sildenafil-citrate and Memory-Disorders

Noise exposure has been well characterized as an environmental stressor, and is known to have auditory and non-auditory effects. Phosphodiesterase 5 (PDE5) inhibitors affect memory and hippocampus plasticity through various signaling cascades which are regulated by cGMP. In this study, we investigated the effects of sildenafil on memory deficiency, neuroprotection and oxidative stress in mice caused by chronic noise exposure. Mice were exposed to noise for 4h every day up to 14days at 110dB SPL of noise level. Sildenafil (15mg/kg) was orally administered 30min before noise exposure for 14days. Behavioral assessments were performed using novel object recognition (NOR) test and radial arm maze (RAM) test. Higher levels of memory dysfunction and oxidative stress were observed in noise alone-induced mice compared to control group. Interestingly, sildenafil administration increased memory performance, decreased oxidative stress, and increased neuroprotection in the hippocampus region of noise alone-induced mice likely through affecting memory related pathways such as cGMP/PKG/CREB and p25/CDK5, and induction of free radical scavengers such as SOD1, SOD2, SOD3, Prdx5, and catalase in the brain of stressed mice.

Topics: Animals; Brain-Derived Neurotrophic Factor; CREB-Binding Protein; Cytokines; Disease Models, Animal; Indoles; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Noise; Norepinephrine; Oxidative Stress; Reactive Oxygen Species; Recognition, Psychology; Sildenafil Citrate; Stress, Psychological; Superoxide Dismutase; tau Proteins

Aging is characterized by a progressive cognitive decline that leads to memory impairment. Because the cyclic nucleotide cascade is essential for the integrity of synaptic function and memory, and it is down-regulated during aging and in neurodegenerative disorders, we investigated whether an increase in cGMP levels might rescue age-related synaptic and memory deficits in mice. We demonstrated that acute perfusion with the phosphodiesterase-5 inhibitor sildenafil (50 nM) ameliorated long-term potentiation in hippocampal slices from 26-30-month-old mice. Moreover, chronic intraperitoneal injection of sildenafil (3mg/kg for 3 weeks) improved age-related spatial learning and reference memory as tested by the Morris Water Maze, and recognition memory as tested by the Object Recognition Test. Finally, sildenafil restored central cAMP responsive element-binding protein (CREB) phosphorylation, which is crucial for synaptic plasticity and memory. Our data suggest that inhibition of phosphodiesterase-5 may be beneficial to treat age-related cognitive dysfunction in a physiological mouse model of aging.

Topics: Aging; Animals; Cyclic AMP Response Element-Binding Protein; Cyclic GMP; Female; Hippocampus; Long-Term Potentiation; Male; Memory; Memory Disorders; Mice; Mice, Inbred C57BL; Phosphodiesterase 5 Inhibitors; Phosphorylation; Piperazines; Purines; Recognition, Psychology; Sildenafil Citrate; Sulfones; Synaptic Transmission