Mechanisms ofDrug Resistance

epileptic behavior and EEG data through proteomic analysis. The results showed that HIF-1α was overexpressed in VPA-resistant epileptic mice and regulated the expression of interleukin-1β and tumor necrosis factor-α. Increased expression of HIF-1α led to an increase in the number of microglia and induced their polarization from the M2 phenotype to the M1 phenotype, which triggered the release of proin­ammatory mediators. Bioinformatics analysis of public databases revealed that miR-221-3p expression was reduced in VPA-resistant epilepsy and negatively regu­lated HIF-1α expression. Treatment with miR-221-3p mimics signicantly reduced HIF-1α expression and inhibited microglial activation and inammatory mediator release, resulting in the relief of seizures in VPA-resistant epilepsy patients. These ndings suggest that the miR-221-3p/HIF-1α pathway is a critical component in the pathogenesis of VPA-resistant epilepsy and represents a potential therapeutic target for antiepileptic treatment. Wang etal. [220] explored the potential mechanism of VPA resistance by administering VPA (250mg/kg) to rats with chronic epilepsy induced by pentylenetetrahydroxybenzene (Penta) for 14days. The seizure stage (seizure score [before Day 14]≤ 0) and latency time (latency time [before Day 14]≥0) were evaluated, and rats with controlled seizures were considered respon­sive to VPA treatment, while the others were considered unresponsive. Differentially expressed genes (DEGs) were identied in the hippocampal transcriptomes of rats that responded to VPA and those that did not respond to VPA treatment, and their functions were evaluated. The roles of the postsynaptic dense region (PSD) and the Homer1 protein were determined. Homer1 was more highly expressed in the hip­pocampi of rats unresponsive to VPA treatment than in that of rats responsive to VPA treatment. Homer1b/c overexpression blocked the therapeutic effects of VPA by increasing reactive oxygen species production, lactate dehydrogenase release, and calcium levels. In addition, Homer1b/c overexpression induced mGluR1 and mGluR5 overexpression. These ndings suggest that Homer1b/c overexpression affects the therapeutic effect of VPA and that Homer1b/c overexpression is a poten­tial marker for improving the efcacy of this treatment.

topiramate (TPM), VPA is associated with a notably lower incidence of ADRs in epilepsy patients [221]. VPA toxicity can arise accidentally or therapeutically. In individuals with metabolic disorders, drug interactions, or intentional overdose, toxic reactions may manifest when doses are manipulated to achieve therapeutic levels. Acute VPA overdose typically presents with symptoms such as central ner­vous system dysfunction, electrolyte imbalances (e.g., hypernatremia), elevated liver enzymes, hyperammonemia, and hepatotoxicity. Severe overdoses may lead to hypotension, tachycardia, respiratory depression, metabolic acidosis, cerebral edema, and VPA-induced hyperammonemic encephalopathy, potentially progress­ing to coma and fatal outcomes without prompt intervention. Conventional manage­ment strategies for VPA toxicity typically involve administering levothyroxine, activated charcoal, and hemodialysis.

human brain remains unclear, as most relevant studies are conducted in two­dimensional cell cultures and animal models. Meng et al. [246] utilized human forebrain-like organoids (hFOs) and reported that VPA exposure in three­dimensional cell cultures derived from hFOs altered the expression of genes enriched in neurodevelopmental processes, synaptic transmission, oxytocin signal­ing, and calcium and potassium signaling pathways (e.g., CAMK4, CLCN4, DPP10, GABRB3, KCNB1, PRKCB, SCN1A, SLC24A2)—all of which are implicated in ASD.The genes whose expression was affected by VPA exposure overlapped sig­nicantly with those dysregulated in the brains or organoids of ASD patients, known ASD risk genes, and genes within ASD risk-associated coexpression modules. Single-cell RNA sequencing analysis revealed that VPA exposure inuenced gene expression in hFOs, particularly in the choroid plexus, excitatory neurons, imma­ture neurons, and medial ganglionic rongeur cells. Furthermore, microelectrode arrays conrmed that VPA exposure disrupted synaptic transmission in hFOs. This study established a link between VPA exposure and ASD pathogenesis using hFOs, providing valuable insights into the etiology of ASD and potential therapeutic tar­gets. Moreover, fetal exposure to VPA during the rst trimester of pregnancy is associated with a greater incidence of autism in offspring. Epigenetic mechanisms are speculated to contribute to VPA-induced ASD, as VPA can affect DNA tran­scription through epigenetic mechanisms, increasing susceptibility to the transmis­sion of new traits to subsequent generations. The use of VPA has been restricted based on retrospective and prospective studies demonstrating its role as a risk factor for ASD [150]. Conversely, an animal study conducted using pregnant rats [247] revealed that supplementation with vitamin A signicantly mitigated VPA-induced autism-related behaviors. Additionally, NONRATT021475.2 and Dhh expression were upregulated in the hippocampi of rats exhibiting autism-like behaviors, sug­gesting a potential therapeutic role for vitamin A in treating this disorder. Integrating these ndings with further clinical evidence will be crucial for fully understanding the impact of VPA on different stages of neurodevelopment and exploring addi­tional therapeutic options. Honybun etal. [248] investigated the inuence of sex and drug dosage on the relationship between prenatal VPA exposure and postnatal behavioral outcomes. They examined 121 children aged 4–11years, including 54 children prenatally exposed to VPA (28 males, 26 females; mean dose +/− SD: 644 +/− 310mg/day) and 67 children exposed to other ASMs. The results indicated that males exhibited more ASD symptoms (p=0.01), but this sex difference was not observed in VPA-exposed children. Furthermore, there was no evidence of a dose– response relationship between VPA exposure and ASD symptoms. Although males had higher ADHD scores than females did, no association between ADHD symp­toms and VPA exposure was found. These initial ndings suggest that prenatal VPA exposure may counteract the usual male predominance in ASD incidence, indicat­ing that VPA is a “behavioral teratogen” whose effects may be sex-dependent, with females being particularly sensitive. Additionally, no association was observed between VPA dosage and adverse postnatal behavioral outcomes, possibly due to the relatively low VPA dosage used in the study. In a study by Bjørk etal. [249], Nordic health registry and social registry data from 1996 to 2017 were analyzed to