QUOTE
Phosphodiesterase type 5 inhibition improves early memory consolidation of object information.
* Prickaerts J,
* Sik A,
* van Staveren WC,
* Koopmans G,
* Steinbusch HW,
* van der Staay FJ,
* de Vente J,
* Blokland A.
Department of Psychiatry and Neuropsychology, Maastricht University, P.O. Box 616, 6200 MD Maastricht,
The nitric oxide (NO)-cyclic GMP (cGMP) signaling pathway is assumed to play an important role in processes underlying learning and memory. We used phosphodiesterase type 5 (PDE5) inhibitors to study the role of cGMP in object- and spatial memory. Our results and those reported in other studies indicate that elevated hippocampal cGMP levels are required to improve the memory performance of rodents in object recognition and passive avoidance learning, but not in spatial learning. The timing of treatment modulates the effects on memory and strongly supports a role for cGMP in early stages of memory formation. Alternative explanations for the improved memory performance of PDE5 inhibitors are also discussed. Immunocytochemical studies showed that in vitro slice incubations with PDE5 inhibitors increase NO-stimulated cGMP levels mainly in hippocampal varicose fibers. Reviewing the available data on the localization of the different components of the NO-cGMP signaling pathway, indicates a complex interaction between NO and cGMP, which may be independent of each other. It is discussed that further studies are needed, immunocytochemical and behavioral, to better understand the cGMP-mediated molecular mechanisms underlying memory formation.
PMID: 15312986 [PubMed - indexed for MEDLINE]
* Prickaerts J,
* Sik A,
* van Staveren WC,
* Koopmans G,
* Steinbusch HW,
* van der Staay FJ,
* de Vente J,
* Blokland A.
Department of Psychiatry and Neuropsychology, Maastricht University, P.O. Box 616, 6200 MD Maastricht,
The nitric oxide (NO)-cyclic GMP (cGMP) signaling pathway is assumed to play an important role in processes underlying learning and memory. We used phosphodiesterase type 5 (PDE5) inhibitors to study the role of cGMP in object- and spatial memory. Our results and those reported in other studies indicate that elevated hippocampal cGMP levels are required to improve the memory performance of rodents in object recognition and passive avoidance learning, but not in spatial learning. The timing of treatment modulates the effects on memory and strongly supports a role for cGMP in early stages of memory formation. Alternative explanations for the improved memory performance of PDE5 inhibitors are also discussed. Immunocytochemical studies showed that in vitro slice incubations with PDE5 inhibitors increase NO-stimulated cGMP levels mainly in hippocampal varicose fibers. Reviewing the available data on the localization of the different components of the NO-cGMP signaling pathway, indicates a complex interaction between NO and cGMP, which may be independent of each other. It is discussed that further studies are needed, immunocytochemical and behavioral, to better understand the cGMP-mediated molecular mechanisms underlying memory formation.
PMID: 15312986 [PubMed - indexed for MEDLINE]
QUOTE
Phosphodiesterase type 5 (PDE5) inhibition and cognitive enhancement
Devan, B.D., Duffy, K.B., Bowker, J.L., Bharati, I.S., Nelson, C.M., Daffin, L.W. Jr., Spangler, E.L., Ingram, D.K.
Drug development for the treatment of dementia and age-related cognitive decline has been slow to produce clinically viable alternatives to the two existing FDA approved drug treatments, AChE inhibitors and the noncompetitive NMDA receptor antagonist, memantine. Recent human and preclinical animal studies suggest that one class of compounds, phosphodiesterase type 5 (PDE5) inhibitors, already in clinical use for the treatment of erectile dysfunction in men, may have central cognitive enhancing effects. Recent behavioral pharmacological studies with rodents demonstrate that PDE5 inhibitors improve memory consolidation in young animals using passive avoidance and object recognition tasks. In addition, we have shown that pretraining administration of the PDE5 inhibitor sildenafil citrate can attenuate a spatial learning impairment in the 14-unit T-maze induced by systemic blockade of cholinergic muscarinic receptors and nonspecific inhibition of nitric oxide synthase in young animals. Research findings with aged animals show that pretraining administration of sildenafil can improve the long-term retention of spatial memory 1 week following maze acquisition. Taken together with other reports of neuroprotective effects of sildenafil, we propose that the available research findings provide preclinical support for a possible alternative use of PDE5 inhibitors as cognitive enhancing agents that improve different kinds of learning and memory and protect brain systems against neurodegeneration.
