pyrimidinones and Cognitive-Dysfunction

Clinical trials of MEK inhibitors are underway in pediatric low-grade glioma (PLGG) with BRAF oncogene mutations and recurrent/refractory disease. Cognitive and behavioral impacts of MEK inhibitors, such as trametinib, are unknown as these outcomes have not yet been studied. This case series compared cognition and behavior in eight PLGG cases prior to and while on treatment with trametinib compared to four PLGG controls. Intelligence in the trametinib cases was mainly unchanged while on treatment, with mild decline in one of seven cases with complete data. Parent-reported depression symptoms increased in five of eight trametinib cases relative to one of four controls.

Topics: Antineoplastic Agents; Brain Neoplasms; Child; Child, Preschool; Cognitive Dysfunction; Depression; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Glioma; Humans; Infant; Male; Neuropsychological Tests; Prognosis; Pyridones; Pyrimidinones

BACE1 (beta site amyloid precursor protein cleaving enzyme 1) is the rate limiting protease in amyloid β production, hence a promising drug target for the treatment of Alzheimer's disease. Inhibition of BACE1, as the major β-secretase in vivo with multiple substrates, however is likely to have mechanism-based adverse effects. We explored the impact of long-term pharmacological inhibition of BACE1 on dendritic spine dynamics, synaptic functions, and cognitive performance of adult mice.. Sandwich enzyme-linked immunosorbent assay was used to assess Aβ40 levels in brain and plasma after oral administration of BACE1 inhibitors SCH1682496 or LY2811376. In vivo two-photon microscopy of the somatosensory cortex was performed to monitor structural dynamics of dendritic spines while synaptic functions and plasticity were measured via electrophysiological recordings of excitatory postsynaptic currents and hippocampal long-term potentiation in brain slices. Finally, behavioral tests were performed to analyze the impact of pharmacological inhibition of BACE1 on cognitive performance.. Dose-dependent decrease of Aβ40 levels in vivo confirmed suppression of BACE1 activity by both inhibitors. Prolonged treatment caused a reduction in spine formation of layer V pyramidal neurons, which recovered after withdrawal of inhibitors. Congruently, the rate of spontaneous and miniature excitatory postsynaptic currents in pyramidal neurons and hippocampal long-term potentiation were reduced in animals treated with BACE1 inhibitors. These effects were not detected in Bace1(-/-) mice treated with SCH1682496, confirming BACE1 as the pharmacological target. Described structural and functional changes were associated with cognitive deficits as revealed in behavioral tests.. Our findings indicate important functions to BACE1 in structural and functional synaptic plasticity in the mature brain, with implications for cognition.

Topics: Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Brain; Cognition; Cognitive Dysfunction; Dendritic Spines; Dose-Response Relationship, Drug; Enzyme Inhibitors; Exploratory Behavior; Humans; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Peptide Fragments; Pyramidal Cells; Pyrimidines; Pyrimidinones; Synaptic Potentials; Thiazines; Thiophenes; Time Factors