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Modulation of dendritic spine development and plasticity by BDNF and vesicular trafficking: fundamental roles in neurodevelopmental disorders associated with mental retardation and autism / C. A. CHAPLEAU in Journal of Neurodevelopmental Disorders, 1-3 (September 2009)
[article]
Titre : Modulation of dendritic spine development and plasticity by BDNF and vesicular trafficking: fundamental roles in neurodevelopmental disorders associated with mental retardation and autism Type de document : Texte imprimé et/ou numérique Auteurs : C. A. CHAPLEAU, Auteur ; J. L. LARIMORE, Auteur ; A. THEIBERT, Auteur ; L. POZZO-MILLER, Auteur Article en page(s) : p.185-96 Langues : Anglais (eng) Mots-clés : Autism Bdnf Dendritic spine Hippocampus Mental retardation Pyramidal neuron Rett syndrome Vesicle trafficking Index. décimale : PER Périodiques Résumé : The process of axonal and dendritic development establishes the synaptic circuitry of the central nervous system (CNS) and is the result of interactions between intrinsic molecular factors and the external environment. One growth factor that has a compelling function in neuronal development is the neurotrophin brain-derived neurotrophic factor (BDNF). BDNF participates in axonal and dendritic differentiation during embryonic stages of neuronal development, as well as in the formation and maturation of dendritic spines during postnatal development. Recent studies have also implicated vesicular trafficking of BDNF via secretory vesicles, and both secretory and endosomal trafficking of vesicles containing synaptic proteins, such as neurotransmitter and neurotrophin receptors, in the regulation of axonal and dendritic differentiation, and in dendritic spine morphogenesis. Several genes that are either mutated or deregulated in neurodevelopmental disorders associated with mental retardation have now been identified, and several mouse models of these disorders have been generated and characterized. Interestingly, abnormalities in dendritic and synaptic structure are consistently observed in human neurodevelopmental disorders associated with mental retardation, and in mouse models of these disorders as well. Abnormalities in dendritic and synaptic differentiation are thought to underlie altered synaptic function and network connectivity, thus contributing to the clinical outcome. Here, we review the roles of BDNF and vesicular trafficking in axonal and dendritic differentiation in the context of dendritic and axonal morphological impairments commonly observed in neurodevelopmental disorders associated with mental retardation. En ligne : http://dx.doi.org/10.1007/s11689-009-9027-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=341
in Journal of Neurodevelopmental Disorders > 1-3 (September 2009) . - p.185-96[article] Modulation of dendritic spine development and plasticity by BDNF and vesicular trafficking: fundamental roles in neurodevelopmental disorders associated with mental retardation and autism [Texte imprimé et/ou numérique] / C. A. CHAPLEAU, Auteur ; J. L. LARIMORE, Auteur ; A. THEIBERT, Auteur ; L. POZZO-MILLER, Auteur . - p.185-96.