Devan, B.D., Duffy, K.B., Bowker, J.L., Bharati, I.S., Nelson, C.M., Daffin, L.W. Jr., Spangler, E.L., Ingram, D.K.
Drug development for the treatment of dementia and age-related cognitive decline has been slow to produce clinically viable alternatives to the two existing FDA approved drug treatments, AChE inhibitors and the noncompetitive NMDA receptor antagonist, memantine. Recent human and preclinical animal studies suggest that one class of compounds, phosphodiesterase type 5 (PDE5) inhibitors, already in clinical use for the treatment of erectile dysfunction in men, may have central cognitive enhancing effects. Recent behavioral pharmacological studies with rodents demonstrate that PDE5 inhibitors improve memory consolidation in young animals using passive avoidance and object recognition tasks. In addition, we have shown that pretraining administration of the PDE5 inhibitor sildenafil citrate can attenuate a spatial learning impairment in the 14-unit T-maze induced by systemic blockade of cholinergic muscarinic receptors and nonspecific inhibition of nitric oxide synthase in young animals. Research findings with aged animals show that pretraining administration of sildenafil can improve the long-term retention of spatial memory 1 week following maze acquisition. Taken together with other reports of neuroprotective effects of sildenafil, we propose that the available research findings provide preclinical support for a possible alternative use of PDE5 inhibitors as cognitive enhancing agents that improve different kinds of learning and memory and protect brain systems against neurodegeneration.
QUOTE
Time-dependent involvement of cAMP and cGMP in consolidation of object memory: studies using selective phosphodiesterase type 2, 4 and 5 inhibitors.
* Rutten K,
* Prickaerts J,
* Hendrix M,
* van der Staay FJ,
* Sik A,
* Blokland A.
Department of Psychiatry and Neuropsychology, Brain and Behavior Institute, EURON, Maastricht
The present study investigated the time-dependent memory enhancing properties of three selective phosphodiesterase inhibitors (PDE-I) vardenafil (PDE5-I), rolipram (PDE4-I) and BAY 60-7550 (PDE2-I) in the object recognition task. In particular, the time-dependent involvement of cAMP and cGMP in memory consolidation was assessed by altering the time points of drug administration. Vardenafil (1 mg/kg, p.o.), rolipram (0.03 mg/kg, i.p.), and BAY 60-7550 (3 mg/kg, p.o.) were tested in rats with a 24 h delay between the learning and the test trial. The PDE-Is were administered at different time points, i.e. directly after, 1 h, 3 h and 6 h after the first trial. Using a 24 h interval, vardenafil only showed an effect on object memory when injected directly after trial 1, rolipram only showed an improvement when injected 3 h after trial 1 and BAY 60-7550 improved memory when injected either directly after or 3 h after trial 1. No treatment effects were found when the compounds were administered 1 h or 6 h after the first trial. Our results extend our previous data that different types of PDE-Is affect different stages of memory consolidation. Moreover, the present study provides further support that selective PDE-Is can influence memory consolidation in a time-dependent manner, assumingly by elevating central cAMP and cGMP levels.
PMID: 17207788 [PubMed - indexed for MEDLINE]
* Rutten K,
* Prickaerts J,
* Hendrix M,
* van der Staay FJ,
* Sik A,
* Blokland A.
Department of Psychiatry and Neuropsychology, Brain and Behavior Institute, EURON, Maastricht
The present study investigated the time-dependent memory enhancing properties of three selective phosphodiesterase inhibitors (PDE-I) vardenafil (PDE5-I), rolipram (PDE4-I) and BAY 60-7550 (PDE2-I) in the object recognition task. In particular, the time-dependent involvement of cAMP and cGMP in memory consolidation was assessed by altering the time points of drug administration. Vardenafil (1 mg/kg, p.o.), rolipram (0.03 mg/kg, i.p.), and BAY 60-7550 (3 mg/kg, p.o.) were tested in rats with a 24 h delay between the learning and the test trial. The PDE-Is were administered at different time points, i.e. directly after, 1 h, 3 h and 6 h after the first trial. Using a 24 h interval, vardenafil only showed an effect on object memory when injected directly after trial 1, rolipram only showed an improvement when injected 3 h after trial 1 and BAY 60-7550 improved memory when injected either directly after or 3 h after trial 1. No treatment effects were found when the compounds were administered 1 h or 6 h after the first trial. Our results extend our previous data that different types of PDE-Is affect different stages of memory consolidation. Moreover, the present study provides further support that selective PDE-Is can influence memory consolidation in a time-dependent manner, assumingly by elevating central cAMP and cGMP levels.
