sildenafil-citrate and Cognition-Disorders

The objective of this paper is to look at how natural medicines can improve cognition and memory when used with sildenafil, a popular erectile dysfunction medicine that also has nootropic properties. Newer treatment strategies to treat the early stages of these diseases need to be developed. Multiple factors lead to complex pathophysiological conditions, which are responsible for various long-term complications. In this review, a combination of treatments targeting these pathologies is discussed. These combinations may help manage early and later phases of cognitive impairments. The purpose of this article is to discuss a link between these pathologies and a combinational approach with the objective of considering newer therapeutic strategies in the treatment of cognitive impairments. The natural drugs and their ingredients play a major role in the management of disease progression. Additionally, their combination with sildenafil allows for more efficacy and better response. Studies showing the effectiveness of natural drugs and sildenafil are mentioned, and how these combinations could be beneficial for the treatment of cognitive impairments and amnesia are summarised. Furthermore, preclinical and clinical trials are required to explore the medicinal potential of these drug combinations.

Topics: Amnesia; Cognition; Cognition Disorders; Cognitive Dysfunction; Humans; Male; Sildenafil Citrate

Phosphodiesterase 5 (PDE5) inhibitors increase cyclic guanosine monophosphate (cGMP) concentrations in the intracellular pathway activated by N-methyl-D-aspartic acid receptors which is believed to mediate long-term potentiation and memory consolidation. The PDE5 inhibitor sildenafil has been shown to enhance memory in animal models. In addition, neuronal nitric oxide synthase, another component of the NMDA/nitric oxide/cGMP intracellular pathway, has been reported to be dysregulated in schizophrenia patients.. Seventeen adult schizophrenia outpatients treated with a stable dose of antipsychotic received a single oral dose of placebo, sildenafil 50 mg, and sildenafil 100 mg in random order with a 48-h interval between administrations. Psychiatric symptom ratings and a cognitive battery were performed at baseline and 1 hour following each administration of the study drug. In addition, memory consolidation was examined by testing recall 48 h later, prior to the next administration of the study drug.. Fifteen subjects completed all three treatment conditions. One subject developed irritability and required hospitalization 2 days after receiving sildenafil 100 mg. Neither dose of sildenafil significantly affected cognitive performance or symptom ratings compared to the placebo.. Despite evidence for cognitive-enhancing effects of sildenafil in animal models, the strategy for treating putative NMDA receptor-mediated memory deficits in schizophrenia with sildenafil 50 and 100 mg was not successful. It is possible that the doses used in this study were not optimal or that repeated dosing may be necessary to achieve therapeutic effects. Agents under development that inhibit other subtypes of PDE remain promising for schizophrenia and dementia.

Topics: Cognition Disorders; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Memory; Middle Aged; Neuropsychological Tests; Phosphodiesterase Inhibitors; Piperazines; Psychiatric Status Rating Scales; Psychomotor Performance; Purines; Schizophrenia; Schizophrenic Psychology; Sildenafil Citrate; Sulfones

The senescence-accelerated mouse-prone 8 (SAMP8), used as a model of aging, displays many established pathological features of Alzheimer's disease. Cognitive impairments and increased levels of hyperphosphorylated tau are found in the hippocampus of SAMP8 mice along with an increased β-secretase activity and amyloid-β (Aβ) depositions that increase in number and extent with age. Based on a previous study from our laboratory showing an amelioration of cognitive impairments and tau pathology by sildenafil, in this study we tested whether this drug could also modulate the amyloid precursor protein amyloidogenic processing in this mouse model. Our results show that the protein levels of the β-secretases β-site amyloid precursor protein cleaving enzyme 1 and cathepsin B are higher in the hippocampus of 9-month-old SAMP8 mice than those of age-matched senescence-resistant-1. Sildenafil (7.5mg/kg for 4 weeks) attenuated learning and memory impairments shown by SAMP8 mice in the passive avoidance test. The increased expression of β-site amyloid precursor protein cleaving enzyme 1 was also reduced by sildenafil, an effect paralleled to decreases in the activities of two β-site amyloid precursor protein cleaving enzyme 1 modulators, calpain and cyclin-dependent kinase 5 protein. Interestingly, sildenafil enhanced both Akt and glycogen synthase kinase-3β (ser9) phosphorylation, which could be mediating the reduction in cathepsin B levels found in the hippocampus of sildenafil-treated SAMP8 mice. Sildenafil-induced reduction in β-site amyloid precursor protein cleaving enzyme 1 and cathepsin B expression in SAMP8 mice was associated with a decrease in hippocampal Aβ42 levels which, in turn, could mediate the parallel decline in glial fibrillary acidic protein expression observed in these animals. These findings highlight the therapeutic potential of sildenafil in Alzheimer's disease pathogenesis.

