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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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Levels of various neurotrophic factors in sera from autistic and control children.(A and B) Representative images and quantification of Western blots for evaluation of levels of various neurotrophic factors in 3 pairs of sera from autistic and control children used in the study are shown. A1, A2, A3, and C1, C2, C3, represent 3 autism and 3 control cases, respectively. *p<0.05, **p<0.01, and ***p<0.001. Student’s t-test.
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pone.0118627.g002: Levels of various neurotrophic factors in sera from autistic and control children.(A and B) Representative images and quantification of Western blots for evaluation of levels of various neurotrophic factors in 3 pairs of sera from autistic and control children used in the study are shown. A1, A2, A3, and C1, C2, C3, represent 3 autism and 3 control cases, respectively. *p<0.05, **p<0.01, and ***p<0.001. Student’s t-test.

Mentions: The inappropriate brain milieu because of altered levels of various neurotrophic factors in the sera has been hypothesized to play a major role in abnormal brain development in autistic individuals. We thus evaluated the levels of various key neurotrophic factors in the 3 pairs of autism/control sera (Table 2) which induced increased cell death and oxidative stress in primary cultured cortical neurons. Indeed, the levels of various neurotrophic factors were found to be altered in sera from autistic children compared to those from age and gender matched control children as evaluated by quantitative Western blots (Fig. 2). The levels of mature CNTF and BDNF were markedly decreased in autism sera (Fig. 2A and B; CNTF, Student’s t-test, p = 0.0026; BDNF, Student’s t-test, p = 0.0003). Conversely, the levels of pro-BDNF, FGF-2, and LIF were found to be increased in autism sera compared to control (Fig. 2A and B; pro-BDNF, Student’s t-test, p = 0.0043; LIF, Student’s t-test, p = 0.0216; FGF-2, Student’s t-test, p = 0.0194). No statistically significant differences were observed in the levels of NGF (Fig. 2A and B; Student’s t-test, p = 0.5693). These data suggested the presence of neurotrophic abnormalities in the sera from autistic children that could have contributed to altered development of neurons and increase in cell death and oxidative stress found above (Fig. 1).


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)

Levels of various neurotrophic factors in sera from autistic and control children.(A and B) Representative images and quantification of Western blots for evaluation of levels of various neurotrophic factors in 3 pairs of sera from autistic and control children used in the study are shown. A1, A2, A3, and C1, C2, C3, represent 3 autism and 3 control cases, respectively. *p<0.05, **p<0.01, and ***p<0.001. Student’s t-test.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0118627.g002: Levels of various neurotrophic factors in sera from autistic and control children.(A and B) Representative images and quantification of Western blots for evaluation of levels of various neurotrophic factors in 3 pairs of sera from autistic and control children used in the study are shown. A1, A2, A3, and C1, C2, C3, represent 3 autism and 3 control cases, respectively. *p<0.05, **p<0.01, and ***p<0.001. Student’s t-test.
Mentions: The inappropriate brain milieu because of altered levels of various neurotrophic factors in the sera has been hypothesized to play a major role in abnormal brain development in autistic individuals. We thus evaluated the levels of various key neurotrophic factors in the 3 pairs of autism/control sera (Table 2) which induced increased cell death and oxidative stress in primary cultured cortical neurons. Indeed, the levels of various neurotrophic factors were found to be altered in sera from autistic children compared to those from age and gender matched control children as evaluated by quantitative Western blots (Fig. 2). The levels of mature CNTF and BDNF were markedly decreased in autism sera (Fig. 2A and B; CNTF, Student’s t-test, p = 0.0026; BDNF, Student’s t-test, p = 0.0003). Conversely, the levels of pro-BDNF, FGF-2, and LIF were found to be increased in autism sera compared to control (Fig. 2A and B; pro-BDNF, Student’s t-test, p = 0.0043; LIF, Student’s t-test, p = 0.0216; FGF-2, Student’s t-test, p = 0.0194). No statistically significant differences were observed in the levels of NGF (Fig. 2A and B; Student’s t-test, p = 0.5693). These data suggested the presence of neurotrophic abnormalities in the sera from autistic children that could have contributed to altered development of neurons and increase in cell death and oxidative stress found above (Fig. 1).

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