pyrimidinones and Huntington-Disease

Our group has recently shown that brain-penetrant ataxia telangiectasia-mutated (ATM) kinase inhibitors may have potential as novel therapeutics for the treatment of Huntington's disease (HD). However, the previously described pyranone-thioxanthenes (e.g.,

Topics: Animals; Ataxia Telangiectasia Mutated Proteins; Binding Sites; Brain; Class III Phosphatidylinositol 3-Kinases; Crystallography, X-Ray; Drug Design; Half-Life; Humans; Huntington Disease; Male; Mice; Mice, Inbred C57BL; Molecular Dynamics Simulation; Morpholinos; Pyridones; Pyrimidinones; Structure-Activity Relationship

Several neurophysiological abnormalities have been described in Huntington's disease, including auditory gating deficit, which are considered to reflect impaired brain information-processing. Since transgenic animal models of Huntington's disease capture basic neuropathology of the disorder, auditory gating was studied in BACHD (line5) transgenic rats and Q175 transgenic mice, together with local field gamma power in the hippocampus and primary auditory cortex. Using clinically equivalent acoustic-stimulation paradigms, impaired auditory gating was detected in transgenic BACHD rats under anesthesia and in freely-moving condition. In addition, transgenic BACHD rats showed a lower level of hippocampal and cortical field gamma band power compared to wild-type counterpart, which might be related to their compromised mitochondrial function. Systemic administration of the recently developed phosphodiesterase 9A (PDE9A) inhibitor PF-04447943 dose-dependently improved gating deficit in transgenic BACHD rats in both brain regions. Q175 mice, including wild-type, heterozygote and homozygote mice showed similarly poor gating, and administration of PF-04447943 was without effect. Treatment of transgenic BACHD rats with daily administration of PF-04447943 (1mg/kg) over 7-days resulted in an improvement in their auditory gating both in the hippocampus and primary auditory cortex as evaluated 24h after the last treatment. In fact, differences in auditory gating between wild-type and transgenic BACHD rats were totally abolished after sub-chronic treatment with the PDE9A inhibitor. Our findings indicate that BACHD transgenic rats show abnormal auditory gating with features resembling those of Huntington's disease patients, which could be considered as potential translational biomarker for drug development in treatment of this disease.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Acoustic Stimulation; Animals; Auditory Cortex; Disease Models, Animal; Electrophysiology; Enzyme Inhibitors; Evoked Potentials, Auditory; Hippocampus; Huntington Disease; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pyrazoles; Pyrimidinones; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Sensory Gating

Huntington's Disease (HD) is a neurodegenerative disorder caused by an abnormally expanded polyglutamine trait in the amino-terminal region of huntingtin. Pathogenic mechanisms involve a gained toxicity of mutant huntingtin and a potentially reduced neuroprotective function of the wild-type allele. Among the molecular abnormalities reported, HD cells are characterized by the presence of aggregates, transcriptional dysregulation, altered mitochondrial membrane potential and aberrant Ca++ handling. In addition, upon exposure to toxic stimuli, increased mitochondrial release of cytochrome C and activation of caspase-9 and caspase-3 are found in HD cells and tissue. Here we report that HTRA2 and Smac/DIABLO, two additional mitochondrial pro-apoptotic factors, are aberrantly released from brain-derived cells expressing mutant huntingtin. This event causes a reduction in levels of the cytosolic IAP1 (Inhibitor of Apoptosis Protein-1) and XIAP (X-linked inhibitor apoptosis) antiapoptotic IAP family members. Reduced IAP levels are also found in post-mortem HD brain tissue. Treatment with ucf101, a serine protease HTRA2 specific inhibitor, counteracts IAPs degradation in HD cells and increases their survival. These results point to the IAPs as potential pharmacological targets in Huntington's Disease.

Topics: Animals; Apoptosis Regulatory Proteins; Brain; Carrier Proteins; Cell Line; Cell Survival; Cyclosporine; Cytosol; High-Temperature Requirement A Serine Peptidase 2; Humans; Huntingtin Protein; Huntington Disease; Inhibitor of Apoptosis Proteins; Intracellular Signaling Peptides and Proteins; Mice; Mitochondria; Mitochondrial Proteins; Mutation; Nerve Tissue Proteins; Nuclear Proteins; Proteins; Pyrimidinones; Serine Endopeptidases; Thiones; Ubiquitin-Protein Ligases; X-Linked Inhibitor of Apoptosis Protein