Langues : Anglais (eng)
in Journal of Neurodevelopmental Disorders > 1-3 (September 2009) . - p.185-96
Mots-clés : Autism Bdnf Dendritic spine Hippocampus Mental retardation Pyramidal neuron Rett syndrome Vesicle trafficking Index. décimale : PER Périodiques Résumé : The process of axonal and dendritic development establishes the synaptic circuitry of the central nervous system (CNS) and is the result of interactions between intrinsic molecular factors and the external environment. One growth factor that has a compelling function in neuronal development is the neurotrophin brain-derived neurotrophic factor (BDNF). BDNF participates in axonal and dendritic differentiation during embryonic stages of neuronal development, as well as in the formation and maturation of dendritic spines during postnatal development. Recent studies have also implicated vesicular trafficking of BDNF via secretory vesicles, and both secretory and endosomal trafficking of vesicles containing synaptic proteins, such as neurotransmitter and neurotrophin receptors, in the regulation of axonal and dendritic differentiation, and in dendritic spine morphogenesis. Several genes that are either mutated or deregulated in neurodevelopmental disorders associated with mental retardation have now been identified, and several mouse models of these disorders have been generated and characterized. Interestingly, abnormalities in dendritic and synaptic structure are consistently observed in human neurodevelopmental disorders associated with mental retardation, and in mouse models of these disorders as well. Abnormalities in dendritic and synaptic differentiation are thought to underlie altered synaptic function and network connectivity, thus contributing to the clinical outcome. Here, we review the roles of BDNF and vesicular trafficking in axonal and dendritic differentiation in the context of dendritic and axonal morphological impairments commonly observed in neurodevelopmental disorders associated with mental retardation. En ligne : http://dx.doi.org/10.1007/s11689-009-9027-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=341 Mesenchymal Stem Cell Transplantation Promotes Neurogenesis and Ameliorates Autism Related Behaviors in BTBR Mice / Hadar SEGAL-GAVISH in Autism Research, 9-1 (January 2016)
[article]
Titre : Mesenchymal Stem Cell Transplantation Promotes Neurogenesis and Ameliorates Autism Related Behaviors in BTBR Mice Type de document : Texte imprimé et/ou numérique Auteurs : Hadar SEGAL-GAVISH, Auteur ; Golan KARVAT, Auteur ; Noy BARAK, Auteur ; Ran BARZILAY, Auteur ; Javier GANZ, Auteur ; Liat EDRY, Auteur ; Israel AHARONY, Auteur ; Daniel OFFEN, Auteur ; Tali KIMCHI, Auteur Article en page(s) : p.17-32 Langues : Anglais (eng) Mots-clés : BTBR animal model MSC BDNF neurogenesis Index. décimale : PER Périodiques Résumé : Autism spectrum disorders (ASD) are characterized by social communication deficits, cognitive rigidity, and repetitive stereotyped behaviors. Mesenchymal stem cells (MSC) have a paracrine regenerative effect, and were speculated to be a potential therapy for ASD. The BTBR inbred mouse strain is a commonly used model of ASD as it demonstrates robust behavioral deficits consistent with the diagnostic criteria for ASD. BTBR mice also exhibit decreased brain-derived neurotrophic factor (BDNF) signaling and reduced hippocampal neurogenesis. In the current study, we evaluated the behavioral and molecular effects of intracerebroventricular MSC transplantation in BTBR mice. Transplantation of MSC resulted in a reduction of stereotypical behaviors, a decrease in cognitive rigidity and an improvement in social behavior. Tissue analysis revealed elevated BDNF protein levels in the hippocampus accompanied by increased hippocampal neurogenesis in the MSC-transplanted mice compared with sham treated mice. This might indicate a possible mechanism underpinning the behavioral improvement. Our study suggests a novel therapeutic approach which may be translatable to ASD patients in the future. En ligne : http://dx.doi.org/10.1002/aur.1530 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=282
in Autism Research > 9-1 (January 2016) . - p.17-32[article] Mesenchymal Stem Cell Transplantation Promotes Neurogenesis and Ameliorates Autism Related Behaviors in BTBR Mice [Texte imprimé et/ou numérique] / Hadar SEGAL-GAVISH, Auteur ; Golan KARVAT, Auteur ; Noy BARAK, Auteur ; Ran BARZILAY, Auteur ; Javier GANZ, Auteur ; Liat EDRY, Auteur ; Israel AHARONY, Auteur ; Daniel OFFEN, Auteur ; Tali KIMCHI, Auteur . - p.17-32.
