cGMP-Phosphodiesterase Inhibition Enhances Photic Responses and Synchronization of the Biological Circadian Clock in Rodents
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{"title"=>"CGMP-phosphodiesterase inhibition enhances photic responses and synchronization of the biological circadian clock in rodents", "type"=>"journal", "authors"=>[{"first_name"=>"Santiago A.", "last_name"=>"Plano", "scopus_author_id"=>"8700335100"}, {"first_name"=>"Patricia V.", "last_name"=>"Agostino", "scopus_author_id"=>"6506504178"}, {"first_name"=>"Horacio O.", "last_name"=>"de la Iglesia", "scopus_author_id"=>"6602832047"}, {"first_name"=>"Diego A.", "last_name"=>"Golombek", "scopus_author_id"=>"7005783583"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"364803045", "sgr"=>"84861014717", "issn"=>"19326203", "pmid"=>"22590651", "scopus"=>"2-s2.0-84861014717", "doi"=>"10.1371/journal.pone.0037121", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)"}, "id"=>"673a0787-3267-38e9-a10f-7062441164c6", "abstract"=>"The master circadian clock in mammals is located in the hypothalamic suprachiasmatic nuclei (SCN) and is synchronized by several environmental stimuli, mainly the light-dark (LD) cycle. Light pulses in the late subjective night induce phase advances in locomotor circadian rhythms and the expression of clock genes (such as Per1-2). The mechanism responsible for light-induced phase advances involves the activation of guanylyl cyclase (GC), cGMP and its related protein kinase (PKG). Pharmacological manipulation of cGMP by phosphodiesterase (PDE) inhibition (e.g., sildenafil) increases low-intensity light-induced circadian responses, which could reflect the ability of the cGMP-dependent pathway to directly affect the photic sensitivity of the master circadian clock within the SCN. Indeed, sildenafil is also able to increase the phase-shifting effect of saturating (1200 lux) light pulses leading to phase advances of about 9 hours, as well as in C57 a mouse strain that shows reduced phase advances. In addition, sildenafil was effective in both male and female hamsters, as well as after oral administration. Other PDE inhibitors (such as vardenafil and tadalafil) also increased light-induced phase advances of locomotor activity rhythms and accelerated reentrainment after a phase advance in the LD cycle. Pharmacological inhibition of the main downstream target of cGMP, PKG, blocked light-induced expression of Per1. Our results indicate that the cGMP-dependent pathway can directly modulate the light-induced expression of clock-genes within the SCN and the magnitude of light-induced phase advances of overt rhythms, and provide promising tools to design treatments for human circadian disruptions.", "link"=>"http://www.mendeley.com/research/cgmpphosphodiesterase-inhibition-enhances-photic-responses-synchronization-biological-circadian-cloc", "reader_count"=>21, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Researcher"=>5, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>8, "Student > Master"=>2, "Professor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Researcher"=>5, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>8, "Student > Master"=>2, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>2, "Agricultural and Biological Sciences"=>14, "Medicine and Dentistry"=>1, "Neuroscience"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Neuroscience"=>{"Neuroscience"=>1}, "Chemistry"=>{"Chemistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>14}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Argentina"=>1, "United Kingdom"=>2, "Germany"=>2}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/640580"], "description"=>"<p>Administration of KT-5823 (icv, 200 µM, 1,5 µl), a PKG inhibitor, significantly blocked light-induced <i>Per1</i> expression in the hamster SCN (p = 0.023 compared with light, ANOVA followed by Tukey's test), while KT-5823 alone had no effect on <i>Per1</i> induction. Data represented as mean of relative OD (ratio OD SCN/OD surrounding hypothalamus) ±SD.</p>", "links"=>[], "tags"=>["inhibition", "pkg", "blocks", "light-induced"], "article_id"=>311072, "categories"=>["Physiology", "Molecular Biology", "Neuroscience", "Pharmacology"], "users"=>["Santiago A. Plano", "Patricia V. Agostino", "Horacio O. de la Iglesia", "Diego A. Golombek"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0037121.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_inhibition_of_PKG_blocks_light_induced_Per1_expression_in_the_SCN_/311072", "title"=>"The inhibition of PKG blocks light-induced <i>Per1</i> expression in the SCN.