PDE3 inhibition by cilostazol attenuated developmental hyperserotonemia induced behavioural and biochemical deficits in a rat model of autism spectrum disorder / Kanishk LUHACH in Research in Autism Spectrum Disorders, 99 (November)  

Public ISBD [article]  inResearch in Autism Spectrum Disorders > 99 (November) . - 102052 Titre : PDE3 inhibition by cilostazol attenuated developmental hyperserotonemia induced behavioural and biochemical deficits in a rat model of autism spectrum disorder Type de document : texte imprimé Auteurs : Kanishk LUHACH, Auteur ; Bhagwat SINGH, Auteur ; Himanshu AGGARWAL, Auteur ; Bhupesh SHARMA, Auteur Article en page(s) : 102052 Langues : Anglais (eng) Mots-clés : Developmental hyperserotonemia  Phosphodiesterase 3  BDNF  Neuroinflammation  Oxidative stress Index. décimale : PER Périodiques Résumé : Background Hyperserotonemia, in the early developmental phase generates behavioural and biochemical phenotypes associated with autism spectrum disorder (ASD) in rats. Phosphodiesterase-3 (PDE3) inhibition by cilostazol has been shown to provide benefits in various brain conditions. We investigated the role of a selective PDE3 inhibitor cilostazol on ASD related behavioural phenotypes. Method Administration of 5-Methoxytryptamine (5-MT) to rats perinatally (GD12-Parturition) and in early developmental stages (PND0-PND20), resulted into developmental hyperserotonemia (DHS). DHS associated behavioural changes (social behaviour deficits, repetitive behaviour, anxiety and hyperlocomotion) were assessed using a battery of behavioural examinations. Also, effect on biochemical markers related with neuronal function (BDNF - neuronal survival and pCREB - neuronal transcription factor), inflammation (IL-6, IL-10 and TNF-ÃŽ+) and oxidative stress (TBARS and GSH) were studied in important brain areas (frontal cortex, cerebellum, hippocampus, and striatum). Cilostazol was administered in two doses 30 & 60 mg.kg-1 p.o. each day to male rats from PND21 to PND48. Result Administration of cilostazol to 5-MT rats resulted in improvement of behavioural deficits. Also, cilostazol administration significantly increased the levels of BDNF, pCREB, IL-10, GSH and significantly decreased TNF-ÃŽ+, IL-6 and TBARS levels in different brain areas. Conclusion DHS during prenatal and early postnatal developmental stages leads to pervasive harm to the serotonergic system, leading to prolonged effects as observed via behavioural and biochemical outcomes of the study. Serotonin regulates early brain neurogenesis, synaptogenesis, and neuronal differentiation probably via the CREB/BDNF pathway and DHS is known to reduce the activity of CREB/BDNF pathway. Cilostazol administration to pups exposed to DHS perinatally has resulted in increase of neurotrophic factors, reduced inflammation and reduced oxidative stress, probably via increased cAMP/CREB/BDNF signalling. Also, improvement in behavioural profile of animals subjected to DHS. Thus, PDE3 and its inhibitors could be considered as molecules of interest for research in developmental disorders. En ligne : https://doi.org/10.1016/j.rasd.2022.102052 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=490 [article] PDE3 inhibition by cilostazol attenuated developmental hyperserotonemia induced behavioural and biochemical deficits in a rat model of autism spectrum disorder [texte imprimé] / Kanishk LUHACH, Auteur ; Bhagwat SINGH, Auteur ; Himanshu AGGARWAL, Auteur ; Bhupesh SHARMA, Auteur . - 102052. Langues : Anglais (eng) in Research in Autism Spectrum Disorders > 99 (November) . - 102052 Mots-clés : Developmental hyperserotonemia  Phosphodiesterase 3  BDNF  Neuroinflammation  Oxidative stress Index. décimale : PER Périodiques Résumé : Background Hyperserotonemia, in the early developmental phase generates behavioural and biochemical phenotypes associated with autism spectrum disorder (ASD) in rats. Phosphodiesterase-3 (PDE3) inhibition by cilostazol has been shown to provide benefits in various brain conditions. We investigated the role of a selective PDE3 inhibitor cilostazol on ASD related behavioural phenotypes. Method Administration of 5-Methoxytryptamine (5-MT) to rats perinatally (GD12-Parturition) and in early developmental stages (PND0-PND20), resulted into developmental hyperserotonemia (DHS). DHS associated behavioural changes (social behaviour deficits, repetitive behaviour, anxiety and hyperlocomotion) were assessed using a battery of behavioural examinations. Also, effect on biochemical markers related with neuronal function (BDNF - neuronal survival and pCREB - neuronal transcription factor), inflammation (IL-6, IL-10 and TNF-ÃŽ+) and oxidative stress (TBARS and GSH) were studied in important brain areas (frontal cortex, cerebellum, hippocampus, and striatum). Cilostazol was administered in two doses 30 & 60 mg.kg-1 p.o. each day to male rats from PND21 to PND48. Result Administration of cilostazol to 5-MT rats resulted in improvement of behavioural deficits. Also, cilostazol administration significantly increased the levels of BDNF, pCREB, IL-10, GSH and significantly decreased TNF-ÃŽ+, IL-6 and TBARS levels in different brain areas. Conclusion DHS during prenatal and early postnatal developmental stages leads to pervasive harm to the serotonergic system, leading to prolonged effects as observed via behavioural and biochemical outcomes of the study. Serotonin regulates early brain neurogenesis, synaptogenesis, and neuronal differentiation probably via the CREB/BDNF pathway and DHS is known to reduce the activity of CREB/BDNF pathway. Cilostazol administration to pups exposed to DHS perinatally has resulted in increase of neurotrophic factors, reduced inflammation and reduced oxidative stress, probably via increased cAMP/CREB/BDNF signalling. Also, improvement in behavioural profile of animals subjected to DHS. Thus, PDE3 and its inhibitors could be considered as molecules of interest for research in developmental disorders. En ligne : https://doi.org/10.1016/j.rasd.2022.102052 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=490

