pyrimidinones and Nerve-Degeneration

Multiple system atrophy (MSA) is a rare and fatal α-synucleinopathy characterized by a distinctive oligodendrogliopathy with glial cytoplasmic inclusions and associated neuronal multisystem degeneration. The majority of patients presents with a rapidly progressive parkinsonian disorder and atypical features such as early autonomic failure and cerebellar ataxia. We have previously reported that complete MSA pathology can be modeled in transgenic mice overexpressing oligodendroglial α-synuclein under conditions of oxidative stress induced by 3-nitropropionic acid (3-NP) including striatonigral degeneration, olivopontocerebellar atrophy, astrogliosis, and microglial activation. Here, we show that myeloperoxidase (MPO), a key enzyme involved in the production of reactive oxygen species by phagocytic cells, is expressed in both human and mouse MSA brains. We also demonstrate that in the MSA mouse model, MPO inhibition reduces motor impairment and rescues vulnerable neurons in striatum, substantia nigra pars compacta, cerebellar cortex, pontine nuclei, and inferior olives. MPO inhibition is associated with suppression of microglial activation but does not affect 3-NP induced astrogliosis in the same regions. Finally, MPO inhibition results in reduced intracellular aggregates of α-synuclein. This study suggests that MPO inhibition may represent a novel candidate treatment strategy against MSA-like neurodegeneration acting through its anti-inflammatory and anti-oxidative properties.

Topics: Aged; alpha-Synuclein; Animals; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gliosis; Humans; Male; Mice; Mice, Transgenic; Microglia; Middle Aged; Motor Activity; Multiple System Atrophy; Nerve Degeneration; Peroxidase; Pyrimidinones; Pyrroles

Alterations in glutamatergic synapse function have been implicated in the pathogenesis of many different neurological disorders, including ischemia, epilepsy, Parkinson's disease, Alzheimer's disease, and Huntington's disease. While studying glutamate receptor function in juvenile Batten disease on the C57BL/6J and 129S6/S(v)E(v) mouse backgrounds, we noticed differences unlikely to be due to mutation difference alone. We report here that primary cerebellar granule cell cultures from C57BL/6J mice are more sensitive to N-methyl-D-aspartate (NMDA)-mediated cell death. Moreover, sensitivity to AMPA-mediated excitotoxicity is more variable and is dependent on the treatment conditions and age of the cultures. Glutamate receptor surface expression levels examined in vitro by in situ ELISA and in vivo by Western blot in surface cross-linked cerebellar samples indicated that these differences in sensitivity likely are due to strain-dependent differences in cell surface receptor expression levels. We propose that differences in glutamate receptor expression and in excitotoxic vulnerability should be taken into consideration in the context of characterizing disease models on the C57BL/6J and 129S6/S(v)E(v) mouse backgrounds.

Topics: Alanine; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Animals, Newborn; Cell Death; Cell Survival; Cells, Cultured; Cerebellar Cortex; Dose-Response Relationship, Drug; Drug Resistance; Excitatory Amino Acid Agonists; Male; Mice; Mice, Inbred C57BL; N-Methylaspartate; Nerve Degeneration; Neurotoxins; Organ Culture Techniques; Pyrimidinones; Receptors, Glutamate; Species Specificity

Telbivudine is a novel nucleoside drug recently approved for the treatment of patients with chronic hepatitis B. Its nonclinical safety was evaluated in a comprehensive program of studies, including safety pharmacology, acute and chronic toxicity, reproductive and developmental toxicity, genotoxicity, and carcinogenicity. There were no test article-related effects observed in an in vitro hERG assay or in a core battery of safety pharmacology studies (central nervous system, respiratory, and cardiovascular safety pharmacology studies). Telbivudine was well tolerated in rats and in monkeys following single oral doses up to 2,000 mg/kg/day. Except for equivocal axonopathic findings in monkeys and occasional incidences of emesis, soft feces, and minor changes in body weight and food consumption, there was no target organ toxicity observed in mice, rats, or monkeys following oral administration for up to 3, 6, or 9 months, respectively, at doses up to 3,000 mg/kg/day. Axonopathy in the sciatic nerves and in the spinal cords of monkeys dosed at 1,000 mg/kg/day observed in a 9-month study was considered equivocal, as the role of telbivudine in the injury could not be determined. Slightly higher incidences of abortion and premature delivery observed in rabbits dosed at 1,000 mg/kg/day were considered secondary to maternal toxicity. There was no evidence of genotoxicity or carcinogenicity. These results suggest that telbivudine has a favorable safety profile and support its use in patients with chronic compensated hepatitis B viral infection.

Topics: Administration, Oral; Animals; Antiviral Agents; Carcinogenicity Tests; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Tolerance; Female; Hepatitis B, Chronic; Humans; Macaca fascicularis; Male; Mice; Mice, Transgenic; Mutagenicity Tests; Nerve Degeneration; Nucleosides; Pregnancy; Pyrimidinones; Rabbits; Rats; Rats, Sprague-Dawley; Reproduction; Safety; Telbivudine; Thymidine