Joel A. Saydoff, Ana Olariu, Jin Sheng, Zhongyi Hu, Qin Li, Rolando Garcia, Jiong Pei, Grace Y. Sun, Reid von Borstel
Uridine prodrug PN401 has been shown to have neuroprotective effects in models of Parkinson's disease and Huntington's disease. These age-related neurodegenerative diseases including Alzheimer's disease (AD) are associated with mitochondrial dysfunction, oxidative stress, and inflammation. Attenuation of these pathological factors in AD, in addition to amyloid fibrils and neurofibrillary tangles, is critical to prevent cognitive impairment. The effects of PN401 treatment were tested in the Tg2576 and Tg2576 X P301L (TAPP) mouse models of AD. Treatment with PN401 reduced impairments in the Tg2576 mice in contextual fear conditioning and novel object recognition. In the TAPP mice, PN401 reduced the impairments in novel object recognition and social transmission of food preference. PN401 also improved motor behavior and reduced anxiety-like behavior in the TAPP mice. TAPP mouse hippocampal tau phosphorylation and lipid peroxidation were reduced by PN401 treatment. Increased tau phosphorylation was significantly correlated with worsening novel object recognition memory. PN401 did not affect amyloid plaque area in the AD mice. In other AD-related animal studies, PN401 treatment reduced blood-brain barrier damage due to intracortical LPS, elevation of serum TNFα due to systemic LPS, and hippocampal CA1 neuronal loss in the gerbil stroke model. Uridine dose-dependently protected cells from chemical hypoxia and ceramide, and decreased formation of reactive oxygen species and mitochondrial DNA damage due to hydrogen peroxide. These protective effects were achieved by raising uridine levels to at least 25–50 μM and serum uridine levels in this range in humans were obtained with oral PN401.