Autism Spectrum Disorder (ASD) is associated with neuroinflammation and oxidative stress that disrupt neurodevelopmental processes. Resveratrol (RSV) is a polyphenol with antioxidant and anti-inflammatory properties, but its poor bioavailability limits therapeutic use. This study investigated whether PEGylated liposomes encapsulating RSV (LipRSV) could modulate oxidative and behavioral alterations in a valproic acid (VPA)-induced rat model of ASD. PEGylated LipRSV were synthesized, characterized as hemocompatible, and administered to offspring from postnatal day (PND) 6 to 27. Behavioral tests included developmental milestones, olfactory discrimination, negative geotaxis, open field, and three-chamber social interaction. Oxidative stress markers and neurotrophins (BDNF, NGF) were quantified in the following brain regions: hippocampus, hypothalamus, striatum, cerebellum, frontal and posterior cortex. LipRSV exerted limited and region-dependent redox effects, reducing ROS levels only in the hippocampus, cerebellum, and posterior cortex, while failing to improve behavioral outcomes and being associated with unfavorable neurochemical alterations, including reduced BDNF and NGF levels. Importantly, LipRSV also induced behavioral deficits, redox imbalance, and neurochemical alterations in control animals, indicating treatment-related effects in the absence of VPA exposure. LipRSV modulated oxidative stress in a region-dependent manner without improving behavioral deficits in the VPA model and was associated with reduced BDNF and NGF levels. This study provides evidence that modulation of oxidative stress alone is insufficient to rescue behavioral phenotypes in the VPA model of ASD. These findings highlight the partial neurochemical efficacy and translational limitations of this formulation, suggesting the need for optimized nanocarrier design and dosing strategies in ASD pharmacotherapy.

Drug-resistant epilepsy (DRE) affects approximately one-third of patients with epilepsy and represents a major unmet clinical need. While traditional hypotheses of pharmacoresistance have focused on alterations in drug targets, efflux transporter overexpression, and intrinsic disease severity, the gut microbiome has recently emerged as a potentially modifiable factor that may function as a systems-level modifier of these established mechanisms rather than a standalone pathway. The gut microbiome harbors a vast repertoire of drug-metabolizing enzymes capable of directly biotransforming orally administered antiseizure medications (ASMs)-including valproic acid, lamotrigine, carbamazepine, and oxcarbazepine-thereby altering their pharmacokinetics, bioavailability, and therapeutic efficacy. Additionally, microbial metabolites modulate host cytochrome P450 enzymes, nuclear receptors, and efflux transporters such as P-glycoprotein, while bacterial β-glucuronidases influence the enterohepatic recirculation of glucuronidated ASMs. Conversely, chronic ASM exposure reshapes the gut microbial ecosystem, creating a self-perpetuating cycle of dysbiosis and pharmacoresistance. This narrative review synthesizes current evidence on microbiome-ASM interactions in DRE, proposes a concrete experimental pipeline for characterizing ASM-specific microbial biotransformation, and outlines a framework for integrating physiologically based pharmacokinetic modeling with microbiome data. We discuss clinical implications for epileptologists-including the role of therapeutic drug monitoring in detecting microbiome-mediated pharmacokinetic variability, the concept of microbiome-neutral ASM selection, and earlier deployment of the ketogenic diet as a microbiome-targeted intervention. We highlight the translational potential of pharmacomicrobiomics-the study of how microbiome variation influences drug disposition and response-and identify critical knowledge gaps that warrant future investigation. PLAIN LANGUAGE SUMMARY: About one in three people with epilepsy continue to have seizures despite treatment. This review summarizes growing evidence that the gut microbiome-the community of bacteria living in the intestines-can influence how seizure medications work by altering their absorption, metabolism, and clearance. The medications themselves can reshape the microbiome in return, creating a cycle that may sustain treatment failure. Understanding this gut-drug relationship may open new paths to personalized epilepsy care through diet, probiotics, and microbiome-guided prescribing.

Therapeutic resistance remains a major barrier to treating aggressive breast cancers, particularly triple-negative breast cancer (TNBC), in which hypoxia-associated stress adaptation within the tumor microenvironment limits treatment efficacy. Here, we investigated a multi-targeted therapeutic strategy combining histone deacetylase (HDAC) inhibition with blockade of hypoxia-associated chaperones HSP90β and mitochondrial TRAP1 in 3-D breast cancer models grown from TNBC human cells. HDAC inhibitors (HDACi; vorinostat [SAHA; pan-HDACi], valproic acid [VPA; HDAC1i], and CAY10603 [CAY; HDAC6i]; showed greater efficacy than paclitaxel at reducing viability and mammosphere formation in 3-D cultures, and induced apoptosis and G2/M cell cycle arrest in TNBC cells. Combined inhibition of HDACs with our novel agents targeting HSP90β (NDNB-25) or TRAP1 (NDNT-34) synergistically reduced mammosphere viability and disrupted spheroid architecture. Mechanistically, HSP90β and TRAP1 inhibition attenuated hypoxia-associated adaptive signaling by suppressing HIF-1α, VEGFA, HSP90β, and TRAP1 gene and protein expression. In co-cultures with HUVEC cells, these effects were accompanied by impaired endothelial network formation, tumor cell migration and invasion, mitotic progression, and clonogenic growth. Following Cleavage Under Targets and Release Using Nuclease (CUT&RUN) analysis, genome-wide HIF-1α occupancy analysis revealed extensive reprogramming of HIF-1α-associated regulatory programs under HDAC, HSP90β, and TRAP1 inhibition, including pathways linked to innate immunity, interferon signaling, redox balance, autophagy, mitochondrial function, and metabolic adaptation. Together, these findings identify hypoxia-associated stress adaptation as a therapeutically actionable vulnerability in aggressive breast cancer and support coordinated targeting of epigenetic regulation, proteostasis, and mitochondrial stress adaptation to enhance treatment response.

