Karlsson Oskar, Kultima Kim, Wadensten Henrik, Nilsson Anna, Roman Erika, Andrén Per E, Brittebo Eva B
Department of Pharmaceutical Biosciences, Uppsala University , SE-751 24 Uppsala, Sweden.
J Proteome Res. 2013 Apr 5;12(4):1678-90. doi: 10.1021/pr3010265. Epub 2013 Mar 5.
The cyanobacterial toxin β-N-methylamino-l-alanine (BMAA) is suggested to play a role in neurodegenerative disease. We have previously shown that although the selective uptake of BMAA in the rodent neonatal striatum does not cause neuronal cell death, exposure during the neonatal development leads to cognitive impairments in adult rats. The aim of the present study was to characterize the changes in the striatal neuropeptide systems of male and female rat pups treated neonatally (postnatal days 9-10) with BMAA (40-460 mg/kg). The label-free quantification of the relative levels of endogenous neuropeptides using mass spectrometry revealed that 25 peptides from 13 neuropeptide precursors were significantly changed in the rat neonatal striatum. The exposure to noncytotoxic doses of BMAA induced a dose-dependent increase of neurosecretory protein VGF-derived peptides, and changes in the relative levels of cholecystokinin, chromogranin, secretogranin, MCH, somatostatin and cortistatin-derived peptides were observed at the highest dose. In addition, the results revealed a sex-dependent increase in the relative level of peptides derived from the proenkephalin-A and protachykinin-1 precursors, including substance P and neurokinin A, in female pups. Because several of these peptides play a critical role in the development and survival of neurons, the observed neuropeptide changes might be possible mediators of BMAA-induced behavioral changes. Moreover, some neuropeptide changes suggest potential sex-related differences in susceptibility toward this neurotoxin. The present study also suggests that neuropeptide profiling might provide a sensitive characterization of the BMAA-induced noncytotoxic effects on the developing brain.
蓝藻毒素β-N-甲基氨基-L-丙氨酸（BMAA）被认为在神经退行性疾病中起作用。我们之前已经表明，尽管BMAA在啮齿动物新生纹状体中的选择性摄取不会导致神经元细胞死亡，但在新生发育期间接触会导致成年大鼠出现认知障碍。本研究的目的是表征在新生期（出生后第9 - 10天）用BMAA（40 - 460 mg/kg）处理的雄性和雌性大鼠幼崽纹状体神经肽系统的变化。使用质谱对内源性神经肽的相对水平进行无标记定量分析表明，来自13种神经肽前体的25种肽在大鼠新生纹状体中有显著变化。暴露于非细胞毒性剂量的BMAA会导致神经分泌蛋白VGF衍生肽的剂量依赖性增加，并且在最高剂量下观察到胆囊收缩素、嗜铬粒蛋白、分泌粒蛋白、黑素细胞刺激素、生长抑素和可体松衍生肽的相对水平发生变化。此外，结果显示在雌性幼崽中，源自脑啡肽原-A和速激肽-1前体的肽（包括P物质和神经激肽A）的相对水平存在性别依赖性增加。由于这些肽中的几种在神经元的发育和存活中起关键作用，观察到的神经肽变化可能是BMAA诱导的行为变化的潜在介导因素。此外，一些神经肽变化表明对这种神经毒素的易感性可能存在潜在的性别差异。本研究还表明，神经肽谱分析可能为BMAA对发育中大脑的非细胞毒性作用提供敏感的表征。
