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Sera from children with autism induce autistic features which can be rescued with a CNTF small peptide mimetic in rats.

Kazim SF, Cardenas-Aguayo Mdel C, Arif M, Blanchard J, Fayyaz F, Grundke-Iqbal I, Iqbal K - PLoS ONE (2015)

Bottom Line: The effects of sera from autistic children were rescued by pre-treatment with a ciliary neurotrophic factor (CNTF) small peptide mimetic, Peptide 6 (P6), which was previously shown to exert its neuroprotective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression.Similar neurotoxic effects and neuroinflammation were observed in young Wistar rats injected intracerebroventricularly with autism sera within hours after birth.Both the neurobiological changes and the behavioral autistic phenotype were ameliorated by P6 treatment.

View Article: PubMed Central - PubMed

Affiliation: Inge Grundke-Iqbal Research Floor, Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities (NYSIBR), Staten Island, New York, United States of America; Neural and Behavioral Science Graduate Program, State University of New York (SUNY) Downstate Medical Center, Brooklyn, New York, United States of America; SUNY Downstate/NYSIBR Center for Developmental Neuroscience (CDN), Staten Island, New York, United States of America.

ABSTRACT
Autism is a neurodevelopmental disorder characterized clinically by impairments in social interaction and verbal and non-verbal communication skills as well as restricted interests and repetitive behavior. It has been hypothesized that altered brain environment including an imbalance in neurotrophic support during early development contributes to the pathophysiology of autism. Here we report that sera from children with autism which exhibited abnormal levels of various neurotrophic factors induced cell death and oxidative stress in mouse primary cultured cortical neurons. The effects of sera from autistic children were rescued by pre-treatment with a ciliary neurotrophic factor (CNTF) small peptide mimetic, Peptide 6 (P6), which was previously shown to exert its neuroprotective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression. Similar neurotoxic effects and neuroinflammation were observed in young Wistar rats injected intracerebroventricularly with autism sera within hours after birth. The autism sera injected rats demonstrated developmental delay and deficits in social communication, interaction, and novelty. Both the neurobiological changes and the behavioral autistic phenotype were ameliorated by P6 treatment. These findings implicate the involvement of neurotrophic imbalance during early brain development in the pathophysiology of autism and a proof of principle of P6 as a potential therapeutic strategy for autism.

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Design of the in vivo study and the effects of autism and control sera in the presence or absence of P6 on neurobehavioral development in rats.(A) Newly born Wistar rat pups were injected intracerebroventricularly on on postnatal day (P) 0.5 with saline (sham) or 2% autism or control serum with or without 20 nM P6. Behavioral studies were performed from postnatal day 2 to 25 in rats. (B) Evaluation of neurobehavioral development in Wistar rat pups from postnatal day 1–21(B1) Day of appearance of surface righting, negative geotaxis, cliff aversion, rooting, and forelimb grasp and (B2) air righting, eye opening, auditory startle, ear twitch, and fore limb placing. Data are presented as mean±S.E.M. based on sham (n = 17), autism serum (n = 15–16), autism serum+P6 (n = 16–17), control serum (n = 15–16), and control serum+P6 (n = 16–17). *p<0.05, **p<0.01, and ***p<0.001. ANOVA with Bonferroni’s post-hoc test and/or Student’s t-test.
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pone.0118627.g003: Design of the in vivo study and the effects of autism and control sera in the presence or absence of P6 on neurobehavioral development in rats.(A) Newly born Wistar rat pups were injected intracerebroventricularly on on postnatal day (P) 0.5 with saline (sham) or 2% autism or control serum with or without 20 nM P6. Behavioral studies were performed from postnatal day 2 to 25 in rats. (B) Evaluation of neurobehavioral development in Wistar rat pups from postnatal day 1–21(B1) Day of appearance of surface righting, negative geotaxis, cliff aversion, rooting, and forelimb grasp and (B2) air righting, eye opening, auditory startle, ear twitch, and fore limb placing. Data are presented as mean±S.E.M. based on sham (n = 17), autism serum (n = 15–16), autism serum+P6 (n = 16–17), control serum (n = 15–16), and control serum+P6 (n = 16–17). *p<0.05, **p<0.01, and ***p<0.001. ANOVA with Bonferroni’s post-hoc test and/or Student’s t-test.

Mentions: The Wistar rat pups were injected intracerebroventricularly with autism or control sera with or without P6 within 24 hours of birth to evaluate their possible neurotoxic effect and potential neuroprotection by P6 in vivo. The in vivo studies were carried out using the same 3 pairs of autism/control sera as above for in vitro studies. Five groups of animals of 5–6/group were employed (Fig. 3A): (1) sham group injected with saline; (2) pups injected with sera from autistic children (5–6 rat pups for each serum); (3) pups injected with sera from normal healthy controls (5–6 rat pups for each serum); (4) pups injected with sera from autistic children plus P6 (5–6 rat pups for each serum); and (5) pups injected with sera from controls plus P6 (5–6 rat pups for each serum). The body weight recorded daily for infant rats (both male and female) from postnatal day 1 to postnatal day 21 did not differ significantly among the groups [S1 Fig; repeated measures 2-way ANOVA; group effect, F = 0.36 (4, 672), p = 0.836].


