Therapeutic Effects of MOTS-c in the Valproic Acid-Induced Autism Model in Rats: Role of Tetrahydrobiopterin and Brain-Derived Neurotrophic Factor.

Güvenir Seven S, Sahin H, Erkanlı Şentürk G, Uysal N, Uzun H, Ekici O, Rakıcı G, Şimşek G

Molecular neurobiology18 Feb 2026

PMID41706383PMCIDPMC12916525DOI10.1007/s12035-026-05741-yPepBankPUB-41706383

Summary

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction and repetitive behaviors, with currently limited therapeutic options. Oxidative stress is suggested as significant in ASD pathophysiology, making antioxidant strategies a promising therapeutic direction. Exercise reduces oxidative stress, alleviates ASD symptoms, and increases tetrahydrobiopterin (BH4) and brain-derived neurotrophic factor (BDNF) levels through AMP-activated protein kinase (AMPK) activation. MOTS-c, a mitochondrial-derived peptide acting through AMPK, mimics the effects of exercise but reportedly does not cross the blood-brain barrier (BBB). Considering the challenges in exercise adherence in ASD, our study hypothesizes that MOTS-c could increase circulating BH4 and BDNF, both of which are BBB-permeable, and alleviate oxidative stress and ASD symptoms. To evaluate this hypothesis, we investigated the effects of MOTS-c in the valproic acid-induced rat model of autism. Pregnant Sprague-Dawley rats received intraperitoneal 500 mg/kg valproic acid or saline on embryonic day 12. Female and male offspring were treated with 0.5 mg/kg/day MOTS-c or saline intraperitoneally from postnatal days 21 to 46. Following behavioral testing, animals were sacrificed, and histological and biochemical analyses were performed. Valproic acid exposure led to impaired sociability, repetitive behaviors, anxiety, cerebellar Purkinje cell loss, and increased oxidative stress and neuronal damage in the prefrontal cortex. These alterations were reversed by MOTS-c, except for anxiety and neocortical damage. No significant changes in plasma BH4 or BDNF levels were detected. Through its neuroprotective and antioxidant effects independent of BH4 and BDNF, MOTS-c may alleviate autism-like behaviors, suggesting its potential as a therapeutic candidate for ASD.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study8

8 results from studies that gave the peptide. No result from this study comes from people.