Langues : Anglais (eng)
in Autism Research > 9-1 (January 2016) . - p.17-32
Mots-clés : BTBR animal model MSC BDNF neurogenesis Index. décimale : PER Périodiques Résumé : Autism spectrum disorders (ASD) are characterized by social communication deficits, cognitive rigidity, and repetitive stereotyped behaviors. Mesenchymal stem cells (MSC) have a paracrine regenerative effect, and were speculated to be a potential therapy for ASD. The BTBR inbred mouse strain is a commonly used model of ASD as it demonstrates robust behavioral deficits consistent with the diagnostic criteria for ASD. BTBR mice also exhibit decreased brain-derived neurotrophic factor (BDNF) signaling and reduced hippocampal neurogenesis. In the current study, we evaluated the behavioral and molecular effects of intracerebroventricular MSC transplantation in BTBR mice. Transplantation of MSC resulted in a reduction of stereotypical behaviors, a decrease in cognitive rigidity and an improvement in social behavior. Tissue analysis revealed elevated BDNF protein levels in the hippocampus accompanied by increased hippocampal neurogenesis in the MSC-transplanted mice compared with sham treated mice. This might indicate a possible mechanism underpinning the behavioral improvement. Our study suggests a novel therapeutic approach which may be translatable to ASD patients in the future. En ligne : http://dx.doi.org/10.1002/aur.1530 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=282 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)
[article]
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 et/ou numérique 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-Î+) 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 & 60Â 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-Î+, 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
in Research in Autism Spectrum Disorders > 99 (November) . - 102052[article] PDE3 inhibition by cilostazol attenuated developmental hyperserotonemia induced behavioural and biochemical deficits in a rat model of autism spectrum disorder [Texte imprimé et/ou numérique] / 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-Î+) 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 & 60Â 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-Î+, 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 A pilot open-label trial of minocycline in patients with autism and regressive features / Carlos A. PARDO in Journal of Neurodevelopmental Disorders, 5-1 (December 2013)
[article]
Titre : A pilot open-label trial of minocycline in patients with autism and regressive features Type de document : Texte imprimé et/ou numérique Auteurs : Carlos A. PARDO, Auteur ; A. BUCKLEY, Auteur ; A. THURM, Auteur ; L. C. LEE, Auteur ; A. AZHAGIRI, Auteur ; D. M. NEVILLE, Auteur ; Susan E. SWEDO, Auteur Article en page(s) : p.9 Langues : Anglais (eng) Mots-clés : Autism Bdnf Chemokines Clinical trial Cytokines Metalloproteinases Microglia Minocycline Neuroinflammation Neurotrophins Index. décimale : PER Périodiques Résumé : BACKGROUND: Minocycline is a tetracycline derivative that readily crosses the blood brain barrier and appears to have beneficial effects on neuroinflammation, microglial activation and neuroprotection in a variety of neurological disorders. Both microglial activation and neuroinflammation have been reported to be associated with autism. The study was designed to evaluate the effects of minocycline treatment on markers of neuroinflammation and autism symptomatology in children with autism and a history of developmental regression. METHODS: Eleven children were enrolled in an open-label trial of six months of minocycline (1.4 mg/kg). Ten children completed the trial. Behavioral measures were collected and cerebrospinal fluid (CSF), serum and plasma were obtained before and at the end of minocycline treatment and were analyzed for markers of neuroinflammation. RESULTS: Clinical improvements were negligible. The laboratory assays demonstrated significant changes in the expression profile of the truncated form of brain derived neurotrophic factor (BDNF) (P = 0.042) and hepatic growth factor (HGF) (P = 0.028) in CSF. In serum, the ratio of the truncated BDNF form and alpha-2 macroglobulin (alpha-2 M), was also significantly lower (P = 0.028) while the mature BDNF/alpha-2 M ratio revealed no difference following treatment. Only the chemokine CXCL8 (IL-8) was significantly different (P = 0.047) in serum while no significant changes were observed in CSF or serum in chemokines such as CCL2 (MCP-1) or cytokines such as TNF-alpha, CD40L, IL-6, IFN-gamma and IL-1beta when pre- and post-treatment levels of these proteins were compared. No significant pre- and post-treatment changes were seen in the profiles of plasma metalloproteinases, putative targets of the effects of minocycline. CONCLUSIONS: Changes in the pre- and post-treatment profiles of BDNF in CSF and blood, HGF in CSF and CXCL8 (IL-8) in serum, suggest that minocycline may have effects in the CNS by modulating the production of neurotrophic growth factors. However, in this small group of children, no clinical improvements were observed during or after the six months of minocycline administration. TRIAL REGISTRATION: NCT00409747. En ligne : http://dx.doi.org/10.1186/1866-1955-5-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=345
in Journal of Neurodevelopmental Disorders > 5-1 (December 2013) . - p.9[article] A pilot open-label trial of minocycline in patients with autism and regressive features [Texte imprimé et/ou numérique] / Carlos A. PARDO, Auteur ; A. BUCKLEY, Auteur ; A. THURM, Auteur ; L. C. LEE, Auteur ; A. AZHAGIRI, Auteur ; D. M. NEVILLE, Auteur ; Susan E. SWEDO, Auteur . - p.9.
