Pharmacological intervention in young adolescents rescues synaptic physiology and behavioural deficits in Syngap1+/- mice.

Haploinsufficiency in SYNGAP1 is implicated in intellectual disability (ID) and autism spectrum disorder (ASD) and affects the maturation of dendritic spines. The abnormal spine development has been suggested to cause a disbalance of excitatory and inhibitory (E/I) neurotransmission at distinct developmental periods. In addition, E/I imbalances in Syngap1+/- mice might be due to abnormalities in K+-Cl- co-transporter function (NKCC1, KCC2), in a maner similar to the murine models of Fragile-X and Rett syndromes. To study whether an altered intracellular chloride ion concentration represents an underlying mechanism of modified function of GABAergic synapses in Dentate Gyrus Granule Cells of Syngap1+/- recordings were performed at different developmental stages of the mice. We observed depolarised neurons at P14-15 as illustrated by decreased Cl- reversal potential in Syngap1+/- mice. The KCC2 expression was decreased compared to Wild-type (WT) mice at P14-15. The GSK-3ß inhibitor, 6-bromoindirubin-3'-oxime (6BIO) that crosses the blood-brain barrier, was tested to restore the function of GABAergic synapses. We discovered that the intraperitoneal administration of 6BIO during the critical period or young adolescents [P30 to P80 (4-week to 10-week)] normalised an altered E/I balance, the deficits of synaptic plasticity, and behavioural performance like social novelty, anxiety, and memory of the Syngap1+/- mice. In summary, altered GABAergic function in Syngap1+/- mice is due to reduced KCC2 expression leading to an increase in the intracellular chloride concentration that can be counteracted by the 6BIO, which restored cognitive, emotional, and social symptoms by pharmacological intervention, particularly in adulthood.

Spatiotemporal analysis of soluble aggregates and autophagy markers in the R6/2 mouse model.

Maintenance of cellular proteostasis is vital for post-mitotic cells like neurons to sustain normal physiological function and homeostasis, defects in which are established hallmarks of several age-related conditions like AD, PD, HD, and ALS. The Spatio-temporal accumulation of aggregated proteins in the form of inclusion bodies/plaques is one of the major characteristics of many neurodegenerative diseases, including Huntington's disease (HD). Toxic accumulation of HUNTINGTIN (HTT) aggregates in neurons bring about the aberrant phenotypes of HD, including severe motor dysfunction, dementia, and cognitive impairment at the organismal level, in an age-dependent manner. In several cellular and animal models, aggrephagy induction has been shown to clear aggregate-prone proteins like HTT and ameliorate disease pathology by conferring neuroprotection. In this study, we used the mouse model of HD, R6/2, to understand the pathogenicity of mHTT aggregates, primarily focusing on autophagy dysfunction. We report that basal autophagy is not altered in R6/2 mice, whilst being functional at a steady-state level in neurons. Moreover, we tested the efficacy of a known autophagy modulator, Nilotinib (Tasigna™), presently in clinical trials for PD, and HD, in curbing mHTT aggregate growth and their potential clearance, which was ineffective in both inducing autophagy and rescuing the pathological phenotypes in R6/2 mice.

Potency and pharmacokinetics of broad spectrum and isoform-specific p110γ and δ inhibitors in cancers.

Emerging data on cancer suggesting that target-based therapy is promising strategy in cancer treatment. PI3K-AKT pathway is extensively studied in many cancers; several inhibitors target this pathway in different levels. Recent finding on this pathway uncovered the therapeutic applications of PI3K-specific inhibitors; PI3K, AKT, and mTORC broad spectrum inhibitors. Noticeably, class I PI3K isoforms, p110γ and p110δ catalytic subunits have rational therapeutic application than other isoforms. Therefore, three classes of inhibitors: isoform-specific, dual-specific and broad spectrum were selected for molecular docking and dynamics. First, p110δ structure was modelled; active site was analyzed. Then, molecular docking of each class of inhibitors were studied; the docked complexes were further used in 1.2 ns molecular dynamics simulation to report the potency of each class of inhibitor. Remarkably, both the studies retained the similar kind of protein ligand interactions. GDC-0941, XL-147 (broad spectrum); TG100-115 (dual-specific); and AS-252424, PIK-294 (isoform-specific) were found to be potential inhibitors of p110γ and p110δ, respectively. In addition to that pharmacokinetic properties are within recommended ranges. Finally, molecular phylogeny revealed that p110γ and p110δ are evolutionarily divergent; they probably need separate strategies for drug development.