Effects of LRRK2 Inhibitors in Nonhuman Primates.

Toxicology studies in nonhuman primates were conducted to evaluate selective, brain penetrant inhibitors of LRRK2. GNE 7915 was limited to 7-day administration in cynomolgus monkeys at 65 mg/kg/day or limited to 14 days in rhesus at 22.5 mg/kg b.

The effect of methylmercury exposure on behavior and cerebellar granule cell physiology in aged mice.

Epidemiology studies have clearly documented that the central nervous system is highly susceptible to methylmercury toxicity, and exposure to this neurotoxicant in humans primarily results from consumption of contaminated fish. While the effects of methylmercury exposure have been studied in great detail, comparatively little is known about the effects of moderate to low dose methylmercury toxicity in the aging central nervous system. We examined the toxic effects of a moderate dose of methylmercury on the aging mouse cerebellum.

Early toxicology signal generation in the mouse.

The rat has been the preferred rodent toxicology species since before regulatory requirements have been in place, and there exists in the pharmaceutical industry and the regulatory agencies a significant amount of historical data for the rat. The resulting experience base with the rat makes the possibility of replacing it with the mouse for regulated toxicology studies untenable for all but the most extreme circumstances. However, toxicologists are very familiar with the mouse as a model for chronic carcinogenicity studies, and there exist multiple preclinical mouse models of disease.

Soluble Jagged1 attenuates lateral inhibition, allowing for the clonal expansion of neural crest stem cells.

The activation of Notch signaling in neural crest stem cells (NCSCs) results in the rapid loss of neurogenic potential and differentiation into glia. We now show that the attenuation of endogenous Notch signaling within expanding NCSC clones by the Notch ligand soluble Jagged1 (sJ1), maintains NCSCs in a clonal self-renewing state in vitro without affecting their sensitivity to instructive differentiation signals observed previously during NCSC self-renewal. sJ1 functions as a competitive inhibitor of Notch signaling to modulate endogenous cell-cell communication to levels sufficient to inhibit neural differentiation but insufficient to instruct gliogenic differentiation.

Changes in biochemical processes in cerebellar granule cells of mice exposed to methylmercury.

At postnatal day 34, male and female C57BL/6J mice were exposed orally once a day to a total of five doses totaling 1.0 or 5.0 mg/kg of methylmercuric chloride or sterile deionized water in moistened rodent chow.