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-10 00:17:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/640357"], "description"=>"<p>In control animals a 300 lux light pulse induced a significantly higher phase advance than a 50 lux light pulse, while there was no difference between the 1200 lux and 300 lux groups. In contrast, the analysis of sildenafil treatment shows significant differences within the three groups (see text for details). All data represented as mean (± SD). Representative actograms (top) are presented for vehicle or drug treatment; time of injection and LP are indicated by a star, a grey bar shows estimated onset.</p>", "links"=>[], "tags"=>["increases", "light-induced"], "article_id"=>310851, "categories"=>["Physiology", "Molecular Biology", "Neuroscience", "Pharmacology"], "users"=>["Santiago A. Plano", "Patricia V. Agostino", "Horacio O. de la Iglesia", "Diego A. Golombek"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0037121.g001", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Sildenafil_administration_increases_light_induced_phase_advances_/310851", "title"=>"Sildenafil administration increases light-induced phase advances.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-10 00:14:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/640720"], "description"=>"<p>A) and B) 50 lux light pulses at CT18 induced a phase advance that was significantly increased by sildenafil, vardenafil or taladafil as compared to vehicle-treated animals. Representative actograms in panel A show vehicle or drug treated-animals; time of injection and LP are indicated by a star and the grey bar shows locomotor activity onsets. Panel B shows the average results, ANOVA-p<0.001- followed by Tukey's Test **p<0,0025. C) Representative actograms showing reentrainment to a 6 h phase advance of the LD cycle for vehicle or drug-treated animals; dark phases are indicated by gray shading and a black bar depicts the transient days until the new phase. Grey horizontal bars indicate computer malfunction. D) Animals injected with PDEs inhibitors entrained significantly faster to a 6-hr advance of the LD cycle than those injected with vehicle. N = 6 per group. ANOVA-P = 0.0011- followed by Tukey's Test *P<0.05, **p<0.0025. All data represented as mean (± SD).</p>", "links"=>[], "tags"=>["inhibition", "compounds", "increases", "low-intensity", "light-induced", "advances", "accelerates", "circadian"], "article_id"=>311203, "categories"=>["Physiology", "Molecular Biology", "Neuroscience", "Pharmacology"], "users"=>["Santiago A. Plano", "Patricia V. Agostino", "Horacio O. de la Iglesia", "Diego A. Golombek"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0037121.g006", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PDE_inhibition_by_different_compounds_increases_low_intensity_light_induced_phase_advances_and_accelerates_circadian_reentrainment_/311203", "title"=>"PDE inhibition by different compounds increases low-intensity light-induced phase advances and accelerates circadian reentrainment.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-10 00:20:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/640509"], "description"=>"<p>300 lux light pulse (10 min.) at CT19 after sildenafil injection induced a phase advance that was significantly higher than the one for vehicle-treated animals. **p<0,0025 Student's t-test (n = 8 per group). Data represented as mean (±SD) Representative actograms (top) show vehicle or drug treatment, time of injection and LP are indicated by a star.</p>", "links"=>[], "tags"=>["inhibition", "increases", "300", "lux", "light-induced"], "article_id"=>310999, "categories"=>["Physiology", "Molecular Biology", "Neuroscience", "Pharmacology"], "users"=>["Santiago A. Plano", "Patricia V. Agostino", "Horacio O. de la Iglesia", "Diego A. Golombek"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0037121.g003", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PDE_inhibition_increases_300_lux_light_induced_phase_advance_in_mice_/310999", "title"=>"PDE inhibition increases 300 lux light-induced phase advance in mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-10 00:16:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/330346"], "description"=>"<div><p>The master circadian clock in mammals is located in the hypothalamic suprachiasmatic nuclei (SCN) and is synchronized by several environmental stimuli, mainly the light-dark (LD) cycle. Light pulses in the late subjective night induce phase advances in locomotor circadian rhythms and the expression of clock genes (such as <em>Per1-2</em>). The mechanism responsible for light-induced phase advances involves the activation of guanylyl cyclase (GC), cGMP and its related protein kinase (PKG). Pharmacological manipulation of cGMP by phosphodiesterase (PDE) inhibition (e.g., sildenafil) increases low-intensity light-induced circadian responses, which could reflect the ability of the cGMP-dependent