In a recent review and meta-analysis, Goudarzi et al. (Stress, 2026 Dec 31; 29(1):2641561) show that valproic acid (VPA) exhibits antidepressant (AD)-like effects in several procedures involving the induction of depression-like symptoms by prior sub-chronic or chronic stress in laboratory rats or mice. In their review, the authors included reports of experimental studies (covering only from 2007 to 2024), using several validated depression-like behaviors, such as decreased sucrose preference, increased immobility in the forced swim test (FST), decreased activity in the open field test, and/or impaired novel object recognition memory. The meta-analysis of the 19 included studies showed that sub-chronic/chronic VPA treatment improves most of these depression-like symptoms. The present "Comment" article aims to highlight that the first demonstrations of VPA AD-like and passive coping-reducing effects date back to the 1980s. Our group was the first to demonstrate AD-like effects of sub-acute and chronic VPA treatments in the forced swim test in rats (in 1988). These effects were partially antagonized by pre-test injections of the GABA-A receptor complex antagonists bicuculline and picrotoxin, thus suggesting that VPA-induced passive coping reduction was at least partly mediated by enhancement of GABA-A neurotransmission. Shortly thereafter (1989), the AD-like effects of VPA were confirmed in the FST in mice. These reports from the late 1980s, showing positive effects of VPA on the FST in rats and mice, constitute relevant precedents that further strengthen the profile of AD-like effects of VPA reported by Goudarzi et al.

BackgroundBenign recurrent vertigo (BRV) accounts for a high proportion of episodic vestibular syndrome (EVS) patients. To date, randomized controlled trials and guidelines are lacking, and preventive treatment has not been established.ObjectiveIn clinical practice, we have found that sodium valproate has excellent effect on reducing vertigo attacks in BRV patients. Herein, these cases were collected and analyzed to share our clinical experience.MethodsIn this retrospective case series, we evaluated 84 patients with BRV or vestibular migraine (VM) who received prophylactic treatment with sodium valproate (400-500 mg/day) between April 2022 and July 2024. The primary clinical outcomes were the proportion of patients achieving a ≥50% reduction in monthly vertigo days (50% reduction rate) and the complete remission rate. Patients who achieved complete symptom resolution and subsequently discontinued medication were monitored to assess post-withdrawal recurrence rates.ResultsA total of 84 patients were enrolled, including 43 in the BRV group and 41 in the VM group. After 3 months of prophylactic treatment with sodium valproate, 91.1% of patients had a 50% reduction rate in monthly vertigo days and 71.4% had complete remission. There was no significant difference in preventive efficacy between the VM group and BRV group (p = 0.348). There was no significant difference in the cumulative recurrence rates between different preventive treatment courses (<6 and ≥6 months) (p = 0.907). The cumulative recurrence rate after discontinuing medication was 38.2% at 3 months, and this rate after 6 months was 70.0%. Among the 25 patients who experienced recurrence, 44.0% needed to undergo prophylactic treatment again.ConclusionLow-dose sodium valproate showed a good preventive effect in patients with BRV, comparable to that in patients with VM.

Lithium, the gold-standard treatment for bipolar disorder, exhibits highly heterogeneous clinical responses and no validated biological predictors of responsiveness are currently available. Emerging evidence suggests that the gut microbiota influences mood disorders and psychotropic drug response, raising the hypothesis that specific microbial signatures may modulate lithium responsiveness. In this study, we characterized taxonomic and functional gut microbiota profiles in 77 patients with bipolar disorder, of whom 40 were receiving lithium (20 responders, 20 non-responders) and 37 were treated with valproate as the main mood stabilizer (valproate, n = 31; lamotrigine, n = 6), with the aim of identifying potential microbial markers of clinical response. Microbiota composition was assessed through 16S rRNA sequencing targeting the V3-V4 region. Differential abundance was evaluated using Analysis of Composition of Microbiomes with Bias Correction (ANCOM-BC2), and the functional potential was inferred using the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2 (PICRUSt2). Our finding showed that lithium treatment was associated with a selective gut microbiota reorganization, including reduced Actinobacteria (Actinomycetota) phylum, notably Coriobacteriia class, and enrichment in Firmicutes (Bacillota) taxa, including Selenomonadales, Megamonas and Clostridia taxa, alongside reductions in primary fermentative and biosynthetic pathways. This shift, characterized by a reduction of primary fermenters and enrichment of secondary fermenters and SCFA-producing taxa, suggests a more efficient fermentative ecosystem in lithium-treated patients. Responders showed enrichment in methanogenic taxa (Methanobrevibacter) and Clostridiales vadinBB60 group when compared with patients treated with other mood stabilizers; however, these differences were not observed in the direct comparison between lithium responders and non-responders. While causal relationships cannot be inferred, these findings indicate treatment-associated microbial patterns and support further investigation into microbiota-directed adjunctive therapies.