Vinpocetine amended prenatal valproic acid induced features of ASD possibly by altering markers of neuronal function, inflammation, and oxidative stress / Kanishk LUHACH in Autism Research, 14-11 (November 2021)  

Public ISBD [article]  inAutism Research > 14-11 (November 2021) . - p.2270-2286 Titre : Vinpocetine amended prenatal valproic acid induced features of ASD possibly by altering markers of neuronal function, inflammation, and oxidative stress Type de document : texte imprimé Auteurs : Kanishk LUHACH, Auteur ; Giriraj T. KULKARNI, Auteur ; V.P. SINGH, Auteur ; Bhupesh SHARMA, Auteur Article en page(s) : p.2270-2286 Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder  Behavior, Animal  Biomarkers  Disease Models, Animal  Doublecortin Protein  Female  Inflammation  Oxidative Stress  Pregnancy  Prenatal Exposure Delayed Effects  Rats  Rats, Wistar  Valproic Acid  Vinca Alkaloids  Bdnf  doublecortin  phosphodiesterase  synapsin-IIa  valproic acid  vinpocetine Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex etiology and phenotypes. Phosphodiesterase-1 (PDE1) inhibitors are known to provide benefits in various brain conditions manifesting similar behavioral phenotypes. The pharmacological consequences of vinpocetine administration a PDE1 inhibitor in prenatal-valproic acid (pre-VPA) induced ASD related behavioral phenotypes (social behavior deficits, repetitive behavior, anxiety, hyperlocomotion, and nociception) was assessed. Also, effects on important biochemical markers of neuronal function (DCX-neurogenesis, BDNF-neuronal survival, synapsin-IIa-synaptic transmission, pCREB-neuronal transcription factor), inflammation (interleukin [IL]-6, IL-10, and TNF-α) and oxidative stress (thiobarbituric acid reactive substance [TBARS] and glutathione (GSH) were studied in important brain areas (frontal cortex, cerebral cortex, hippocampus, and striatum). Further, neuronal cell viability was determined in dentate gyrus using Nissl staining. Pre-VPA administration resulted into impaired behavior, brain biochemistry, and neuronal cell viability. Administration of vinpocetine resulted in improvements of pre-VPA impaired social behavior, repetitive behavior, anxiety, locomotion, and nociception. Also, vinpocetine resulted in a significant increase in the levels of BDNF, synapsin-IIa, DCX, pCREB/CREB, IL-10, and GSH along with significant decrease in TNF-α, IL-6, TBARS, number of pyknotic and chromatolytic cells in different brain areas of pre-VPA group. Finally, high association between behavioral parameters and biochemical parameters was observed upon Pearson's correlation analysis. Vinpocetine, a PDE1 inhibitor rectified important behavioral phenotypes related with ASD, possibly by improving neuronal function, brain inflammation and brain oxidative stress. Thus, PDE1 may be a possible target for further understanding ASD. LAY SUMMARY: ASD is a brain developmental disorder with a wide array of genetic and environmental factors. Many targets have been identified till date, but a clinical treatment is still afar. The results of this study indicate that vinpocetine administration resulted in amelioration of ASD associated symptomatology in rats, prenatally exposed to VPA. Our research adds a widely expressed brain enzyme PDE1, as a possible novel pharmacological target and opens-up a new line of enquiry for ASD