Programa de Pós-Graduação Em Ciências Farmacêuticas, Universidade Federal Do Rio Grande Do Sul, Avenida Ipiranga, 2752, CEP 90610-000, Porto Alegre, RS, Brazil; Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350, CEP 90035-003, Porto Alegre, RS, Brazil.
Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350, CEP 90035-003, Porto Alegre, RS, Brazil.
Arch Biochem Biophys. 2023 Nov;749:109792. doi: 10.1016/j.abb.2023.109792. Epub 2023 Oct 18.
Phenylketonuria (PKU) is the most common inherited metabolic disorders caused by severe deficiency or absence of phenylalanine hydroxylase activity that converts phenylalanine (Phe) to tyrosine. PKU patients were treated with a Phe restricted diet supplemented with a special formula containing l-carnitine (L-car), well-known antioxidant compound. The lack of treatment can cause neurological and cognitive impairment, as severe mental retardation, neuronal cell loss and synaptic density reduction. Although Phe has been widely demonstrated to be involved in PKU neurotoxicity, the mechanisms responsible for the CNS injury are still not fully known. In this work, we evaluated markers of neurodegeneration, namely BDNF (brain-derived neurotrophic factor), PAI-1 total (Plasminogen activator inhibitor-1 total), Cathepsin D, PDGF AB/BB (platelet-derived growth factor), and NCAM (neuronal adhesion molecule) in plasma of PKU patients at early and late diagnosis and under treatment. We found decreased Phe levels and increased L-car concentrations in PKU patients treated with L-car compared to the other groups, indicating that the proposed treatment was effective. Furthermore, we found increased BDNF levels in the patients under treatment compared to patients at early diagnosis, and a positive correlation between BDNF and L-car and a negative correlation between BDNF and Phe. Our results may indicate that in PKU patients treated with L-car there is an attempt to adjust neuronal plasticity and recover the damage suffered, reflecting a compensatory response to brain injury.
苯丙酮尿症（PKU）是最常见的遗传性代谢疾病，由苯丙氨酸羟化酶活性严重缺乏或缺失引起，该酶可将苯丙氨酸（Phe）转化为酪氨酸。PKU 患者接受低苯丙氨酸饮食治疗，并补充含有左旋肉碱（L-car）的特殊配方，L-car 是一种众所周知的抗氧化化合物。如果不进行治疗，可能会导致神经和认知障碍，如严重的智力迟钝、神经元细胞丢失和突触密度降低。尽管苯丙氨酸已被广泛证明与 PKU 神经毒性有关，但导致中枢神经系统损伤的机制仍不完全清楚。在这项工作中，我们评估了神经退行性变的标志物，即脑源性神经营养因子（BDNF）、总纤溶酶原激活物抑制剂-1（PAI-1 总）、组织蛋白酶 D、血小板衍生生长因子 AB/BB（PDGF AB/BB）和神经细胞黏附分子（NCAM）在早期和晚期诊断及治疗的 PKU 患者血浆中的表达。与其他组相比，接受 L-car 治疗的 PKU 患者的 Phe 水平降低，L-car 浓度升高，表明所提出的治疗是有效的。此外，我们发现与早期诊断的患者相比，治疗中的患者 BDNF 水平升高，BDNF 与 L-car 呈正相关，BDNF 与 Phe 呈负相关。我们的结果可能表明，在接受 L-car 治疗的 PKU 患者中，存在调整神经元可塑性和恢复受损的尝试，反映了对脑损伤的代偿反应。
