Sildenafil citrate attenuates a complex maze impairment induced by intracerebroventricular infusion of the NOS inhibitor Nomega-nitro-L-arginine methyl ester.
In a previous study, our laboratory reported that sildenafil citrate, a cyclic nucleotide phosphodiesterase type 5 inhibitor, reversed a learning impairment in rats induced by systemic inhibition of nitric oxide synthase (60 mg/kg, i.p., Nomega-nitro-L-arginine methyl ester; L-NAME). To limit the peripheral effects of L-NAME and further localize the site of action of sildenafil, L-NAME (48 microg, i.c.v.) was infused bilaterally into the lateral cerebral ventricles 30 min prior to maze training. Saline or sildenafil citrate (1.5 or 3.0 mg/kg, i.p.) was administered systemically 15 min before training. Drug injections occurred 24 h after pretraining rats to avoid foot shock on a one-way active avoidance straight runway. Following drug treatment, the rats received 15 training trials on a 14-unit T-maze task that requires learning a complex sequence of turns to avoid mild foot shock. This complex maze paradigm is sensitive to aging and blockade of cholinergic, N-methyl-D-aspartate and nitric oxide signaling systems. Behavioral measures of performance included deviations from the correct pathway (errors), runtime from start to goal (latency), shock frequency and shock duration. Statistical analysis revealed that central infusion of L-NAME impaired maze performance and that sildenafil (3.0 mg/kg) significantly attenuated the impairment. These results suggest that sildenafil citrate may serve as a cognitive enhancer by modulating central nitric oxide/cGMP signal transduction following N-methyl-D-aspartate receptor activation. This pathway has been implicated in age-related cognitive decline and may be a useful target for pharmacological intervention of neurodegenerative disease.
Devan
Bryan D
BD
Behavioral Neuroscience Section, Laboratory of Experimental Gerontology, National Institute on Aging, National Institutes of Health, Gerontology Research Center, 5600 Nathan Shock Dr., Baltimore MD 21204, United States. bdevan@towson.edu
Pistell
Paul J
PJ
Daffin
Lee W
LW
Nelson
Christopher M
CM
Duffy
Kara B
KB
Bowker
Jonna L
JL
Bharati
Ila S
IS
Sierra-Mercado
Demetrio
D
Spangler
Edward L
EL
Ingram
Donald K
DK
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007263:Infusions, Parenteral; D007274:Injections, Intraperitoneal; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018697:Nootropic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000187:drug effects; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D018697:Nootropic Agents; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester