Neuroinflammatory Response to Postnatal Administration of Valproic Acid in Wistar Rats as a Mechanism for the Development of Autism Spectrum Disorders: The Role of Neutrophils
Aug 2026· Brain Science· Vol 16, pp. 831· 0 citations· 108 references
Medicine
TL;DR
Early postnatal administration of VPA to Wistar rats induces physiological and behavioral changes characteristic of ASD, confirming the validity of the experimental model used.
Abstract
Highlights What are the main findings? Postnatal administration of VPA induces an autism-like phenotype in rats. Autism-like behavior is associated with increased activity of neutrophil elastase, α1-proteinase inhibitor, and the complement system, indicating systemic inflammation. What are the implications of the main findings? Increased activity of neutrophil elastase in the cerebellum indirectly indicates neutrophil infiltration into the central nervous system. Neutrophils are suggested to be involved in the neuroinflammatory mechanism of autism spectrum disorders. Abstract Background/Objectives: According to current concepts, neuroinflammation is one of the putative causes of autism spectrum disorders (ASD) development. However, the role of neutrophils in neuroinflammation remains insufficiently studied. The study was aimed to determine the role of neutrophils in the neuroinflammatory mechanism of ASD development based on a comparative analysis of physiological and behavioral disturbances and the inflammatory response to early postnatal administration of valproic acid (VPA) to Wistar rats. Methods: The study was performed on 38 rat pups of both sexes, half of which were injected intraperitoneally with an aqueous solution of VPA at a dose of 150 mg/kg from 6 to 12 postnatal days (PND); control rats received water. Standard physiological and behavioral tests were used: weight monitoring, pain sensitivity (Hot Plate test) on 25 PND, and social behavior (sib/non-sib test) on 55 PND. Neutrophil elastase (NE) and alpha1-proteinase inhibitor (α1-PI) activity in serum and cerebellum homogenate was measured spectrophotometrically. Complement system (CS) activity was analyzed by the death rate of Tetrahymena pyriformis ciliates in the presence of rat serum. Results: Early postnatal administration of VPA to Wistar rats induces physiological and behavioral changes characteristic of ASD, confirming the validity of the experimental model used. These changes are accompanied by increased activity of inflammatory factors (CS, α1-PI, NE) in the rat serum, indicating the development of inflammation. VPA treatment increased NE activity in the cerebellum, which may indicate neutrophil infiltration of the brain and neuroinflammation development. Conclusions: The data obtained indicate the role of neutrophils in neuroinflammatory mechanisms of ASD development.
Investigation of Trigonelline's effects on autistic phenotype, gene expression of tight junction proteins associated with BBB integrity, neuroinflammation and histopathological changes in the hippocampus in valproic acid - induced autism in rats found it significantly attenuated autistic behaviors.
Zahra Forouzandeh Shahraki, A. Noori, Hossin Amini-Khoei et al.· World Journal of Biological...· 0 citations
Aging is importantly associated to the development of neurodegenerative diseases, including those affecting the motor control and striatum function. It is clear the need to study those changes affecting that brain nucleus during aging, such as the neuroinflammatory phenomenon. This project was directed to evaluate the possible age-related changes in the inflammatory response against an excitotoxic stimulus through the evaluation of the RAGE/S100B axis, exploring at the same time the role of mast cells (MC), one of the less studied cell elements in the brain.
We used mice of different ages (16, 64 and 80 weeks), in which we induced an excitotoxic response by the unilateral administration of the NMDA agonist quinolic acid (QA), directly into the striatum of WT (C57BL6/J) and mast cell-deficient c-Kit Wsh/Wsh (Wsh) mice. After QA administration we measured the neurological damage through the evaluation of ipsilateral turns induced by apomorphine. Then, the integrity of perineuronal nets (PNNs), as well as the presence of different inflammatory markers like S100B protein, RAGE receptor and different cytokines was assessed.
