Klinik für Anaesthesiologie der Technischen Universität München, Klinikum rechts der Isar, Munich, Germany.
Eur J Anaesthesiol. 2011 Sep;28(9):655-63. doi: 10.1097/EJA.0b013e3283497ce1.
Nitric oxide acts as an important neurotransmitter as well as a sepsis mediator. During sepsis, high levels of nitric oxide, produced by the inducible form of the nitric oxide synthase (iNOS), may lead to disturbances concerning these conflicting roles and cause septic encephalopathy. To evaluate this theory, we aimed at first, to demonstrate cognitive dysfunction in a rat model based on systemic iNOS induction; second, to elucidate molecular mechanisms; and third, to prevent cognitive deficits in our sepsis model.
We used a rat systemic inflammation model that is based on the induction of iNOS by heat-killed Corynebacterium parvum in different doses (30 or 60 mg kg). NO2/NO3 plasma levels were measured to prove iNOS induction. Cognitive performance was investigated. In brain tissue, NOS protein and NOS activity were determined. To prevent cognitive deficits, two groups of rats received L-N-(1-Iminoethyl)-lysine (L-NIL), a specific iNOS inhibitor in the drinking water.
The rats[Combining Acute Accent] cognitive performance, that is, short-term memory as well as long-term memory was impaired in C. parvum rats with a peak at the third day after injection in the 60 mg kg group. At the same day, neuronal NOS (nNOS)-protein content in the prefrontal cortex was reduced in C. parvum rats. nNOS activity was also reduced in C. parvum rats. The cognitive deficit in short-term memory could be prevented by L-NIL.
We demonstrate early, reversible cognitive deficits in a rat model of systemic inflammation with increased systemic iNOS activity. As systemic inhibition of iNOS activity prevented rats from the deficit in short-term memory, an involvement of systemic iNOS induction in this deficit is likely. Whether the reduced nNOS-protein expression and nNOS activity are connected to systemic iNOS induction, however, remains unclear.
一氧化氮作为一种重要的神经递质和脓毒症介质。在脓毒症中，诱导型一氧化氮合酶（iNOS）产生的高水平一氧化氮可能导致这些相互冲突的作用发生紊乱，并导致脓毒性脑病。为了验证这一理论，我们首先旨在基于全身诱导 iNOS 的大鼠模型证明认知功能障碍；其次阐明分子机制；第三，在我们的脓毒症模型中预防认知缺陷。
我们使用了一种基于不同剂量（30 或 60mg/kg）热灭活柯萨奇氏菌（Corynebacterium parvum）诱导 iNOS 的大鼠全身炎症模型。测量血浆中 NO2/NO3 水平以证明 iNOS 诱导。研究认知表现。在脑组织中，测定 NOS 蛋白和 NOS 活性。为了预防认知缺陷，两组大鼠接受 L-N-（1-亚氨基乙基）-赖氨酸（L-NIL），一种特异性 iNOS 抑制剂，溶于饮用水中。
C. parvum 大鼠的认知表现，即短期记忆和长期记忆，在注射后第 3 天达到峰值时受到影响，而在 60mg/kg 组中受损更为严重。同日，C. parvum 大鼠前额叶皮质神经元 NOS（nNOS）-蛋白含量减少。C. parvum 大鼠的 nNOS 活性也降低。短期记忆中的认知缺陷可以通过 L-NIL 预防。
我们在全身炎症大鼠模型中证明了早期、可逆的认知缺陷，该模型的全身 iNOS 活性增加。由于全身抑制 iNOS 活性可防止大鼠出现短期记忆缺陷，因此全身性 iNOS 诱导可能与该缺陷有关。然而，nNOS-蛋白表达和 nNOS 活性的降低是否与全身性 iNOS 诱导有关尚不清楚。
