Acute Systemic Inflammatory Response Alters Transcription Profile of Genes Related to Immune Response and Ca2+ Homeostasis in Hippocampus; Relevance to Neurodegenerative Disorders.

Acute systemic inflammatory response (SIR) triggers an alteration in the transcription of brain genes related to neuroinflammation, oxidative stress and cells death. These changes are also characteristic for Alzheimer's disease (AD) neuropathology. Our aim was to evaluate gene expression patterns in the mouse hippocampus (MH) by using microarray technology 12 and 96 h after SIR evoked by lipopolysaccharide (LPS). The results were compared with microarray analysis of human postmortem hippocampal AD tissues. It was found that 12 h after LPS administration the expression of 231 genes in MH was significantly altered (FC > 2.0); however, after 96 h only the S100a8 gene encoding calgranulin A was activated (FC = 2.9). Gene ontology enrichment analysis demonstrated the alteration of gene expression related mostly to the immune-response including the gene Lcn2 for Lipocalin 2 (FC = 237.8), involved in glia neurotoxicity. The expression of genes coding proteins involved in epigenetic regulation, histone deacetylases (Hdac4,5,8,9,11) and bromo- and extraterminal domain protein Brd3 were downregulated; however, Brd2 was found to be upregulated. Remarkably, the significant increase in expression of Lcn2, S100a8, S100a9 and also Saa3 and Ch25h, was found in AD brains suggesting that early changes of immune-response genes evoked by mild SIR could be crucial in AD pathogenesis.

Assessment of antioxidative activity of alkaloids from Huperzia selago and Diphasiastrum complanatum using in vitro systems.

Free radical-induced oxidative damage is implicated in the pathogenesis of neurodegenerative disorders, and antioxidants are presumably of therapeutic value in such diseases. Our previous data indicated that free radicals are strongly associated with brain aging and also play an important role in cytotoxicity of amyloidogenic proteins including -synuclein and amyloid , which accumulate in brains during Parkinson's and Alzheimer's diseases. Disruption of the equilibrium of pro-oxidants and antioxidants results in oxidative stress that leads to the modification of DNA, proteins, carbohydrates, and lipids. It is widely accepted that antioxidants acting as radical scavengers protect the brain against oxidative damage in neurodegenerative diseases. Plant products are rich sources of phytochemicals and have been found to possess a variety of biological activities, including antioxidative potential. The aim of this study was to analyse the antioxidative potential of alkaloid fractions from Huperzia selago and Diphasiastrum complanatum to protect macromolecules against oxidative damage. Thin layer chromatography (TLC) and high-performance liquid chromatography with diode array (HPLC-DAD) and electrospray ionisation mass spectrometric detection (ESI-MS/MS) were used to carry out a comprehensive characterization of alkaloids isolated from the plant material. The effect of the tested compounds on iron/ascorbate-induced lipid peroxidation and carbonyl group formation was analysed in the rat brain homogenate. Direct free radical scavenging (DPPH assay) and the effect on dityrosine formation were measured in cell-free systems. Our results indicated that a number of alkaloid extracts at concentration of 25 µg/ml exhibited antioxidant activity as indicated by DPPH radical scavenging potential (up to 59% inhibition) and inhibition of dityrosine formation. Selected alkaloid fractions provided significant protection against lipid peroxidation and protein oxidation in rat brain tissue homogenate, reducing iron/ascorbate-induced damage by about 20% and 76%, respectively. Overall, the results indicated that selected alkaloids isolated from Huperzia selago effectively protect macromolecules from oxidative stress injury, which will give us an insight into the potential of alkaloids in terms of opening up a new therapeutic approach for oxidative stress-dependent disorders.