Hydroxyurea protects hippocampal neurons against oxidative, metabolic and excitotoxic stress, and improves spatial memory in a mouse model of Alzheimer’s disease (Rat)

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 determined if hydroxyurea (HU), a ribonucleotide reductase inhibitor known to activate adaptive cellular stress responses in fibroblasts, could protect rat hippocampal neurons against oxidative-, excitatory-, mitochondrial-, and Aβ-induced stress and if HU treatment could improve learning and memory in a mouse model of AD (APP/PS1 double mutant transgenic mice). HU treatment attenuated the loss of cell viability induced by treatment of hippocampal neurons with hydrogen peroxide, glutamate, rotenone, and Aβ1-42. HU treatment also attenuated reductions of mitochondrial reserve capacity, maximal respiration, and cellular ATP content induced by hydrogen peroxide treatment. In vivo, treatment of APP/PS1 AD mice with HU (45 mg/kg/day) improved spatial memory performance in the hippocampus-dependent Morris water maze task. In summary, HU provides neuroprotection against toxic insults, improves mitochondrial bioenergetics, and improves spatial memory in a mouse model of AD. HU may offer a new therapeutic approach to delay cognitive decline in AD. Embryonic Day 18 rat hippocampal neurons were cultured for 6-9 days before treatment with hydroxyurea (HU, 5 µM) for 2, 6, 12, or 24 hours or left untreated (UT), with three replicates (#1,2,3) for each condition for a total of 15 samples.