sildenafil-citrate and 3-nitropropionic-acid

Phosphodiesterase inhibitors have been reported to be beneficial in cognitive and motor disorders. In the present study, we have investigated the effects of RO 20-1724 (PDE4 inhibitor) and sildenafil (PDE5 inhibitor) in 3-nitropropionic acid (3-NP) induced experimental Huntington's disease in rats. 3-Nitropropionic acid was administered for 14 days (10 mg/kg i.p.) 1h following 3-NP administration, the rats were treated with either vehicle, RO 20-1724 (0.25 and 0.5 mg/kg i.p.) or sildenafil (2 and 4 mg/kg i.p.) for 14 days. Cognitive functions were assessed by using Morris water maze whereas, motor functions were assessed by spontaneous locomotor activity, limb withdrawal and suspended wire test at different time points. Biochemically, markers of oxidative stress and cell damage, such as reduced glutathione, malondialdehyde, nitrite and lactate dehydrogenase levels were assessed terminally in the brain homogenate. Chronic administration of 3-NP produced significant decrease in body weight, showed marked abnormalities in cognitive and motor functions. Further, significant oxidative-nitrosative stress and cell damage was also observed. Chronic administration of RO 20-1724 and sildenafil in 3-NP treated rats significantly and dose dependently attenuated 3-NP induced behavioral and biochemical abnormalities in rats. Both these drugs were equally effective in attenuating 3-NP induced neurotoxicity. These results suggesting that the inhibition of PDE4 and PDE5 would be therapeutic in neurodegenerative disorders associated with cognitive and motor dysfunction.

Topics: 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; Animals; Behavior, Animal; Body Weight; Brain; Glutathione; L-Lactate Dehydrogenase; Malondialdehyde; Maze Learning; Memory; Neuroprotective Agents; Nitro Compounds; Phosphodiesterase 4 Inhibitors; Phosphodiesterase 5 Inhibitors; Piperazines; Propionates; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Succinate Dehydrogenase; Sulfones

In this study we tested whether phosphodiesterase 5 (PDE5) inhibitors, sildenafil and vardenafil, would afford protection against 3-nitropropionic acid (3NP), which produces striatal lesions that closely mimic some of the neuropathological features of Huntington's Disease (HD). The neurotoxin was given over 5 days by constant systemic infusion using osmotic minipumps. Animals treated with PDE5 inhibitors (sildenafil or vardenafil) showed improved neurologic scores, reduced the loss of striatal DARPP-32 protein levels and lesion volumes, and decreased calpain activation produced by 3NP. This protective effect was independent of changes in 3NP-induced succinate dehydrogenase inhibition. Furthermore, striatal p-CREB levels along with the expression of BDNF were significantly increased in sildenafil-treated rats. In summary, PDE5 inhibitors protected against 3NP-induced striatal degeneration by reducing calpain activation and by promoting survival pathways. These data encourage further evaluation of PDE5 inhibitors in transgenic mouse models of HD.

Topics: Analysis of Variance; Animals; Blotting, Western; Brain-Derived Neurotrophic Factor; Calpain; Corpus Striatum; Cyclic AMP Response Element-Binding Protein; Dopamine and cAMP-Regulated Phosphoprotein 32; Male; Motor Activity; Neurons; Neurotoxicity Syndromes; Neurotoxins; Nitro Compounds; Phosphodiesterase Inhibitors; Piperazines; Propionates; Purines; Rats; Rats, Inbred Lew; Reverse Transcriptase Polymerase Chain Reaction; Sildenafil Citrate; Succinate Dehydrogenase; Sulfones