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Psychiatry and Clinical Neurosciences May 2024Cognitive impairment is a common comorbidity in individuals with temporal lobe epilepsy (TLE), yet the underlying mechanisms remain unknown. This study explored the...
AIM
Cognitive impairment is a common comorbidity in individuals with temporal lobe epilepsy (TLE), yet the underlying mechanisms remain unknown. This study explored the putative association between in vivo synaptic loss and cognitive outcomes in TLE patients by PET imaging of synaptic vesicle glycoprotein 2A (SV2A).
METHODS
We enrolled 16 TLE patients and 10 cognitively normal controls. All participants underwent SV2A PET imaging using [F]SynVesT-1 and cognitive assessment. Lithium chloride-pilocarpine-induced rats with status epilepticus (n = 20) and controls (n = 6) rats received levetiracetam (LEV, specifically binds to SV2A), valproic acid (VPA), or saline for 14 days. Then, synaptic density was quantified by [F]SynVesT-1 micro-PET/CT. The novel object recognition and Morris water maze tests evaluated TLE-related cognitive function. SV2A expression was examined and confirmed by immunohistochemistry.
RESULTS
Temporal lobe epilepsy patients showed significantly reduced synaptic density in hippocampus, which was associated with cognitive performance. In the rat model of TLE, the expression of SV2A and synaptic density decreased consistently in a wider range of brain regions, including the entorhinal cortex, insula, hippocampus, amygdala, thalamus, and cortex. We treated TLE animal models with LEV or VPA to explore whether synaptic loss contributes to cognitive deficits. It was found that LEV significantly exerted protective effects against brain synaptic deficits and cognitive impairment.
CONCLUSION
This is the first study to link synaptic loss to cognitive deficits in TLE, suggesting [F]SynVesT-1 PET could be a promising biomarker for monitoring synaptic loss and cognitive dysfunction. LEV might help reverse synaptic deficits and ameliorate learning and memory impairments in TLE patients.
PubMed: 38804583
DOI: 10.1111/pcn.13682 -
Communications Biology May 2024Alterations in the experience-dependent and autonomous elaboration of neural circuits are assumed to underlie autism spectrum disorder (ASD), though it is unclear what...
Alterations in the experience-dependent and autonomous elaboration of neural circuits are assumed to underlie autism spectrum disorder (ASD), though it is unclear what synaptic traits are responsible. Here, utilizing a valproic acid-induced ASD marmoset model, which shares common molecular features with idiopathic ASD, we investigate changes in the structural dynamics of tuft dendrites of upper-layer pyramidal neurons and adjacent axons in the dorsomedial prefrontal cortex through two-photon microscopy. In model marmosets, dendritic spine turnover is upregulated, and spines are generated in clusters and survived more often than in control marmosets. Presynaptic boutons in local axons, but not in commissural long-range axons, demonstrate hyperdynamic turnover in model marmosets, suggesting alterations in projection-specific plasticity. Intriguingly, nasal oxytocin administration attenuates clustered spine emergence in model marmosets. Enhanced clustered spine generation, possibly unique to certain presynaptic partners, may be associated with ASD and be a potential therapeutic target.
Topics: Animals; Oxytocin; Callithrix; Disease Models, Animal; Neuronal Plasticity; Male; Synapses; Dendritic Spines; Autism Spectrum Disorder; Autistic Disorder; Prefrontal Cortex; Pyramidal Cells; Valproic Acid; Presynaptic Terminals; Female; Axons
PubMed: 38802535
DOI: 10.1038/s42003-024-06345-9 -
CNS Neuroscience & Therapeutics May 2024
PubMed: 38797971
DOI: 10.1111/cns.14785 -
Behavioural Brain Research Jul 2024Recent clinical studies have highlighted mutations in the voltage-gated potassium channel Kv10.2 encoded by the KCNH5 gene among individuals with autism spectrum...