Results obtained to date demonstrate a differential expression of inflammatory components between C57 and Wsh mice after QA administration, with an increase in RAGE receptor in young male mice striatum. This parameter correlates with a major PNNs degeneration and higher levels in the expression of inflammatory cytokines. A reduction in the expression of components of the inflammatory response was observed in aging.
MC seem to be central components in the magnification of the neuroinflammatory response in the excitotoxic QA-induced model. The absence of response in MC-deficient mice results in a decreased inflammation and less neuronal damage. Also, aged mice display a reduced inflammatory capacity that may be related with the brain frailty observed in aging.
Grant CONAHCYT Grant No. 51488
Neuroimmunology (NEUR)
Jesus Lopez-Castillo, C. González-Espinosa, F. Pérez-Severiano· Journal of Immunology· 0 citations
OBJECTIVE
Neuroinflammation plays a pivotal role in the pathogenesis of autism spectrum disorder (ASD) and represents a potential therapeutic target. Salidroside (SLDS), a bioactive compound isolated from Rhodiola rosea L., exhibits potent anti-inflammatory and neuroprotective effects in various neurological disorders; however, its therapeutic efficacy in ASD remains to be fully established. This study investigated whether SLDS ameliorates autism-like behaviors and hippocampal neuroinflammation in a valproic acid (VPA)-induced mouse model.
METHODS
A total of 92 male C57BL/6 J mice were randomly assigned to four groups (n = 23 per group). Mice received a subcutaneous injection of VPA or saline on postnatal day 14 (P14), followed by intraperitoneal administration of SLDS or saline from postnatal day 28 (P28) for seven consecutive days. Behavioral assessments were conducted at 8 weeks of age. Hippocampal neuroinflammation, microglial polarization, and neurogenesis were analyzed by molecular, immunofluorescence, and histological techniques.
RESULTS
VPA-exposed mice exhibited social interaction deficits, increased repetitive behaviors, elevated levels of pro-inflammatory cytokines, upregulated expression of inflammation-related proteins, microglial activation, and impaired hippocampal neurogenesis. SLDS treatment significantly attenuated these VPA-induced abnormalities.
CONCLUSION
Collectively, these findings suggest that SLDS represents a promising therapeutic candidate for ASD by mitigating neuroinflammation and restoring hippocampal function. Nevertheless, given that these observations are derived from preclinical models, further validation in translationally relevant experimental systems and clinical investigations is warranted before extrapolation to human therapeutic applications.
Xinyi Wang, Rui Li, Yannan Li et al.· International Immunopharmaco...· 0 citations
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social communication and repetitive behaviors. Oxidative stress is increasingly recognized as a key contributor to the neuro-degeneration and behavioral abnormalities associated with ASD. Bacopa monnieri (BM), a medicinal herb with potent antioxidant and neuro-protective properties, has shown promise in mitigating oxidative damage. This study evaluated the preventive effects of BM extract on behavioral and neuro-histological alterations in a valproic acid (VPA)-induced mouse model of ASD. Pregnant mice received BM extract (400 mg/kg, orally) throughout gestation, while VPA (600 mg/kg) was administered intraperitoneally on embryonic day 12 (E12). Behavioral assessments included the open field test, righting reflex, three-chamber social interaction, marble burying, and hot plate tests. Oxidative stress markers, malondialdehyde (MDA) and glutathione (GSH), were quantified in hippocampal and cerebellar tissues. BM-treated offspring showed significant behavioral improvements, including reduced hyperactivity in the open field test (p < 0.0001), along with restored brain tissue architecture. Moreover, BM extract decreased MDA levels and elevated GSH concentrations, indicating attenuation of oxidative stress. In conclusion, Bacopa monnieri extract exerts protective effects against autism-like symptoms by enhancing antioxidant defenses and preserving neural integrity, suggesting its potential as a natural preventive strategy for ASD.