Valproic acid is a clinically important therapeutic agent whose biological properties have stimulated the development of structurally modified derivatives with improved pharmacological profiles. In the present study, nine amino-valproic acid hybrids were synthesized by a rapid mechanochemical approach using a planetary ball mill under solvent-minimized conditions. The synthesized compounds were formulated in a newly developed deep eutectic solvent composed of urea and propylene glycol (1:4 molar ratio), which was characterized by solvatochromic and Kamlet-Taft analyses. The biological activities of the derivatives were evaluated by hydrogen peroxide scavenging activity (HPSA), hydroxyl radical-scavenging activity (HRSA), and inhibition of albumin denaturation (IAD) assays. Among the investigated compounds, derivative 3h exhibited the highest biological activity, showing IC50 values of 291 µM and 163 µM in the HPSA and HRSA assays, respectively, and the strongest anti-inflammatory activity in the IAD assay. All synthesized derivatives demonstrated lower IC50 values than ibuprofen in the albumin denaturation model. Dose-response relationships were analyzed using four- and five-parameter logistic models, with the 5PL model providing a statistically superior fit to the experimental data. Lipophilicity measurements and in silico studies further supported the favorable physicochemical profile of the synthesized compounds. These results identify compound 3h as the most promising derivative and demonstrate the potential of mechanochemical synthesis for the preparation of biologically active valproic acid hybrids.

Patients with cerebrovascular disease frequently require concomitant antiplatelet and antiseizure therapy. However, experimental evidence regarding potential pharmacodynamic interactions between these medications remains limited. The present study investigated whether clopidogrel affects the anticonvulsant effects of valproic acid (VPA) or levetiracetam (LEV) in a pentylenetetrazol (PTZ)-induced seizure model. Forty-two male Wistar rats were randomly allocated to seven groups (n = 6/group): Control, PTZ, clopidogrel (CLP), VPA, LEV, VPA + CLP + PTZ, and LEV + CLP + PTZ. Electroencephalographic recordings, passive avoidance testing, histopathological examination, and glial fibrillary acidic protein (GFAP) immunohistochemistry were performed to evaluate seizure activity, behavioral performance, neuronal injury, and astroglial activation. Both VPA and LEV significantly reduced spike-wave discharge frequency and duration compared with the PTZ group (p < 0.05). Clopidogrel alone did not exhibit anticonvulsant activity, and co-administration with either VPA or LEV did not significantly alter electrophysiological, behavioral, histopathological, or GFAP-associated immunohistochemical outcomes. Overall, these findings indicate that clopidogrel did not significantly affect the anticonvulsant efficacy of VPA or LEV under the experimental conditions of this acute PTZ-induced seizure model.

Oxidative stress and apoptosis contribute to seizure-associated neuronal injury, but the effects of ML-171, a pharmacological NOX-1 inhibitor, on PTZ-associated oxidative and apoptotic injury remain insufficiently defined. This study evaluated the effects of the NOX-1 inhibitor ML-171 in pentylenetetrazole (PTZ)-induced cellular and animal models of neuronal injury. SH-SY5Y cells were exposed to PTZ (30 mM, 24 h) after pretreatment with ML-171 or valproic acid (VPA), and cell viability, redox status, apoptosis-related proteins, and Annexin V-based cell death were assessed. Adult male Wistar Albino rats were subjected to PTZ kindling and acutely treated with VPA or ML-171 (0.1, 1, or 10 mg/kg); behavioral seizures, electrocorticographic activity, hippocampal oxidative stress, apoptotic markers, histopathology, and NOX-1 immunoreactivity were evaluated. ML-171 attenuated PTZ-induced cellular injury in SH-SY5Y cells within a restricted concentration window and reduced oxidant burden, oxidative stress index, and apoptotic signaling. In PTZ-kindled rats, ML-171 improved hippocampal oxidative and apoptotic markers but did not robustly suppress behavioral or electrophysiological seizure parameters. Histopathological injury and NOX-1 immunoreactivity showed region- and dose-dependent responses. These findings suggest that ML-171 primarily attenuates PTZ-associated oxidative and apoptotic injury rather than exerting a conventional antiseizure effect.