01AnimalAnimal study (in vivo)Efficacy outcome
In valproic acid-exposed rat offspring, MOTS‑c reversed the impaired sociability.
In plain wordsIn rats exposed to valproic acid before birth, MOTS‑c reversed poor social behavior.
Peptide
MOTS-c
Outcome
IncreaseSociability
Study
ratn: not reported in source
Valproic acid-induced autism model
Comparator
Saline
Outcome group
Anxiety and mood · Nervous system and cognition
Studied dose
0.5 mg/kg/day · intraperitoneal · postnatal days 21 to 46As given in this study (rat).
Source sentences
Summary
Valproic acid exposure led to impaired sociability, repetitive behaviors, anxiety, cerebellar Purkinje cell loss, and increased oxidative stress and neuronal damage in the prefrontal cortex. These alterations were reversed by MOTS-c, except for anxiety and neocortical damage.
2 context sentences(design, population, supporting numbers)
Summary · context
Pregnant Sprague-Dawley rats received intraperitoneal 500 mg/kg valproic acid or saline on embryonic day 12.
Summary · context
Female and male offspring were treated with 0.5 mg/kg/day MOTS-c or saline intraperitoneally from postnatal days 21 to 46.
Show in the study text Report a problemFND-4170638301
02AnimalAnimal study (in vivo)Efficacy outcome
In valproic acid-exposed rat offspring, MOTS‑c reversed the repetitive behaviors.
In plain wordsIn rats exposed to valproic acid before birth, MOTS‑c reversed repeated behaviors.
Peptide
MOTS-c
Outcome
DecreaseRepetitive behaviors
Study
ratn: not reported in source
Valproic acid-induced autism model
Comparator
Saline
Outcome group
Anxiety and mood · Nervous system and cognition
Studied dose
0.5 mg/kg/day · intraperitoneal · postnatal days 21 to 46As given in this study (rat).
Source sentences
Summary
Valproic acid exposure led to impaired sociability, repetitive behaviors, anxiety, cerebellar Purkinje cell loss, and increased oxidative stress and neuronal damage in the prefrontal cortex. These alterations were reversed by MOTS-c, except for anxiety and neocortical damage.
2 context sentences(design, population, supporting numbers)
Summary · context
Pregnant Sprague-Dawley rats received intraperitoneal 500 mg/kg valproic acid or saline on embryonic day 12.
Summary · context
Female and male offspring were treated with 0.5 mg/kg/day MOTS-c or saline intraperitoneally from postnatal days 21 to 46.
Show in the study text Report a problemFND-4170638302
03AnimalAnimal study (in vivo)Efficacy outcome
In valproic acid-exposed rat offspring, MOTS‑c did not reverse anxiety.
In plain wordsIn rats exposed to valproic acid before birth, MOTS‑c did not reverse anxiety.
Peptide
MOTS-c
Outcome
No significant changeAnxiety
Study
ratn: not reported in source
Valproic acid-induced autism model
Comparator
Saline
Outcome group
Anxiety and mood · Mental health and mood
Studied dose
0.5 mg/kg/day · intraperitoneal · postnatal days 21 to 46As given in this study (rat).
Source sentences
Summary
Valproic acid exposure led to impaired sociability, repetitive behaviors, anxiety, cerebellar Purkinje cell loss, and increased oxidative stress and neuronal damage in the prefrontal cortex. These alterations were reversed by MOTS-c, except for anxiety and neocortical damage.
2 context sentences(design, population, supporting numbers)
Summary · context
Pregnant Sprague-Dawley rats received intraperitoneal 500 mg/kg valproic acid or saline on embryonic day 12.
Summary · context
Female and male offspring were treated with 0.5 mg/kg/day MOTS-c or saline intraperitoneally from postnatal days 21 to 46.
Show in the study text Report a problemFND-4170638303
04AnimalAnimal study (in vivo)Efficacy outcome
In valproic acid-exposed rat offspring, MOTS‑c reversed the cerebellar Purkinje cell loss.
In plain wordsIn rats exposed to valproic acid before birth, MOTS‑c reversed the loss of Purkinje nerve cells in the cerebellum.
Peptide
MOTS-c
Outcome
DecreaseCerebellar Purkinje cell loss
Study
ratn: not reported in source
Valproic acid-induced autism model
Comparator
Saline
Outcome group
Neuroprotection · Nervous system and cognition
Studied dose
0.5 mg/kg/day · intraperitoneal · postnatal days 21 to 46As given in this study (rat).
Source sentences
Summary
Valproic acid exposure led to impaired sociability, repetitive behaviors, anxiety, cerebellar Purkinje cell loss, and increased oxidative stress and neuronal damage in the prefrontal cortex. These alterations were reversed by MOTS-c, except for anxiety and neocortical damage.
2 context sentences(design, population, supporting numbers)
Summary · context
Pregnant Sprague-Dawley rats received intraperitoneal 500 mg/kg valproic acid or saline on embryonic day 12.
Summary · context
Female and male offspring were treated with 0.5 mg/kg/day MOTS-c or saline intraperitoneally from postnatal days 21 to 46.
Show in the study text Report a problemFND-4170638304
05AnimalAnimal study (in vivo)Mechanism
