Phosphodiesterase 5 Inhibition on Dopaminergic and Glutamatergic Neurotransmission: Implications for Memory Enhancement

Abstract

Phosphodiesterases belongs to a family of proteins that metabolize cyclic nucleotides. There are at present eleven types of Phosphodiesterases been isolated and shown to be expressed in various tissues. Phosphodiesterase 5, cyclic guanosine 3',5' monophosphate (cGMP) metabolizing enzyme and influence numerous pharmacological processes including ion channel function and learning. Sildenafil, active substance in the Viagra, is a specific and potent inhibitor of Phosphodiesterase 5. However, the physiological mechanisms underlying the learning and memory enhancement have poorly been studied. In this dissertation the behavioral and molecular modifications due to sildenafil administration in various animal models of Parkinson’s and Alzheimer’s disease have been investigated. Effect of sildenafil on fatigue was evaluated using forced swim test in mice. Sildenafil had no effect on fatigue as seen by the swim time. Neuroprotective effect of sildenafil was investigated using two animal models of Parkinson's disease. 6-hydroxydopamine-lesioned rats were used to determine the effect of sildenafil on rotational behavior. Ipsilateral or contralateral rotational behavior can indicate the amphetamine-like activity or apomorphine-like activity of sildenafil. Sildenafil did not induce contralateral or ipsilateral rotations in 6-hydroxydopamine-lesioned rats. Sildenafil did not protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine depletion in the striatum. The results of this study are significant as sildenafil that cross the blood brain barrier, has neither beneficial nor deleterious effect on nigrostriatal dopaminergic system. Memory enhancing properties of sildenafil were investigated using mice. Single administration of sildenafil enhances hippocampal dependent behavioral tasks. To elucidate the underlying mechanism in the memory enhancement, effects of sildenafil on long term potentiation (LTP) was measured. The level of LTP was significantly elevated in mice treated with sildenafil (1 mg/kg/day) for 15 day compared to control. Thus, these results suggest that the neural mechanisms of memory enhancement through PDE5 inhibition could be due to glutamatergic synaptic modification. The finding that sildenafil exert glutamatergic synaptic modification in the normal animal motivated the investigation on a disease model. Alzheimer’s disease (AD) is a fatal, progressive neurodegenerative disease that occurs in the elderly of the general population. Amyloid plaques, consisting of extracellular deposits of Aβ peptide are found in many AD patients’ brains and considered one of the hallmarks of Alzheimer’s disease. Intracerebroventricular (icv) infusion of Aβ in rat caused severe memory dysfunction. Consistent with the previous observation in mice, sildenafil significantly attenuated the memory deterioration in the Abeta (1-42) infused AD rat model. Thus, these results suggest that neural disturbances caused by abeta infusion may be rescued by treatment with sildenafil.