Topics: Aging; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Calpain; Cathepsin B; Cognition Disorders; Cyclin-Dependent Kinase 5; Glial Fibrillary Acidic Protein; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Hippocampus; Mice; Models, Animal; Phosphodiesterase 5 Inhibitors; Phosphorylation; Piperazines; Proto-Oncogene Proteins c-akt; Purines; RNA, Messenger; Sildenafil Citrate; Sulfonamides

The senescence accelerated mouse-prone 8 (SAMP8) strain of mice is an experimental model of accelerated senescence that also shares several pathological features with Alzheimer's disease. Among them, cognitive impairments and abnormal hyperphosphorylation of tau are ameliorated by the phosphodiesterase 5 inhibitor sildenafil, possibly through the modulation of Cdk5/p25 and Akt/GSK-3β pathways. Here we studied the implication of protein phosphatase 2A (PP2A) and c-Jun N-terminal kinase (JNK) in the therapeutic effects of sildenafil. Results demonstrated that there were no differences in hippocampal PP2A protein levels or activity (measured by its inactive isoform phopho-PP2A Y307) when we compared 6-month old SAMP8 mice and age-matched control, SAMR1 mice, treated with saline or sildenafil (7.5mg/kg i.p. for 4 weeks). However, this same treatment of sildenafil, that had been shown to reverse the cognitive impairment and tau hyperphosphorylation in this animal model, also reversed the increased levels of activated JNK (p-JNK) found in the hippocampus of SAMP8 mice. Moreover, the administration of the JNK inhibitor, D-JNKI-1 (0.2mg/kg i.p. for 3 weeks) also ameliorated the cognitive deficits shown by SAMP8 mice in the Morris water maze and decreased hippocampal levels of phospho-c-Jun(Ser73). When phosphorylated tau (AT8 epitope) was analyzed a significant reduction was observed in the hippocampus of D-JNKI-1 treated SAMP8 mice, providing a plausible explanation for the attenuation of cognitive decline shown by these animals. These findings suggest the involvement of the JNK pathway on tau pathology and cognitive deficits shown by 6-month old SAMP8 mice. They also point to the modulation of this kinase to be among the mechanisms responsible for the beneficial effects shown by sildenafil.

Topics: Aging; Animals; Cognition Disorders; Disease Models, Animal; Hippocampus; Male; MAP Kinase Signaling System; Maze Learning; Mice; Phosphorylation; Piperazines; Purines; Sildenafil Citrate; Space Perception; Sulfones; tau Proteins; Tauopathies; Vasodilator Agents