Sera from children with autism induce autistic features which can be rescued with a CNTF small peptide mimetic in rats.

Kazim SF, Cardenas-Aguayo Mdel C, Arif M, Blanchard J, Fayyaz F, Grundke-Iqbal I, Iqbal K - PLoS ONE (2015)

Design of the in vivo study and the effects of autism and control sera in the presence or absence of P6 on neurobehavioral development in rats.(A) Newly born Wistar rat pups were injected intracerebroventricularly on on postnatal day (P) 0.5 with saline (sham) or 2% autism or control serum with or without 20 nM P6. Behavioral studies were performed from postnatal day 2 to 25 in rats. (B) Evaluation of neurobehavioral development in Wistar rat pups from postnatal day 1–21(B1) Day of appearance of surface righting, negative geotaxis, cliff aversion, rooting, and forelimb grasp and (B2) air righting, eye opening, auditory startle, ear twitch, and fore limb placing. Data are presented as mean±S.E.M. based on sham (n = 17), autism serum (n = 15–16), autism serum+P6 (n = 16–17), control serum (n = 15–16), and control serum+P6 (n = 16–17). *p<0.05, **p<0.01, and ***p<0.001. ANOVA with Bonferroni’s post-hoc test and/or Student’s t-test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359103&req=5

pone.0118627.g003: Design of the in vivo study and the effects of autism and control sera in the presence or absence of P6 on neurobehavioral development in rats.(A) Newly born Wistar rat pups were injected intracerebroventricularly on on postnatal day (P) 0.5 with saline (sham) or 2% autism or control serum with or without 20 nM P6. Behavioral studies were performed from postnatal day 2 to 25 in rats. (B) Evaluation of neurobehavioral development in Wistar rat pups from postnatal day 1–21(B1) Day of appearance of surface righting, negative geotaxis, cliff aversion, rooting, and forelimb grasp and (B2) air righting, eye opening, auditory startle, ear twitch, and fore limb placing. Data are presented as mean±S.E.M. based on sham (n = 17), autism serum (n = 15–16), autism serum+P6 (n = 16–17), control serum (n = 15–16), and control serum+P6 (n = 16–17). *p<0.05, **p<0.01, and ***p<0.001. ANOVA with Bonferroni’s post-hoc test and/or Student’s t-test.
Mentions: The Wistar rat pups were injected intracerebroventricularly with autism or control sera with or without P6 within 24 hours of birth to evaluate their possible neurotoxic effect and potential neuroprotection by P6 in vivo. The in vivo studies were carried out using the same 3 pairs of autism/control sera as above for in vitro studies. Five groups of animals of 5–6/group were employed (Fig. 3A): (1) sham group injected with saline; (2) pups injected with sera from autistic children (5–6 rat pups for each serum); (3) pups injected with sera from normal healthy controls (5–6 rat pups for each serum); (4) pups injected with sera from autistic children plus P6 (5–6 rat pups for each serum); and (5) pups injected with sera from controls plus P6 (5–6 rat pups for each serum). The body weight recorded daily for infant rats (both male and female) from postnatal day 1 to postnatal day 21 did not differ significantly among the groups [S1 Fig; repeated measures 2-way ANOVA; group effect, F = 0.36 (4, 672), p = 0.836].

Bottom Line: The effects of sera from autistic children were rescued by pre-treatment with a ciliary neurotrophic factor (CNTF) small peptide mimetic, Peptide 6 (P6), which was previously shown to exert its neuroprotective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression.Similar neurotoxic effects and neuroinflammation were observed in young Wistar rats injected intracerebroventricularly with autism sera within hours after birth.Both the neurobiological changes and the behavioral autistic phenotype were ameliorated by P6 treatment.

View Article: PubMed Central - PubMed

Affiliation: Inge Grundke-Iqbal Research Floor, Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities (NYSIBR), Staten Island, New York, United States of America; Neural and Behavioral Science Graduate Program, State University of New York (SUNY) Downstate Medical Center, Brooklyn, New York, United States of America; SUNY Downstate/NYSIBR Center for Developmental Neuroscience (CDN), Staten Island, New York, United States of America.

ABSTRACT
Autism is a neurodevelopmental disorder characterized clinically by impairments in social interaction and verbal and non-verbal communication skills as well as restricted interests and repetitive behavior. It has been hypothesized that altered brain environment including an imbalance in neurotrophic support during early development contributes to the pathophysiology of autism. Here we report that sera from children with autism which exhibited abnormal levels of various neurotrophic factors induced cell death and oxidative stress in mouse primary cultured cortical neurons. The effects of sera from autistic children were rescued by pre-treatment with a ciliary neurotrophic factor (CNTF) small peptide mimetic, Peptide 6 (P6), which was previously shown to exert its neuroprotective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression. Similar neurotoxic effects and neuroinflammation were observed in young Wistar rats injected intracerebroventricularly with autism sera within hours after birth. The autism sera injected rats demonstrated developmental delay and deficits in social communication, interaction, and novelty. Both the neurobiological changes and the behavioral autistic phenotype were ameliorated by P6 treatment. These findings implicate the involvement of neurotrophic imbalance during early brain development in the pathophysiology of autism and a proof of principle of P6 as a potential therapeutic strategy for autism.

Show MeSH
Related in: MedlinePlus