Langues : Anglais (eng)
in Journal of Neurodevelopmental Disorders > 5-1 (December 2013) . - p.9
Mots-clés : Autism Bdnf Chemokines Clinical trial Cytokines Metalloproteinases Microglia Minocycline Neuroinflammation Neurotrophins Index. décimale : PER Périodiques Résumé : BACKGROUND: Minocycline is a tetracycline derivative that readily crosses the blood brain barrier and appears to have beneficial effects on neuroinflammation, microglial activation and neuroprotection in a variety of neurological disorders. Both microglial activation and neuroinflammation have been reported to be associated with autism. The study was designed to evaluate the effects of minocycline treatment on markers of neuroinflammation and autism symptomatology in children with autism and a history of developmental regression. METHODS: Eleven children were enrolled in an open-label trial of six months of minocycline (1.4 mg/kg). Ten children completed the trial. Behavioral measures were collected and cerebrospinal fluid (CSF), serum and plasma were obtained before and at the end of minocycline treatment and were analyzed for markers of neuroinflammation. RESULTS: Clinical improvements were negligible. The laboratory assays demonstrated significant changes in the expression profile of the truncated form of brain derived neurotrophic factor (BDNF) (P = 0.042) and hepatic growth factor (HGF) (P = 0.028) in CSF. In serum, the ratio of the truncated BDNF form and alpha-2 macroglobulin (alpha-2 M), was also significantly lower (P = 0.028) while the mature BDNF/alpha-2 M ratio revealed no difference following treatment. Only the chemokine CXCL8 (IL-8) was significantly different (P = 0.047) in serum while no significant changes were observed in CSF or serum in chemokines such as CCL2 (MCP-1) or cytokines such as TNF-alpha, CD40L, IL-6, IFN-gamma and IL-1beta when pre- and post-treatment levels of these proteins were compared. No significant pre- and post-treatment changes were seen in the profiles of plasma metalloproteinases, putative targets of the effects of minocycline. CONCLUSIONS: Changes in the pre- and post-treatment profiles of BDNF in CSF and blood, HGF in CSF and CXCL8 (IL-8) in serum, suggest that minocycline may have effects in the CNS by modulating the production of neurotrophic growth factors. However, in this small group of children, no clinical improvements were observed during or after the six months of minocycline administration. TRIAL REGISTRATION: NCT00409747. En ligne : http://dx.doi.org/10.1186/1866-1955-5-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=345 Vinpocetine amended prenatal valproic acid induced features of ASD possibly by altering markers of neuronal function, inflammation, and oxidative stress / K. LUHACH in Autism Research, 14-11 (November 2021)
[article]
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 et/ou numérique Auteurs : K. LUHACH, Auteur ; G. T. KULKARNI, Auteur ; V. P. SINGH, Auteur ; B. 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-?) 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-?, 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
in Autism Research > 14-11 (November 2021) . - p.2270-2286[article] Vinpocetine amended prenatal valproic acid induced features of ASD possibly by altering markers of neuronal function, inflammation, and oxidative stress [Texte imprimé et/ou numérique] / K. LUHACH, Auteur ; G. T. KULKARNI, Auteur ; V. P. SINGH, Auteur ; B. 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-?) 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-?, 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