Memory deficit is a marker of Alzheimer's disease (AD) that has been highly associated with the dysfunction of cyclic GMP (cGMP) signaling and an ongoing inflammatory process. Phosphodiesterase-5 (PDE5) inhibitors prevent the breakdown of cGMP and are currently studied as a possible target for cognitive enhancement. However, it is still unknown whether inhibition of PDE5 reversed β-amyloid peptide (Aβ)-induced neuroinflammation in APP/PS1 transgenic (Tg APP/PS1) mice. The present study evaluated the cognitive behaviors, inflammatory mediators, and cGMP/PKG/pCREB signaling in 15-month-old Tg APP/PS1 mice and age-matched wild-type (WT) mice that were treated with PDE5 inhibitor sildenafil and the inhibitor of cGMP-dependent protein kinase Rp-8-Br-PET-cGMPS. In comparison with WT mice, Tg APP/PS1 mice were characterized by impaired cognitive ability, neuroinflammatory response, and down-regulated cGMP signaling. Sildenafil reversed these memory deficits and cGMP/PKG/pCREB signaling dysfunction; it also reduced both the soluble Aβ1-40 and Aβ1-42 levels in the hippocampus. These effects of sildenafil were prevented by intra-hippocampal infusion of the Rp-8-Br-PET-cGMPS. These results suggest that sildenafil could restore cognitive deficits in Tg APP/PS1 mice by the regulation of PKG/pCREB signaling, anti-inflammatory response and reduction of Aβ levels.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Cognition Disorders; Cyclic GMP; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalitis; Exploratory Behavior; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Phosphodiesterase 5 Inhibitors; Piperazines; Presenilin-1; Purines; Recognition, Psychology; RNA, Messenger; Sildenafil Citrate; Sulfones; Thionucleotides

Huntington's disease (HD) patients and mouse models show learning and memory impairment associated with hippocampal dysfunction. The neuronal nitric oxide synthase/3',5'-cyclic guanosine monophosphate (nNOS/cGMP) pathway is implicated in synaptic plasticity, and in learning and memory processes. Here, we examined the nNOS/cGMP pathway in the hippocampus of HD mice to determine whether it can be a good therapeutic target for cognitive improvement in HD. We analyzed hippocampal nNOS and phosphodiesterase (PDE) 5 and 9 levels in R6/1 mice, and cGMP levels in the hippocampus of R6/1, R6/2 and Hdh(Q7/Q111) mice, and of HD patients. We also investigated whether sildenafil, a PDE5 inhibitor, could improve cognitive deficits in R6/1 mice. We found that hippocampal cGMP levels were 3-fold lower in 12-week-old R6/1 mice, when they show deficits in object recognition memory and in passive avoidance learning. Consistent with hippocampal cGMP levels, nNOS levels were down-regulated, while there were no changes in the levels of PDE5 and PDE9 in R6/1 mice. A single intraperitoneal injection of sildenafil (3 mg/Kg) immediately after training increased cGMP levels, and improved memory in R6/1 mice, as assessed by using the novel object recognition and the passive avoidance test. Importantly, cGMP levels were also reduced in R6/2 mouse and human HD hippocampus. Therefore, the regulation of hippocampal cGMP levels can be a suitable treatment for cognitive impairment in HD.

Topics: Adult; Aged; Aged, 80 and over; Animals; Anxiety; Autopsy; Avoidance Learning; Blotting, Western; Cognition Disorders; Cyclic GMP; Down-Regulation; Female; Hippocampus; Humans; Huntington Disease; Male; Memory; Mice; Mice, Transgenic; Middle Aged; Motor Activity; Nitric Oxide Synthase Type I; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Previous studies have demonstrated that cognitive function can be restored in mouse models of Alzheimer's disease (AD) following administration of sildenafil, a specific PDE5 inhibitor (Puzzo et al., 2009; Cuadrado-Tejedor et al.). Another very potent PDE5 inhibitor with a longer half-life and safe in chronic treatments, tadalafil, may represent a better alternative candidate for AD therapy. However, tadalafil was proven unable to achieve similar benefits than those of sildenafil in AD animal models (Puzzo et al., 2009). The lack of efficacy was attributed to inability to cross the blood-brain barrier (BBB). In this paper we first measured the blood and brain levels of tadalafil to prove that the compound crosses BBB and that chronic treatment leads to accumulation in the brain of the J20 transgenic mouse model of AD. We demonstrated the presence of PDE5 mRNA in the brain of the mice and also in the human brain. After a 10 week treatment with either of these PDE5 inhibitors, the performance of the J20 mice in the Morris water maze test improved when compared with the transgenic mice that received vehicle. Biochemical analysis revealed that neither sildenafil nor tadalafil altered the amyloid burden, although both compounds reduced Tau phosphorylation in the mouse hippocampus. This study provides evidence of the potential benefits of a chronic tadalafil treatment in AD therapy. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Topics: Alzheimer Disease; Animals; Blood-Brain Barrier; Brain; Carbolines; Cognition Disorders; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Female; Gene Expression Regulation, Enzymologic; Half-Life; Humans; Macaca fascicularis; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nootropic Agents; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Species Specificity; Sulfones; Tadalafil; Tissue Distribution