treatment. En ligne : http://dx.doi.org/10.1002/aur.2597 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=450 [article] Vinpocetine amended prenatal valproic acid induced features of ASD possibly by altering markers of neuronal function, inflammation, and oxidative stress [texte imprimé] / Kanishk LUHACH, Auteur ; Giriraj T. KULKARNI, Auteur ; V.P. SINGH, Auteur ; Bhupesh SHARMA, Auteur . - p.2270-2286. Langues : Anglais (eng) in Autism Research > 14-11 (November 2021) . - p.2270-2286 Mots-clés : Animals  Autism Spectrum Disorder  Behavior, Animal  Biomarkers  Disease Models, Animal  Doublecortin Protein  Female  Inflammation  Oxidative Stress  Pregnancy  Prenatal Exposure Delayed Effects  Rats  Rats, Wistar  Valproic Acid  Vinca Alkaloids  Bdnf  doublecortin  phosphodiesterase  synapsin-IIa  valproic acid  vinpocetine Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex etiology and phenotypes. Phosphodiesterase-1 (PDE1) inhibitors are known to provide benefits in various brain conditions manifesting similar behavioral phenotypes. The pharmacological consequences of vinpocetine administration a PDE1 inhibitor in prenatal-valproic acid (pre-VPA) induced ASD related behavioral phenotypes (social behavior deficits, repetitive behavior, anxiety, hyperlocomotion, and nociception) was assessed. Also, effects on important biochemical markers of neuronal function (DCX-neurogenesis, BDNF-neuronal survival, synapsin-IIa-synaptic transmission, pCREB-neuronal transcription factor), inflammation (interleukin [IL]-6, IL-10, and TNF-α) and oxidative stress (thiobarbituric acid reactive substance [TBARS] and glutathione (GSH) were studied in important brain areas (frontal cortex, cerebral cortex, hippocampus, and striatum). Further, neuronal cell viability was determined in dentate gyrus using Nissl staining. Pre-VPA administration resulted into impaired behavior, brain biochemistry, and neuronal cell viability. Administration of vinpocetine resulted in improvements of pre-VPA impaired social behavior, repetitive behavior, anxiety, locomotion, and nociception. Also, vinpocetine resulted in a significant increase in the levels of BDNF, synapsin-IIa, DCX, pCREB/CREB, IL-10, and GSH along with significant decrease in TNF-α, IL-6, TBARS, number of pyknotic and chromatolytic cells in different brain areas of pre-VPA group. Finally, high association between behavioral parameters and biochemical parameters was observed upon Pearson's correlation analysis. Vinpocetine, a PDE1 inhibitor rectified important behavioral phenotypes related with ASD, possibly by improving neuronal function, brain inflammation and brain oxidative stress. Thus, PDE1 may be a possible target for further understanding ASD. LAY SUMMARY: ASD is a brain developmental disorder with a wide array of genetic and environmental factors. Many targets have been identified till date, but a clinical treatment is still afar. The results of this study indicate that vinpocetine administration resulted in amelioration of ASD associated symptomatology in rats, prenatally exposed to VPA. Our research adds a widely expressed brain enzyme PDE1, as a possible novel pharmacological target and opens-up a new line of enquiry for ASD treatment. En ligne : http://dx.doi.org/10.1002/aur.2597 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=450

---

1 (1 - 2 / 2) Par page : 25 50 100 200