title: Neuroprotective role of PDE4 and PDE5 inhibitors in 3-nitropropionic acid induced behavioral and biochemical toxicities in rats.
abstract: 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.
authors.affiliation: Neuropharmacology Division, ISF College of Pharmacy, Moga 142001, Punjab, India.
authors.forename: Tarun
authors.initials: T
authors.lastname: Thakur
authors.forename: Sorabh
authors.initials: S
authors.lastname: Sharma
authors.forename: Kushal
authors.initials: K
authors.lastname: Kumar
authors.forename: Rahul
authors.initials: R
authors.lastname: Deshmukh
authors.forename: Pyare Lal
authors.initials: PL
authors.lastname: Sharma
mesh_terms: D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009574:Nitro Compounds / Q000633:toxicity*; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011422:Propionates / Q000633:toxicity*; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D018696:Neuroprotective Agents; D009574:Nitro Compounds; D058988:Phosphodiesterase 4 Inhibitors; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011422:Propionates; D011687:Purines; D013450:Sulfones; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D008315:Malondialdehyde; D000068677:Sildenafil Citrate; D007770:L-Lactate Dehydrogenase; D013385:Succinate Dehydrogenase; D005978:Glutathione; C015392:3-nitropropionic acid
keywords: 3-Nitropropionic acid; Huntington's disease; Motor disorder; Oxidative stress; PDE inhibitor