Aging is associated with a deterioration of cognitive performance and with increased risk of neurodegenerative disorders. In the present study we tested whether the specific phosphodiesterase 5 inhibitor sildenafil could ameliorate the age-dependent cognitive impairments shown by the senescence-accelerated mouse prone-8 (SAMP8). Sildenafil administration (7.5 mg/kg for 4 weeks) to 5-month-old SAMP8 mice attenuated spatial learning and memory impairments shown by these mice in the Morris Water Maze. Tau hyperphosphorylation (AT8 but not PHF-1 epitope) shown by SAMP8 mice at this age was also decreased in the hippocampus of sildenafil-treated mice, an effect probably related to a decrease in cyclin-dependent kinase 5 protein expression and activity (p25/p35 ratio). Interestingly, sildenafil also phosphorylated Akt, which was associated with an increase of glycogen synthase kinase-3β phosphorylation, providing a plausible explanation for the reductions in tau hyperphosphorylation (AT8 and PHF-1 epitopes) and attenuation of cognitive deficits shown by 9-month-old SAMP8 mice. Overall, sildenafil might be beneficial in age-related brain dysfunction and could be an emerging candidate for the treatment of other neurodegenerative diseases.

Topics: Aging; Animals; Cognition Disorders; Disease Models, Animal; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Male; Mice; Mice, Neurologic Mutants; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tauopathies

The ethical dimensions of pharmacological cognitive enhancement have been widely discussed in academic circles and the popular media, but missing from the conversation have been the perspectives of physicians - key decision makers in the adoption of new technologies into medical practice. We queried primary care physicians in major urban centers in Canada and the United States with the aim of understanding their attitudes towards cognitive enhancement. Our primary hypothesis was that physicians would be more comfortable prescribing cognitive enhancers to older patients than to young adults. Physicians were presented with a hypothetical pharmaceutical cognitive enhancer that had been approved by the regulatory authorities for use in healthy adults, and was characterized as being safe, effective, and without significant adverse side effects. Respondents overwhelmingly reported increasing comfort with prescribing cognitive enhancers as the patient age increased from 25 to 65. When asked about their comfort with prescribing extant drugs that might be considered enhancements (sildenafil, modafinil, and methylphenidate) or our hypothetical cognitive enhancer to a normal, healthy 40 year old, physicians were more comfortable prescribing sildenafil than any of the other three agents. When queried as to the reasons they answered as they did, the most prominent concerns physicians expressed were issues of safety that were not offset by the benefit afforded the individual, even in the face of explicit safety claims. Moreover, many physicians indicated that they viewed safety claims with considerable skepticism. It has become routine for safety to be raised and summarily dismissed as an issue in the debate over pharmacological cognitive enhancement; the observation that physicians were so skeptical in the face of explicit safety claims suggests that such a conclusion may be premature. Thus, physician attitudes suggest that greater weight be placed upon the balance between safety and benefit in consideration of pharmacological cognitive enhancement.

Topics: Adult; Aged; Benzhydryl Compounds; Central Nervous System Stimulants; Cognition; Cognition Disorders; Drug Therapy; Drug Utilization; Female; Health Knowledge, Attitudes, Practice; Humans; Male; Methylphenidate; Middle Aged; Modafinil; Nootropic Agents; Physicians; Piperazines; Practice Patterns, Physicians'; Purines; Safety; Sildenafil Citrate; Sulfones