pathway to directly affect the photic sensitivity of the master circadian clock within the SCN. Indeed, sildenafil is also able to increase the phase-shifting effect of saturating (1200 lux) light pulses leading to phase advances of about 9 hours, as well as in C57 a mouse strain that shows reduced phase advances. In addition, sildenafil was effective in both male and female hamsters, as well as after oral administration. Other PDE inhibitors (such as vardenafil and tadalafil) also increased light-induced phase advances of locomotor activity rhythms and accelerated reentrainment after a phase advance in the LD cycle. Pharmacological inhibition of the main downstream target of cGMP, PKG, blocked light-induced expression of <em>Per1</em>. Our results indicate that the cGMP-dependent pathway can directly modulate the light-induced expression of clock-genes within the SCN and the magnitude of light-induced phase advances of overt rhythms, and provide promising tools to design treatments for human circadian disruptions.</p> </div>", "links"=>[], "tags"=>["cgmp-phosphodiesterase", "inhibition", "enhances", "photic", "responses", "synchronization", "circadian", "rodents"], "article_id"=>125229, "categories"=>["Physiology", "Molecular Biology", "Neuroscience", "Pharmacology"], "users"=>["Santiago A. Plano", "Patricia V. Agostino", "Horacio O. de la Iglesia", "Diego A. Golombek"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0037121", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/cGMP_Phosphodiesterase_Inhibition_Enhances_Photic_Responses_and_Synchronization_of_the_Biological_Circadian_Clock_in_Rodents/125229", "title"=>"cGMP-Phosphodiesterase Inhibition Enhances Photic Responses and Synchronization of the Biological Circadian Clock in Rodents", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-10 01:27:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/640440"], "description"=>"<p>Male hamsters injected with sildenafil entrained their body temperature rhythm to a 6-hr advance of the LD cycle significantly faster than those injected with vehicle. N = 6 per group. *p<0.05, Student's t-test. Data represented as mean (±SD). Representative actograms (top) shows body temperature values between 36 and 39°C. Dark phases are indicated by gray shading.</p>", "links"=>[], "tags"=>["inhibition", "accelerates", "circadian", "reentrainment", "jetlag", "simulation"], "article_id"=>310926, "categories"=>["Physiology", "Molecular Biology", "Neuroscience", "Pharmacology"], "users"=>["Santiago A. Plano", "Patricia V. Agostino", "Horacio O. de la Iglesia", "Diego A. Golombek"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0037121.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PDE_inhibition_accelerates_circadian_reentrainment_of_body_temperature_in_a_jetlag_simulation_model_/310926", "title"=>"PDE inhibition accelerates circadian reentrainment of body temperature in a jetlag simulation model.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-10 00:15:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/640642"], "description"=>"<p>Animals were sacrificed 5 or 60 minutes after LP. Sildenafil administration increased the number of PER1-ir cells in the SCN. Two-way ANOVA indicated a significant effect of treatment (p&lt;0.0001) and time (p&lt;0.0001), with interaction between these two factors (p = 0.0011) due to the basal expression at 5 min group. A t-Test demonstrates no differences in 5 min group between vehicle an sildenafil (100±4.918 vs. 110±3.96. respectably. p = 0.1294) but shows an increase in the PER1-ir cells at 60 min. (314.4±8.103 vs. 401.1±17.99 respectably. P = 0.0009) (n = 8 per group). Representative coronal sections from hamsters containing the medio-caudal portion of the SCN 5 and 60 min after light pulse with previous injection of sildenafil or vehicle (3 V: third ventricle; OC: optic chiasm; Scale bars: 100 mm).</p>", "links"=>[], "tags"=>["sildenafil", "30", "300", "lux", "light-induced"], "article_id"=>311135, "categories"=>["Pharmacology", "Neuroscience", "Molecular Biology", "Physiology"], "users"=>["Santiago A. Plano", "Patricia V. Agostino", "Horacio O. de la Iglesia", "Diego A. Golombek"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0037121.g005", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Administration_of_Sildenafil_3_5_mg_kg_30_min_before_a_300_lux_light_pulse_increase_the_light_induced_phase_advance_/311135", "title"=>"Administration of Sildenafil (3.5 mg/kg) 30 min. before a 300 lux light pulse increase the light-induced phase advance.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-10 00:18:55"}

PMC Usage Stats | Further Information

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Relative Metric

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