Zainab M. Almalki, A. Batawi, Asma Almuhammadi et al.· Molecules· 0 citations
Sex differences in the prevalence, age of onset of symptoms, and symptom presentation have been widely described in autism spectrum disorders, yet the mechanisms underlying these sex differences remain poorly characterized. Exposing rats prenatally to valproic acid (VPA) is widely used as a model to study autism-like phenotypes. Using this model, sex-specific neuroanatomical and functional characteristics were examined in adolescent rats. We found sex differences in cortical pyramidal neuron complexity, spine density, and morphology in VPA-prenatally exposed adolescent rats. The expression of autism has been linked to various processes such as inflammation, cell signalling, endothelial function, and myelination. Sex-specific analysis of cortical gene expression showed that male VPA-prenatally exposed rats had elevated expression of genes related to neuropeptide signaling (Pdyn, Adora2a, Drd2). Female VPA-prenatally exposed rats had lower expression of genes related to vascular permeability (Angptl4, Cldn5) and inflammation (Cyr61, Usp18). Dimethyl fumarate, an activator of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and clinically approved to treat multiple sclerosis, alleviated VPA-induced behavioural alterations in object recognition, anxiety-like behaviour, and social behaviour in female VPA-exposed rats. In addition, dimethyl fumarate corrected the associated VPA-induced changes in neuronal oscillatory power and cross-frequency coupling and suppressed microglial activity, with the latter occurring selectively in female animals. Together, these findings indicate sex as an essential consideration in the development of novel pharmacotherapies for autism. Dimethyl fumarate had therapeutic properties in VPA-prenatally exposed female rats, however further studies examining its therapeutic efficacy in other models of autism are required.
Olivia O. F. Williams, Joshua D. Manduca, Alana Y Coulombe et al.· Neuropharmacology· 0 citations
Introduction Inflammatory processes contribute significantly to the pathophysiology of depression. Although the melanocortin system is well known to regulate inflammation, the specific contribution of melanocortin 1 receptor (MC1R) and its endogenous ligand, α-melanocyte-stimulating hormone (α-MSH), to inflammation-associated depression remains unclear. Methods Systemic lipopolysaccharide (LPS) administration was used to establish an inflammation-associated depression model in mice. Depressive-like behaviors, synaptic functions, and metabolic alterations were evaluated using behavioral tests, patch-clamp recordings, and untargeted metabolomic profiling. To examine the functional involvement of MC1R, adeno-associated virus (AAV)-mediated selective Mc1r overexpression was performed in the medial prefrontal cortex (mPFC). Results LPS administration induced depressive-like behaviors in mice, accompanied by microglial activation and a significant reduction in MC1R expression in the prefrontal cortex (PFC). Treatment with MC1R endogenous ligand α-MSH mimetic Nle4-DPhe7-α-MSH (NDP-MSH) markedly attenuated LPS-induced depressive-like behaviors, enhanced MC1R, postsynaptic density protein 95 (PSD95), glutamate receptor 1 (GluA1) and protein kinase A (PKA) phosphorylation. PKA inhibitor H89-mediated inhibition of the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway partially but robustly abolishes the behavioral, anti-inflammatory, and synaptic protective effects of NDP-MSH. Additionally, untargeted metabolomics confirmed that NDP-MSH effectively corrected LPS-induced metabolic dysregulation, a therapeutic effect that was robustly suppressed by H89; this metabolic remodeling was closely associated with purine metabolism, pantothenate, and coenzyme A biosynthesis. Critically, AAV-mediated Mc1r overexpression in the mPFC was sufficient to rescue LPS-induced depressive-like phenotypes. Conclusion This study highlights MC1R-related signaling in the PFC as an important contributor to inflammation-associated depression and suggests that NDP-MSH alleviates inflammation-associated depressive-like behaviors in association with melanocortin signaling involving MC1R and downstream cAMP/PKA activation.
Shanglan Qu, Xin Peng, Jieyu Ji et al.· Frontiers in Pharmacology· 0 citations
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