Behavioral and Cognitive Improvement Induced by Novel Imidazoline I2 Receptor Ligands in Female SAMP8 Mice

As populations increase their life expectancy, age-related neurodegenerative disorders such as Alzheimer's disease have become more common. I2-Imidazoline receptors (I2-IR) are widely distributed in the central nervous system, and dysregulation of I2-IR in patients with neurodegenerative diseases has been reported, suggesting their implication in cognitive impairment. This evidence indicates that high-affinity selective I2-IR ligands potentially contribute to the delay of neurodegeneration. In vivo studies in the female senescence accelerated mouse-prone 8 mice have shown that treatment with I2-IR ligands, MCR5 and MCR9, produce beneficial effects in behavior and cognition. Changes in molecular pathways implicated in oxidative stress, inflammation, synaptic plasticity, and apoptotic cell death were also studied. Furthermore, treatments with these I2-IR ligands diminished the amyloid precursor protein processing pathway and increased Aβ degrading enzymes in the hippocampus of SAMP8 mice. These results collectively demonstrate the neuroprotective role of these new I2-IR ligands in a mouse model of brain aging through specific pathways and suggest their potential as therapeutic agents in brain disorders and age-related neurodegenerative diseases. Keywords Imidazoline I2 receptors (2-imidazolin-4-yl)phosphonates Behavior Cognition Neurodegeneration Neuroprotection Agin

Epigallocatechin-3-gallate confers protection against corticosterone-induced neuron injuries via restoring extracellular signal-regulated kinase 1/2 and phosphatidylinositol-3 kinase/protein kinase B signaling pathways

Extensive studies suggested epigallocatechin-3-gallate (EGCG) has significant neuroprotection against multiple central neural injuries, but the underlying mechanisms still remain poorly elucidated. Here we provide evidence to support the possible involvement of extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol-3 kinase/ protein kinase B (PI3K/AKT) pathways in EGCG-mediated protection against corticosterone-induced neuron injuries. As an essential stress hormone, corticosterone could induce obvious neurotoxicity in primary hippocampal neurons. Pre-treatment with EGCG ameliorated the corticosterone-induced neuronal injuries; however, it was blocked by pharmacological inhibitors for ERK1/2 (U0126) and PI3K/AKT (LY294002). Furthermore, the results confirmed that EGCG restored the corticosterone-induced decrease of ERK1/2 and PI3K/AKT phosphorylation, and attenuated the corticosterone-induced reduction of peroxisome proliferators-activated receptor-γ coactivator-1α (PGC-1α) expression and ATP production. Taken together, these findings indicated that EGCG has significant neuroprotection against corticosterone-induced neuron injuries partly via restoring the ERK1/2 and PI3K/AKT signaling pathways as well as the PGC-1α-mediated ATP production

Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2

A combined genome-wide association and linkage study was used to identify loci causing variation in CF lung disease severity. A significant association (P=3. 34 × 10(-8)) near EHF and APIP (chr11p13) was identified in F508del homozygotes (n=1,978). The association replicated in F508del homozygotes (P=0.006) from a separate family-based study (n=557), with P=1.49 × 10(-9) for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family-based study identified a significant QTL on chromosome 20q13.2 (LOD=5.03). Our findings provide insight into the causes of variation in lung disease severity in CF and suggest new therapeutic targets for this life-limiting disorder