肝性脑病(HE)是一种神经精神病综合征,在患有严重肝功能障碍和/或门腔分流的患者中发展。尽管对肝脏损害与脑病发展之间的关系进行了一个多世纪的研究,肝性脑病的发病机制尚未完全阐明。人们普遍承认,然而,肝性脑病神经系统并发症的主要触发因素是神经毒素氨/铵,其在血液中的浓度增加到毒性水平(高氨血症),当肝脏的排毒功能受损时。自由穿透脑细胞并影响NMDA受体介导的信号传导,氨引发病理性级联,导致有氧葡萄糖代谢的急剧抑制,氧化应激,脑灌注不足,神经细胞损伤,和神经缺陷的形成。脑灌注不足,反过来,可能是由于红细胞的氧转运功能受损,由于细胞膜和红细胞内部的能量代谢受到干扰,并控制血红蛋白对氧的亲和力,这决定了血液和组织的氧合程度。在我们最近的研究中,证实了这种因果关系,并揭示了由NMDA受体过度激活介导的新型铵诱导的促氧化剂效应,从而导致红细胞的氧转运功能受损.为了更完整地评估减少脑氧合并导致脑病的“红细胞”因素,在这项研究中,糖酵解和Rapoport-Lubering分流的酶活性和代谢物浓度,测定急性高氨血症大鼠红细胞的形态学特征。为了阐明NMDA受体在上述过程中的作用,MK-801,一种非竞争性受体拮抗剂,被使用。根据获得的结果,可以得出结论,有必要考虑铵诱导的红细胞形态功能紊乱和血红蛋白血症,这可能是由于高度整合的代谢途径网络的改变而发生的,可能是一个额外的全身性“红细胞”致病因子,以防止伴有高氨血症的肝性脑病的脑灌注不足的发作和进展。
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that develops in patients with severe liver dysfunction and/or portocaval shunting. Despite more than a century of research into the relationship between liver damage and development of encephalopathy, pathogenetic mechanisms of hepatic encephalopathy have not yet been fully elucidated. It is generally recognized, however, that the main trigger of neurologic complications in hepatic encephalopathy is the neurotoxin ammonia/ammonium, concentration of which in the blood increases to toxic levels (hyperammonemia), when detoxification function of the liver is impaired. Freely penetrating into brain cells and affecting NMDA-receptor-mediated signaling, ammonia triggers a pathological cascade leading to the sharp inhibition of aerobic glucose metabolism, oxidative stress, brain hypoperfusion, nerve cell damage, and formation of neurological deficits. Brain hypoperfusion, in turn, could be due to the impaired oxygen transport function of erythrocytes, because of the disturbed energy metabolism that occurs in the membranes and inside erythrocytes and controls affinity of hemoglobin for oxygen, which determines the degree of oxygenation of blood and tissues. In our recent study, this causal relationship was confirmed and novel ammonium-induced pro-oxidant effect mediated by excessive activation of NMDA receptors leading to impaired oxygen transport function of erythrocytes was revealed. For a more complete evaluation of \"erythrocytic\" factors that diminish brain oxygenation and lead to encephalopathy, in this study, activity of the enzymes and concentration of metabolites of glycolysis and Rapoport-Lubering shunt, as well as morphological characteristics of erythrocytes from the rats with acute hyperammoniemia were determined. To elucidate the role of NMDA receptors in the above processes, MK-801, a non-competitive receptor antagonist, was used. Based on the obtained results it can be concluded that it is necessary to consider ammonium-induced morphofunctional disorders of erythrocytes and hemoglobinemia which can occur as a result of alterations in highly integrated networks of metabolic pathways may act as an additional systemic \"erythrocytic\" pathogenetic factor to prevent the onset and progression of cerebral hypoperfusion in hepatic encephalopathy accompanied by hyperammonemia.