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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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Effect of autism and control sera in the presence or absence of P6 on grooming, social approach and novelty in young Wistar rats.P 0.5 rat pups were injected intracerebroventricularly with saline (sham) or 2% autism or control serum with or without 20 nM P6. (A) Grooming time measured during the first 5 min habituation phase in the central chamber of the 3-chamber social approach/novelty task. (B) Sniffing time and time in the chamber (“stranger rat 1” versus “novel object”) spent in the social approach task. (C) Sniffing time and time in the chamber (“stranger rat 1” versus “stranger rat 2”) spent in the social novelty task. Data are presented as mean±S.E.M. based on sham (n = 15), autism serum (n = 15), autism serum+P6 (n = 16), control serum (n = 15), and control serum+P6 (n = 16). *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.g005: Effect of autism and control sera in the presence or absence of P6 on grooming, social approach and novelty in young Wistar rats.P 0.5 rat pups were injected intracerebroventricularly with saline (sham) or 2% autism or control serum with or without 20 nM P6. (A) Grooming time measured during the first 5 min habituation phase in the central chamber of the 3-chamber social approach/novelty task. (B) Sniffing time and time in the chamber (“stranger rat 1” versus “novel object”) spent in the social approach task. (C) Sniffing time and time in the chamber (“stranger rat 1” versus “stranger rat 2”) spent in the social novelty task. Data are presented as mean±S.E.M. based on sham (n = 15), autism serum (n = 15), autism serum+P6 (n = 16), control serum (n = 15), and control serum+P6 (n = 16). *p<0.05, **p<0.01, and ***p<0.001. ANOVA with Bonferroni’s post-hoc test and/or Student’s t-test.

Mentions: During the first habituation phase of the 3-chamber social approach/novelty task, the grooming time as measured during the 5 min exploration of the central chamber did not differ between the different groups (Fig. 5A; ANOVA, p = 0.2988). Nonetheless, there was a strong trend towards increased grooming time in young rats injected with sera from autistic children compared to the sham group suggesting an increased tendency towards a spontaneous repetitive behavior (Fig. 5A; Bonferroni’s post hoc test, p>0.05; Student’s t-test, p = 0.014).


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)

Effect of autism and control sera in the presence or absence of P6 on grooming, social approach and novelty in young Wistar rats.P 0.5 rat pups were injected intracerebroventricularly with saline (sham) or 2% autism or control serum with or without 20 nM P6. (A) Grooming time measured during the first 5 min habituation phase in the central chamber of the 3-chamber social approach/novelty task. (B) Sniffing time and time in the chamber (“stranger rat 1” versus “novel object”) spent in the social approach task. (C) Sniffing time and time in the chamber (“stranger rat 1” versus “stranger rat 2”) spent in the social novelty task. Data are presented as mean±S.E.M. based on sham (n = 15), autism serum (n = 15), autism serum+P6 (n = 16), control serum (n = 15), and control serum+P6 (n = 16). *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

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

pone.0118627.g005: Effect of autism and control sera in the presence or absence of P6 on grooming, social approach and novelty in young Wistar rats.P 0.5 rat pups were injected intracerebroventricularly with saline (sham) or 2% autism or control serum with or without 20 nM P6. (A) Grooming time measured during the first 5 min habituation phase in the central chamber of the 3-chamber social approach/novelty task. (B) Sniffing time and time in the chamber (“stranger rat 1” versus “novel object”) spent in the social approach task. (C) Sniffing time and time in the chamber (“stranger rat 1” versus “stranger rat 2”) spent in the social novelty task. Data are presented as mean±S.E.M. based on sham (n = 15), autism serum (n = 15), autism serum+P6 (n = 16), control serum (n = 15), and control serum+P6 (n = 16). *p<0.05, **p<0.01, and ***p<0.001. ANOVA with Bonferroni’s post-hoc test and/or Student’s t-test.
Mentions: During the first habituation phase of the 3-chamber social approach/novelty task, the grooming time as measured during the 5 min exploration of the central chamber did not differ between the different groups (Fig. 5A; ANOVA, p = 0.2988). Nonetheless, there was a strong trend towards increased grooming time in young rats injected with sera from autistic children compared to the sham group suggesting an increased tendency towards a spontaneous repetitive behavior (Fig. 5A; Bonferroni’s post hoc test, p>0.05; Student’s t-test, p = 0.014).

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