DHA improves autism-like behaviors in a preclinical rat study

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition marked by social and communication difficulties and repetitive behaviors. Its biology involves genetic, immune, redox and inflammatory factors, and no treatment fully addresses its core symptoms. Children with ASD often show elevated oxidative-stress markers and inflammatory signals, and antioxidant supplementation has shown promise in some studies. Docosahexaenoic acid (DHA), a long-chain omega-3 polyunsaturated fatty acid, supports membrane structure, neural development and myelination, and has anti-oxidative and anti-inflammatory properties. Yet it remained unclear whether DHA could improve autism-like behavior and which molecular pathways mediate such effects. Given these challenges, further research is needed to clarify whether and how DHA improves ASD-related neural and behavioral outcomes.

Researchers at Children's Hospital of Chongqing Medical University and Guangzhou Women and Children's Medical Center tested DHA in neonatal maternal separation (NMS) rats. The study was published (DOI: 10.1002/pdi3.91) online on 19 June 2024 in Pediatric Discovery. It combined three-chamber social testing, open-field and elevated plus-maze assays, a fasting test, network pharmacology, molecular docking, western blotting and enzyme-linked immunosorbent assay (ELISA). The team reported that DHA improved social and anxiety-like behaviors and reduced repetitive grooming, then traced the effects to c-Jun N-terminal kinase (JNK), oxidative-stress and inflammatory markers in the prefrontal cortex (PFC).

In the NMS model, pups were separated from mothers for three hours daily from postnatal day 1 to 21 and then singly housed until day 56; behavioral tests ran from day 42 to 56. DHA was given intraperitoneally at 80 mg/kg/day. Treated NMS rats spent more time with a novel stranger rat in both phases of the three-chamber test, showed fewer repetitive self-grooming bouts, and spent more time and made more entries into the open arms of the elevated plus maze. In the fasting test, DHA shortened feeding latency and increased food intake. Network analysis found 13 overlapping DHA-ASD targets, including genes for tumor necrosis factor (TNF), interleukin-6 (IL6), superoxide dismutase 1 (SOD1), catalase (CAT), brain-derived neurotrophic factor (BDNF) and peroxisome proliferator-activated receptor alpha (PPARA); enrichment pointed to oxidative stress, inflammatory response and JNK signaling. Docking predicted direct binding to catalase (CAT), superoxide dismutase 1 (SOD1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), JNK and heme oxygenase-1 (HO-1), with binding energies from −2.93 to −6.02 kcal/mol. In the PFC, DHA reduced p-JNK and c-JUN and increased nuclear factor erythroid 2-related factor 2 (NRF2), HO-1, SOD1 and CAT; it also lowered TNF-α, IL-6 and interleukin-1 beta (IL-1β). Total JNK was unchanged, indicating reduced activation rather than lower abundance.

The authors said the study connects behavioral improvement to a measurable JNK-centered pathway. They said DHA reduced JNK phosphorylation and c-JUN, restored NRF2, HO-1, SOD1 and CAT defense, and lowered TNF-α, IL-6 and IL-1β. They described the findings as preclinical and hypothesis-generating, and said the next steps are to test longer-term outcomes and refine target networks. They said DHA may be a potential therapeutic candidate for ASD, not a proven treatment. They said the data do not yet justify clinical use in children or changes to care.

The findings suggest DHA could become a low-cost adjunctive candidate for studies of ASD, particularly for pathways involving redox imbalance and inflammation. Because the work used an NMS rat model and early-life dosing, it cannot show whether DHA improves core symptoms in children or which patients might benefit. Future trials would need rigorous behavioral endpoints, biomarker stratification and safety monitoring. The study also highlights JNK, NRF2 and inflammatory cytokines as translational targets for drug discovery. Larger, longer and independent studies are needed, and DHA should not be used to self-treat ASD. For now, DHA should be viewed as a promising preclinical lead, not a substitute for evidence-based autism care or clinical advice.