Assessment of Oral LISPRO Treatment in Ameliorating Amyloid and Tau Pathology in Transgenic Alzheimer’s Mice Model
Poster Jun 19, 2017
Ahsan Habib, Darrell Sawmiller, David Rongo, Yang Xiang, Jun Tian, Huayan Hou, Jin Zeng, Brian Giunta, Lukasz Wojtas, Adam Smith, Douglas R Shytle, Takashi Mori, Glenn Currier and Jun Tan
Lithium is used primarily as a mood stabilizer for bipolar disorder and has been used to treat mania, depression and suicidal thoughts for a long time. In addition, it has also been shown to prevent cognitive decline which indicated that lithium has a potential therapeutic effect in Alzheimer’s disease (AD). However, one of the main problems that exist in the currently FDA-approved lithium pharmaceutics (carbonate and citrate) is that it has narrow therapeutic index and lithium plasma level change drastically which can cause adverse side effects. Here we investigated the safety, pharmacokinetics and therapeutic efficacies of LISPRO (ionic co-crystals of lithium salicylate with organic l-proline), lithium salicylate, Li2CO3 (currently used) and placebo. We found that LISPRO attenuate β-amyloid plaques and phosphorylation of tau through modulation of inflammation and GSK3β inactivation. Cytokine profiles in the brain, plasma and splenocyte suggest that LISPRO (8-weeks) down-regulates pro-inflammatory, up-regulates anti-inflammatory and suppresses renal COX2 expression in Tg2576 mice. Plasma and brain pharmacokinetics of lithium indicated that LISPRO showed significantly higher brain and steady plasma lithium levels on C57BL/6J (2-weeks) and Tg2576 (8-weeks) mice. Interestingly, chronic (20-weeks) administration of LISPRO produces a slightly higher, but non-significant brain to plasma lithium levels and reduces β-amyloid plaques, and tau-phosphorylation through modulation of presynaptic (synaptophysin) and post-synaptic protein (PSD95) expression in 3xTg-AD mice.
Genome-wide association studies (GWAS) have identified more than 100 genetic loci associated with type 2 diabetes. The majority of these are located in the intergenic or intragenic regions suggesting that the implicated variants may alter chromatin conformation. This, in turn, is likely to influence the expression of nearby or more remotely located genes to alter beta cell function. At present, however, detailed molecular and functional analyses are still lacking for most of these variants. We recently analysed one of these loci and mapped five causal variants in an islet-specific enhancer cluster within the STARD10 gene locus. Here, we aimed to understand how these causal variants influence b-cell function by alteration of the chromatin structure of enhancer clusterREAD MORE
The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are closely related transcription factors that regulate the expression of phase I (cytochrome P450s), phase II metabolizing enzymes and transporter genes in response to xenobiotics, including prescription drugs.READ MORE