立体定向手术将 6-OHDA 注射至右侧大脑中动脉束。在毒素注射 8 周后进行行为学测试和治疗。免疫组织化学和 Western blot 检测黑质（SN）酪氨酸羟化酶（TH）阳性神经元的存活以及纹状体和 SN 中葡萄糖调节蛋白 78（GRP78）和 C/EBP 同源蛋白（CHOP）的表达，这两种蛋白均为内质网（ER）应激的标志物。
8 周的行为症状评估显示，硫氢化钠（尤其是 100μmol/kg 剂量）可显著减轻帕金森病的诱导作用，并阻止其进展。硫氢化钠还可增加 TH 阳性神经元的存活，并抑制 6-OHDA 诱导的 GRP78 和 CHOP 的过度表达。用格列本脲（Glib）阻断三磷酸腺苷敏感钾（K-ATP）通道可显著阻止硫氢化钠对诱导相和 TH 阳性神经元存活的作用。但 Glib 对硫氢化钠对进展相的预防作用及其对 ER 应激标志物过度表达的抑制作用无影响。
HS 通过激活 K-ATP 通道减轻 6-OHDA 诱导的帕金森病的诱导作用，并增加多巴胺能神经元的存活。HS 还可能通过抑制 ER 应激来阻止帕金森病的进展。