Recent clinical studies have highlighted mutations in the voltage-gated potassium channel Kv10.2 encoded by the KCNH5 gene among individuals with autism spectrum disorder (ASD). Our preliminary study found that Kv10.2 was decreased in the hippocampus of valproic acid (VPA) - induced ASD rats. Nevertheless, it is currently unclear how KCNH5 regulates autism-like features, or becomes a new target for autism treatment. We employed KCNH5 knockout (KCNH5) rats and VPA - induced ASD rats in this study. Then, we used behavioral assessments, combined with electrophysiological recordings and hippocampal brain slice, to elucidate the impact of KCNH5 deletion and environmental factors on neural development and function in rats. We found that KCNH5 rats showed early developmental delay, neuronal overdevelopment, and abnormal electroencephalogram (EEG) signals, but did not exhibit autism-like behavior. KCNH5 rats exposed to VPA (KCNH5-VPA) exhibit even more severe autism-like behaviors and abnormal neuronal development. The absence of KCNH5 excessively enhances the activity of the Protein Kinase B (Akt)/Mechanistic Target of Rapamycin (mTOR) signaling pathway in the hippocampus of rats after exposure to VPA. Overall, our findings underscore the deficiency of KCNH5 increases the susceptibility to autism under environmental exposures, suggesting its potential utility as a target for screening and diagnosis in ASD.
Topics: Animals; Male; Rats; Autism Spectrum Disorder; Autistic Disorder; Disease Models, Animal; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Hippocampus; Neurons; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Signal Transduction; TOR Serine-Threonine Kinases; Valproic Acid
PubMed: 38797494
DOI: 10.1016/j.bbr.2024.115069 -
International Journal of Molecular... May 2024Perinatal exposure to valproic acid is commonly used for autism spectrum disorder (ASD) animal model development. The inhibition of histone deacetylases by VPA has been...
Perinatal exposure to valproic acid is commonly used for autism spectrum disorder (ASD) animal model development. The inhibition of histone deacetylases by VPA has been proposed to induce epigenetic changes during neurodevelopment, but the specific alterations in genetic expression underlying ASD-like behavioral changes remain unclear. We used qPCR-based gene expression and epigenetics tools and Western blotting in the hippocampi of neonatal valproic acid-exposed animals at 4 weeks of age and conducted the social interaction test to detect behavioral changes. Significant alterations in gene expression were observed in males, particularly concerning mRNA expression of , which was significantly associated with behavioral changes. Moreover, notable differences were observed in H3K27ac chromatin immunoprecipitation, quantitative PCR (ChIP-qPCR), and methylation-sensitive restriction enzyme-based qPCR targeting the Foxo3 gene promoter region. These findings provide evidence that epigenetically regulated hippocampal expression may influence social interaction-related behavioral changes. Furthermore, identifying sex-specific gene expression and epigenetic changes in this model may elucidate the sex disparity observed in autism spectrum disorder prevalence.
Topics: Animals; Valproic Acid; Forkhead Box Protein O3; Hippocampus; Epigenesis, Genetic; Male; Female; Rats; Autism Spectrum Disorder; Animals, Newborn; DNA Methylation; Sex Characteristics; Disease Models, Animal; Pregnancy; Behavior, Animal; Sex Factors; Rats, Sprague-Dawley; Promoter Regions, Genetic
PubMed: 38791325
DOI: 10.3390/ijms25105287 -
International Journal of Molecular... May 2024Drug induced fatty liver disease (DIFLD) is a form of drug-induced liver injury (DILI), which can also be included in the more general metabolic dysfunction-associated... (Review)
Review
Drug-Induced Fatty Liver Disease (DIFLD): A Comprehensive Analysis of Clinical, Biochemical, and Histopathological Data for Mechanisms Identification and Consistency with Current Adverse Outcome Pathways.
