Hydroxyurea attenuates oxidative, metabolic, and excitotoxic stress in rat hippocampal neurons and improves spatial memory in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by accumulation of amyloid β-peptide (Aβ) plaques in the brain and decreased cognitive function leading to dementia. We tested if hydroxyurea (HU), a ribonucleotide reductase inhibitor known to activate adaptive cellular stress responses and ameliorate abnormalities associated with several genetic disorders, could protect rat hippocampal neurons against oxidative-, excitatory-, mitochondrial-, and Aβ-induced stress and if HU treatment could improve learning and memory in the APP/PS1 mouse model of AD. HU treatment attenuated the loss of cell viability induced by treatment of hippocampal neurons with hydrogen peroxide, glutamate, rotenone, and Aβ1-42. HU treatment attenuated reductions of mitochondrial reserve capacity, maximal respiration, and cellular adenosine triphosphate content induced by hydrogen peroxide treatment. In vivo, treatment of APP/PS1 mice with HU (45 mg/kg/d) improved spatial memory performance in the hippocampus-dependent Morris water maze task without reducing Aβ levels. HU provides neuroprotection against toxic insults including Aβ, improves mitochondrial bioenergetics, and improves spatial memory in an AD mouse model. HU may offer a new therapeutic approach to delay cognitive decline in AD.