In valproic acid-exposed rat offspring, MOTS‑c reversed the increased oxidative stress in the prefrontal cortex.
In plain wordsIn rats exposed to valproic acid before birth, MOTS‑c reversed raised oxidative stress in a front brain area.
Peptide
MOTS-c
Outcome
DecreaseOxidative stress in prefrontal cortex
Study
ratn: not reported in source
Valproic acid-induced autism model
Comparator
Saline
Outcome group
Neuroprotection · Nervous system and cognition
Studied dose
0.5 mg/kg/day · intraperitoneal · postnatal days 21 to 46As given in this study (rat).
Source sentences
Summary
Valproic acid exposure led to impaired sociability, repetitive behaviors, anxiety, cerebellar Purkinje cell loss, and increased oxidative stress and neuronal damage in the prefrontal cortex. These alterations were reversed by MOTS-c, except for anxiety and neocortical damage.
2 context sentences(design, population, supporting numbers)
Summary · context
Pregnant Sprague-Dawley rats received intraperitoneal 500 mg/kg valproic acid or saline on embryonic day 12.
Summary · context
Female and male offspring were treated with 0.5 mg/kg/day MOTS-c or saline intraperitoneally from postnatal days 21 to 46.
Show in the study text Report a problemFND-4170638305
06AnimalAnimal study (in vivo)Efficacy outcome
In valproic acid-exposed rat offspring, MOTS‑c did not reverse neocortical damage.
In plain wordsIn rats exposed to valproic acid before birth, MOTS‑c did not reverse damage in the neocortex.
Peptide
MOTS-c
Outcome
No significant changeNeuronal and neocortical damage
Study
ratn: not reported in source
Valproic acid-induced autism model
Comparator
Saline
Outcome group
Neuroprotection · Nervous system and cognition
Studied dose
0.5 mg/kg/day · intraperitoneal · postnatal days 21 to 46As given in this study (rat).
Source sentences
Summary
Valproic acid exposure led to impaired sociability, repetitive behaviors, anxiety, cerebellar Purkinje cell loss, and increased oxidative stress and neuronal damage in the prefrontal cortex. These alterations were reversed by MOTS-c, except for anxiety and neocortical damage.
2 context sentences(design, population, supporting numbers)
Summary · context
Pregnant Sprague-Dawley rats received intraperitoneal 500 mg/kg valproic acid or saline on embryonic day 12.
Summary · context
Female and male offspring were treated with 0.5 mg/kg/day MOTS-c or saline intraperitoneally from postnatal days 21 to 46.
Show in the study text Report a problemFND-4170638306
07AnimalAnimal study (in vivo)Mechanism
In valproic acid-exposed rat offspring, MOTS‑c did not significantly change plasma tetrahydrobiopterin (BH4).
In plain wordsIn rats exposed to valproic acid before birth, MOTS‑c did not change blood BH4 levels.
Peptide
MOTS-c
Outcome
No significant changePlasma BH4
Study
ratn: not reported in source
Valproic acid-induced autism model
Comparator
Saline
Outcome group
Neuroprotection · Nervous system and cognition
Studied dose
0.5 mg/kg/day · intraperitoneal · postnatal days 21 to 46As given in this study (rat).
Source sentences
Summary
No significant changes in plasma BH4 or BDNF levels were detected.
2 context sentences(design, population, supporting numbers)
Summary · context
Pregnant Sprague-Dawley rats received intraperitoneal 500 mg/kg valproic acid or saline on embryonic day 12.
Summary · context
Female and male offspring were treated with 0.5 mg/kg/day MOTS-c or saline intraperitoneally from postnatal days 21 to 46.
Show in the study text Report a problemFND-4170638307
08AnimalAnimal study (in vivo)Mechanism
In valproic acid-exposed rat offspring, MOTS‑c did not significantly change plasma brain-derived neurotrophic factor (BDNF).
In plain wordsIn rats exposed to valproic acid before birth, MOTS‑c did not change blood BDNF levels.
Peptide
MOTS-c
Outcome
No significant changePlasma BDNF
Study
ratn: not reported in source
Valproic acid-induced autism model
Comparator
Saline
Outcome group
Neuroprotection · Nervous system and cognition
Studied dose
0.5 mg/kg/day · intraperitoneal · postnatal days 21 to 46As given in this study (rat).
Source sentences
Summary
No significant changes in plasma BH4 or BDNF levels were detected.
2 context sentences(design, population, supporting numbers)
Summary · context
Pregnant Sprague-Dawley rats received intraperitoneal 500 mg/kg valproic acid or saline on embryonic day 12.
Summary · context
Female and male offspring were treated with 0.5 mg/kg/day MOTS-c or saline intraperitoneally from postnatal days 21 to 46.
Show in the study text Report a problemFND-4170638308

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
9 Oct 2026, 18:17 UTC
Study results updated
Version 1
9 Oct 2026, 02:47 UTC
First added · source update from Europe PMC

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Terms as the source lists them.

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