The α2 Na+/K+-ATPase isoform mediates LPS-induced neuroinflammation.

Na+/K+-ATPase is a transmembrane ion pump that is essential for the maintenance of ion gradients and regulation of multiple cellular functions. Na+/K+-ATPase has been associated with nuclear factor kappa B (NFκB) signalling, a signal associated with lipopolysaccharides (LPSs)-induced immune response in connection with activated Toll-like receptor 4 (TLR4) signalling. However, the contribution of Na+/K+-ATPase to regulating inflammatory responses remains elusive. We report that mice haploinsufficient for the astrocyte-enriched α2Na+/K+-ATPase isoform (α2+/G301R mice) have a reduced proinflammatory response to LPS, accompanied by a reduced hypothermic reaction compared to wild type litter mates. Following intraperitoneal injection of LPS, gene expressions of Tnf-α, Il-1ß, and Il-6 was reduced in the hypothalamus and hippocampus from α2+/G301R mice compared to α2+/+ littermates. The α2+/G301R mice experienced increased expression of the gene encoding an antioxidant enzyme, NRF2, in hippocampal astrocytes. Our findings indicate that α2Na+/K+-ATPase haploinsufficiency negatively modulates LPS-induced immune responses, highlighting a rational pharmacological target for reducing LPS-induced inflammation.

Hypothermia-induced hyperphosphorylation: a new model to study tau kinase inhibitors.

Tau hyperphosphorylation is one hallmark of Alzheimer's disease (AD) pathology. Pharmaceutical companies have thus developed kinase inhibitors aiming to reduce tau hyperphosphorylation. One obstacle in screening for tau kinase inhibitors is the low phosphorylation levels of AD-related phospho-epitopes in normal adult mice and cultured cells. We have shown that hypothermia induces tau hyperphosphorylation in vitro and in vivo. Here, we hypothesized that hypothermia could be used to assess tau kinase inhibitors efficacy. Hypothermia applied to models of biological gradual complexity such as neuronal-like cells, ex vivo brain slices and adult non-transgenic mice leads to tau hyperphosphorylation at multiple AD-related phospho-epitopes. We show that Glycogen Synthase Kinase-3 inhibitors LiCl and AR-A014418, as well as roscovitine, a cyclin-dependent kinase 5 inhibitor, decrease hypothermia-induced tau hyperphosphorylation, leading to different tau phosphorylation profiles. Therefore, we propose hypothermia-induced hyperphosphorylation as a reliable, fast, convenient and inexpensive tool to screen for tau kinase inhibitors.

[Effect of guizhi decoction on adenyl cyclase and phosphodiesterase in hypothalamus of rats models of fever and hypothermia].

OBJECTIVE: To observe the effect of Guizhi Decoction (GZD) on adenyl cyclase (AC) and phosphodiesterase (PDE) activities in hypothalamus of rat models of fever and hypothermia. METHODS: The AC and PDE activities in hypothalamus were determined using radio-isotope method. RESULTS: GZD could lower the AC activity in yeast induced fever rat model (P < 0.05), but cause rise of AC activity in aminopyrine induced hypothermia model (P < 0.05). No significant influence of GZD on PDE activity was shown in both fever or hypothermia models. CONCLUSION: The bi-directional thermo-regulation effect of GZD might be partially due to influence on AC activity.

[Regulation of superoxide dismutase activity during deep hypothermia by simultaneous administration of water and lipid soluble antioxidants]. / Reguliatsiia aktivnosti SOD vo vremia glubokoi gipotermii odnovremennym primeneniem vodo- i zhirorastvorimykh antioksidantov.

Alongside anti-hypoxia activity, the method of deep hypothermia causes discoordination of metabolism in the heart. This is due to increased secretion of catecholamines in the process of cooling, to activation in free radical generation and lipid peroxidation. Pantethine and alpha-tocopherol were used. Pantethine reduced lipid peroxidation, preserved reaction activity of catalyzing resyntheses and transport of high energetic compounds in the heart, while alpha-tocopherol prevented lipid peroxidation activation and decrease in SOD. Simultaneous use of pantethine and alpha-tocopherol caused increase in SOD and normalization of heart metabolism. Thus, for protection of the heart against excessive free radical generation under deep hypothermia simultaneous use of antioxidants like pantethine and alpha-tocopherol is necessary.

[Brain peptide-hydrolase activity in hypothermia]. / Peptid-gidrolaznaia aktivnost' taknei mozga pri gipotermii.

The cooling of rats to the body temperature of 30 and 25 degrees C does not change acidic peptide-hydrolase activity in tissue homogenates of cerebral cortex, hypothalamus, thalamus, hippocampus, midbrain, cerebellum and medulla oblongata. In deep hypothermia (to 20 degrees C) there occurs a significant increase in the peptide-hydrolase activity in tissue of the studied brain areas both in an incubation sample at 37 degrees C, and at temperature corresponding to the body temperature of cooled animals (20 degrees C). But the enzyme activity remains unchanged in homogenates of medulla oblongata incubation at 37 degrees C.