PMID: 17207788 [PubMed - indexed for MEDLINE]
QUOTE
Dissociable effects of acetylcholinesterase inhibitors and phosphodiesterase type 5 inhibitors on object recognition memory: acquisition versus consolidation.
* Prickaerts J,
* Sik A,
* van der Staay FJ,
* de Vente J,
* Blokland A.
Department of Psychiatry and Neuropsychology, Brain and Behavior Institute, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands.
RATIONALE: Phosphodiesterase enzyme type 5 (PDE5) inhibitors and acetylcholinesterase (AChE) inhibitors have cognition-enhancing properties. However, it is not known whether these drug classes affect the same memory processes. OBJECTIVE: We investigated the memory-enhancing effects of the PDE5 inhibitor sildenafil and AChE inhibitors metrifonate and donepezil in the object recognition task to find out whether acquisition or consolidation processes were affected by these drugs. METHODS: The object recognition task measures whether rats remembered an object they have explored in a previous learning trial. All drugs were given orally 30 min before or immediately after learning to study acquisition and consolidation, respectively. RESULTS: Sildenafil given immediately after the first trial improved the memory performance after 24 h and resulted in an inverted U-shaped dose-effect curve with the peak dose at 3 mg/kg. When given before the first trial, sildenafil also improved the memory performance. However, the dose needed for the best performance under this condition was 10 mg/kg, suggesting that the dose-effect curve shifted to the right. This can be explained by the metabolic clearance of the high dose of sildenafil. Donepezil had no memory improving effect when given after the first trial. However, when given before the first trial, a gradually increasing dose-effect curve was found which had its maximum effect at the highest dose tested (1 mg/kg). Likewise, only when metrifonate (30 mg/kg) was given before the first trial did rats show an improved memory performance. CONCLUSION: Our data strongly suggest that PDE5 inhibitors improve processes of consolidation of object information, whereas AChE inhibitors improve processes of acquisition of object information.
PMID: 15630588 [PubMed - indexed for MEDLINE]
* Prickaerts J,
* Sik A,
* van der Staay FJ,
* de Vente J,
* Blokland A.
Department of Psychiatry and Neuropsychology, Brain and Behavior Institute, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands.
RATIONALE: Phosphodiesterase enzyme type 5 (PDE5) inhibitors and acetylcholinesterase (AChE) inhibitors have cognition-enhancing properties. However, it is not known whether these drug classes affect the same memory processes. OBJECTIVE: We investigated the memory-enhancing effects of the PDE5 inhibitor sildenafil and AChE inhibitors metrifonate and donepezil in the object recognition task to find out whether acquisition or consolidation processes were affected by these drugs. METHODS: The object recognition task measures whether rats remembered an object they have explored in a previous learning trial. All drugs were given orally 30 min before or immediately after learning to study acquisition and consolidation, respectively. RESULTS: Sildenafil given immediately after the first trial improved the memory performance after 24 h and resulted in an inverted U-shaped dose-effect curve with the peak dose at 3 mg/kg. When given before the first trial, sildenafil also improved the memory performance. However, the dose needed for the best performance under this condition was 10 mg/kg, suggesting that the dose-effect curve shifted to the right. This can be explained by the metabolic clearance of the high dose of sildenafil. Donepezil had no memory improving effect when given after the first trial. However, when given before the first trial, a gradually increasing dose-effect curve was found which had its maximum effect at the highest dose tested (1 mg/kg). Likewise, only when metrifonate (30 mg/kg) was given before the first trial did rats show an improved memory performance. CONCLUSION: Our data strongly suggest that PDE5 inhibitors improve processes of consolidation of object information, whereas AChE inhibitors improve processes of acquisition of object information.
PMID: 15630588 [PubMed - indexed for MEDLINE]