Max Planck Institute for Biological Cybernetics, High-Field Magnetic Resonance Center, Tübingen, Germany.
Neurotoxicology. 2011 Jan;32(1):50-7. doi: 10.1016/j.neuro.2010.10.006. Epub 2010 Nov 12.
Application of the widely used immunosuppressant (ISS) cyclosporine (CsA) is severely limited by a number of serious side-effects such as kidney and neurotoxicity. As we have shown before, CsA exhibits metabolic toxicity in brain-models. The macrolide ISSs sirolimus (SRL) and everolimus (RAD) are capable of modulating these CsA-induced effects. It was our aim to study the age-dependent metabolic changes in the rat brain after ISS-treatment and the possible role of the blood-brain-barrier in modulation of CsA metabolic toxicity. Young and adult rats were treated orally with one ISS alone or in combination with CsA for six days. Metabolic changes were assessed by nuclear magnetic resonance (NMR) spectroscopy of brain extracts as toxicodynamic endpoints. Brain P-glycoprotein (P-gp) and ISS concentrations were determined as pharmacokinetic endpoints. Young rats were more susceptible to CsA-induced inhibition of the Krebs cycle (glutamate: 78% of controls, glutamine: 82%, GABA: 71% in young vs. 85%, 89%, 92% in adult rats). Increased glycolysis after CsA-treatment was sufficient to maintain the energy state at control levels in adult brains, but not in the young rat brains (phosphocreatine: 35%). Tissue concentrations of CsA and SRL within the brain of young rats were three-fold higher, while concentrations of P-gp were three-fold higher in adult rat brains. Our results suggest that age-dependent differences in the blood-brain barrier led to increased ISS brain concentrations and hence inhibition of brain energy metabolism.
广泛应用的免疫抑制剂（IS）环孢素（CsA）由于许多严重的副作用，如肾毒性和神经毒性，其应用受到严重限制。正如我们之前所展示的，CsA 在脑模型中表现出代谢毒性。大环内酯类 ISs 西罗莫司（SRL）和依维莫司（RAD）能够调节这些 CsA 诱导的作用。我们的目的是研究 ISS 治疗后大鼠大脑中与年龄相关的代谢变化，以及血脑屏障在调节 CsA 代谢毒性中的可能作用。年轻和成年大鼠分别用一种 ISs 单独或与 CsA 联合口服治疗 6 天。通过对脑提取物的核磁共振（NMR）光谱分析作为毒代动力学终点来评估代谢变化。脑 P-糖蛋白（P-gp）和 ISs 浓度作为药代动力学终点进行测定。年轻大鼠对 CsA 诱导的三羧酸循环（谷氨酸：78%的对照，谷氨酰胺：82%，GABA：71%，而成年大鼠：85%，89%，92%）抑制更敏感。CsA 治疗后糖酵解增加足以维持成年大鼠大脑的能量状态，但不能维持年轻大鼠大脑的能量状态（磷酸肌酸：35%）。年轻大鼠脑内 CsA 和 SRL 的组织浓度是成年大鼠的三倍，而 P-gp 浓度是成年大鼠的三倍。我们的研究结果表明，血脑屏障的年龄依赖性差异导致 ISs 脑内浓度增加，从而抑制脑能量代谢。
