The brain is a highly metabolic organ and requires regulatory mechanisms to meet its high energy demand, with the PI3K/Akt and AMPK signalling pathways being central regulators of cellular energy and metabolism, also making them major targets for the development of neurometabolic disorders. Fusaric acid (FA), a toxin of fungal origin, was found to be a potent hypotensive agent in vivo and in clinical trials by altering brain neurochemistry thus demonstrating its neurological effects. Notably, FA is a putative mitochondrial toxin, however, the metabolic effects of FA in the brain remains unknown. Therefore, this study investigates the neurometabolic effects of FA via alterations to Akt and AMPK signalling pathways in C57BL/6 mice at acute (1 day) and prolonged exposure (10 days). Following 1 day exposure, FA augmented Akt signalling by increasing Akt S473 phosphorylation and the upstream regulators PI3K, mTOR and p70S6K. Activated Akt showed inhibition of GSK3 activity with the simultaneous activation of AMPK, p53 phosphorylation and reduced GLUT-1 and -4 receptor expressions, potentially suppressing neuronal glucose entry. However, after 10 days exposure, FA dampened PI3K/Akt and AMPK signalling, but increased the expression of GLUT receptors (1 and 4) in mice brain. Further, FA significantly depleted ATP levels, at 10 days exposure, despite increased PDHE1β activity (at both 1 and 10 days), strongly suggesting that FA mediates ATP depletion independent of metabolic signalling. In conclusion, FA mediates neurometabolic disturbances, at 1 and 10 day exposures, which may negatively influence normal brain aging and predispose to neurodegenerative disorders.

大脑是一个高度代谢的器官，需要调节机制来满足其高能量需求，而PI3K / Akt和AMPK信号通路是细胞能量和代谢的中心调节剂，也使其成为神经代谢疾病发展的主要目标。真菌来源的毒素-富沙酸（FA）被发现是体内有效的降压药并在临床试验中通过改变大脑神经化学来证明其神经学作用。值得注意的是，FA是一种假定的线粒体毒素，但是，FA在脑中的代谢作用仍然未知。因此，本研究通过在急性（1天）和长时间（10天）暴露于C57BL / 6小鼠中，通过改变Akt和AMPK信号通路来研究FA的神经代谢作用。暴露1天后，FA通过增加Akt S473磷酸化和上游调节因子PI3K，mTOR和p70S6K增强Akt信号传导。激活的Akt表现出GSK3活性的抑制，同时激活AMPK，p53磷酸化并降低GLUT-1和-4受体的表达，从而可能抑制神经元葡萄糖的进入。但是，暴露10天后，FA抑制了PI3K / Akt和AMPK信号传导，但增加了小鼠大脑中GLUT受体（1和4）的表达。此外，尽管PDHE1β活性增加（在第1天和第10天），FA暴露10天后FA仍显着耗尽ATP水平，强烈暗示FA介导了ATP耗竭而与代谢信号无关。总之，FA在暴露1天和10天时会介导神经代谢紊乱，这可能会对正常的大脑衰老产生负面影响，并易患神经退行性疾病。