CDP-choline and uridine monophosphate have therapeutic potential on the valproic acid-induced autism model

<p style="margin-bottom: 0px; border: 0px; font-variant-numeric: inherit; font-variant-east-asian: inherit; font-variant-alternates: inherit; font-variant-position: inherit; font-variant-emoji: inherit; font-stretch: inherit; font-size: 14px; line-height: inherit; font-family: roboto; font-optical-sizing: inherit; font-size-adjust: inherit; font-kerning: inherit; font-feature-settings: inherit; font-variation-settings: inherit; font-language-override: inherit; padding: 0px; vertical-align: baseline; color: rgb(120, 120, 120);"><span style="font-weight: 700; border: 0px; font-style: inherit; font-variant: inherit; font-stretch: inherit; font-size: inherit; line-height: inherit; font-family: inherit; font-optical-sizing: inherit; font-size-adjust: inherit; font-kerning: inherit; font-feature-settings: inherit; font-variation-settings: inherit; font-language-override: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">Background</span>: Autistic spectrum disorders (ASD) are characterized by alterations at the molecular level, with increasing rates in recent years, and are considered a serious public health problem worldwide. The valproic acid (VPA)-induced ASD rodent model is a valid preclinical model that allows the study of idiopathic autism, mimicking the structural, functional, and behavioral phenotypes specific to the ASD clinic. Adequate intake of the choline precursors cytidine diphosphate-choline (CDP-Ch) and uridine monophosphate (UMP) during the perinatal period (from placenta and breast milk) is associated with neuronal development. They exert neuroprotective, neuroregenerative, neurodevelopmental, and synaptogenesis-enhancing effects under various experimental conditions. In the study, we evaluated whether CDP-Ch or UMP ameliorated the neurochemical parameters and behavioral impairment in the VPA-induced autism model. <p style="margin-bottom: 0px; border: 0px; font-variant-numeric: inherit; font-variant-east-asian: inherit; font-variant-alternates: inherit; font-variant-position: inherit; font-variant-emoji: inherit; font-stretch: inherit; font-size: 14px; line-height: inherit; font-family: roboto; font-optical-sizing: inherit; font-size-adjust: inherit; font-kerning: inherit; font-feature-settings: inherit; font-variation-settings: inherit; font-language-override: inherit; padding: 0px; vertical-align: baseline; color: rgb(120, 120, 120);"><span style="font-weight: 700; border: 0px; font-style: inherit; font-variant: inherit; font-stretch: inherit; font-size: inherit; line-height: inherit; font-family: inherit; font-optical-sizing: inherit; font-size-adjust: inherit; font-kerning: inherit; font-feature-settings: inherit; font-variation-settings: inherit; font-language-override: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">Methods</span>: Sixteen pregnant rats were divided into four groups. The VPA groups received a 600 mg/kg VPA injection, and the control group received saline on day 12.5 of pregnancy. After the VPA injection, the treatment groups received CDP-Ch (5 mg/ml, 0.5%) or UMP (5 mg/ml, 0.5%) via drinking water. Treatments were administered for one week during pregnancy and three weeks during lactation. Some of the pups were sacrificed on postnatal day (PND) 22 for neurochemical analysis in brain tissues. Behavioral tests, including the Elevated Plus Maze (EPM), spontaneous alternation in the Y-Maze, and the Three-Chamber Test for reciprocal interaction, were conducted. Behavioral tests began on PND 35, and the remaining pups were sacrificed on PND 45 for brain tissue analysis. GABA neurotransmitter, PSD95 synapsin-1 (SYN-1) proteins as markers of synaptogenesis, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 and membrane phospholipids were measured in the cerebellum, hippocampus, and prefrontal cortex. Values were means ± S.E.M., compared by ANOVA and Student’s t test. <p style="margin-bottom: 0px; border: 0px; font-variant-numeric: inherit; font-variant-east-asian: inherit; font-variant-alternates: inherit; font-variant-position: inherit; font-variant-emoji: inherit; font-stretch: inherit; font-size: 14px; line-height: inherit; font-family: roboto; font-optical-sizing: inherit; font-size-adjust: inherit; font-kerning: inherit; font-feature-settings: inherit; font-variation-settings: inherit; font-language-override: inherit; padding: 0px; vertical-align: baseline; color: rgb(120, 120, 120);"><span style="font-weight: 700; border: 0px; font-style: inherit; font-variant: inherit; font-stretch: inherit; font-size: inherit; line-height: inherit; font-family: inherit; font-optical-sizing: inherit; font-size-adjust: inherit; font-kerning: inherit; font-feature-settings: inherit; font-variation-settings: inherit; font-language-override: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">Results</span>: Treatment with UMP or CDP-Ch on PND 22 and PND 46 improved total phospholipid (p&lt;0.01-0.001), phosphatidyl choline, and phosphatidyl inositol (p&lt;0.05-0.001) in male rats compared to only the administered group, depending on brain regions. UMP treatment increased PSD95 level (p&lt;0.05) on PND 22 and increased SYN-1 level (p&lt;0.05) on PND 46 of only male rats. CDP-Ch treatment had effects only on TNF-α levels in both sexes (p&lt;0.01-0.001), particularly in the hippocampus and prefrontal cortex. UMP treatment also improved GABA levels (p&lt;0.05), especially on PND 22. Additionally, both treatments reduced anxiety-like behavior, increased spontaneous alternation, and enhanced reciprocal social interaction. Improvements in parameters were significant, especially at PND 46 in males. <p style="margin-bottom: 0px; border: 0px; font-variant-numeric: inherit; font-variant-east-asian: inherit; font-variant-alternates: inherit; font-variant-position: inherit; font-variant-emoji: inherit; font-stretch: inherit; font-size: 14px; line-height: inherit; font-family: roboto; font-optical-sizing: inherit; font-size-adjust: inherit; font-kerning: inherit; font-feature-settings: inherit; font-variation-settings: inherit; font-language-override: inherit; padding: 0px; vertical-align: baseline; color: rgb(120, 120, 120);"><span style="font-weight: 700; border: 0px; font-style: inherit; font-variant: inherit; font-stretch: inherit; font-size: inherit; line-height: inherit; font-family: inherit; font-optical-sizing: inherit; font-size-adjust: inherit; font-kerning: inherit; font-feature-settings: inherit; font-variation-settings: inherit; font-language-override: inherit; margin: 0px; padding: 0px; vertical-align: baseline;">Conclusion</span>: The results indicate that treatments with UMP and CDP-Ch during the prenatal period have beneficial effects on behavioral impairments associated with autism. These improvements are associated with improving neurotransmitter, phospholipid, and synaptic protein levels as well as a reduction in pro-inflammatory cytokines. The results of behavioral tests support the neurochemical analysis. Based on the study’s results, choline precursors should be considered and further explored as potential therapeutic supplements for individuals with ASD, and more research is necessary.