Drug induced fatty liver disease (DIFLD) is a form of drug-induced liver injury (DILI), which can also be included in the more general metabolic dysfunction-associated steatotic liver disease (MASLD), which specifically refers to the accumulation of fat in the liver unrelated to alcohol intake. A bi-directional relationship between DILI and MASLD is likely to exist: while certain drugs can cause MASLD by acting as pro-steatogenic factors, MASLD may make hepatocytes more vulnerable to drugs. Having a pre-existing MASLD significantly heightens the likelihood of experiencing DILI from certain medications. Thus, the prevalence of steatosis within DILI may be biased by pre-existing MASLD, and it can be concluded that the genuine true incidence of DIFLD in the general population remains unknown. In certain individuals, drug-induced steatosis is often accompanied by concomitant injury mechanisms such as oxidative stress, cell death, and inflammation, which leads to the development of drug-induced steatohepatitis (DISH). DISH is much more severe from the clinical point of view, has worse prognosis and outcome, and resembles MASH (metabolic-associated steatohepatitis), as it is associated with inflammation and sometimes with fibrosis. A literature review of clinical case reports allowed us to examine and evaluate the clinical features of DIFLD and their association with specific drugs, enabling us to propose a classification of DIFLD drugs based on clinical outcomes and pathological severity: Group 1, drugs with low intrinsic toxicity (e.g., ibuprofen, naproxen, acetaminophen, irinotecan, methotrexate, and tamoxifen), but expected to promote/aggravate steatosis in patients with pre-existing MASLD; Group 2, drugs associated with steatosis and only occasionally with steatohepatitis (e.g., amiodarone, valproic acid, and tetracycline); and Group 3, drugs with a great tendency to transit to steatohepatitis and further to fibrosis. Different mechanisms may be in play when identifying drug mode of action: (1) inhibition of mitochondrial fatty acid β-oxidation; (2) inhibition of fatty acid transport across mitochondrial membranes; (3) increased de novo lipid synthesis; (4) reduction in lipid export by the inhibition of microsomal triglyceride transfer protein; (5) induction of mitochondrial permeability transition pore opening; (6) dissipation of the mitochondrial transmembrane potential; (7) impairment of the mitochondrial respiratory chain/oxidative phosphorylation; (8) mitochondrial DNA damage, degradation and depletion; and (9) nuclear receptors (NRs)/transcriptomic alterations. Currently, the majority of, if not all, adverse outcome pathways (AOPs) for steatosis in AOP-Wiki highlight the interaction with NRs or transcription factors as the key molecular initiating event (MIE). This perspective suggests that chemical-induced steatosis typically results from the interplay between a chemical and a NR or transcription factors, implying that this interaction represents the primary and pivotal MIE. However, upon conducting this exhaustive literature review, it became evident that the current AOPs tend to overly emphasize this interaction as the sole MIE. Some studies indeed support the involvement of NRs in steatosis, but others demonstrate that such NR interactions alone do not necessarily lead to steatosis. This view, ignoring other mitochondrial-related injury mechanisms, falls short in encapsulating the intricate biological mechanisms involved in chemically induced liver steatosis, necessitating their consideration as part of the AOP's map road as well.
Topics: Humans; Fatty Liver; Chemical and Drug Induced Liver Injury; Adverse Outcome Pathways; Liver; Oxidative Stress
PubMed: 38791241
DOI: 10.3390/ijms25105203 -
Biomedicines May 2024The safety of the use of psychotropic drugs, widely used in neurological and psychiatric practice, is an urgent problem in personalized medicine. This narrative review... (Review)
Review
The safety of the use of psychotropic drugs, widely used in neurological and psychiatric practice, is an urgent problem in personalized medicine. This narrative review demonstrated the variability in allelic frequencies of low-functioning and non-functional single nucleotide variants in genes encoding key isoenzymes of valproic acid P-oxidation in the liver across different ethnic/racial groups. The sensitivity and specificity of pharmacogenetic testing panels for predicting the rate of metabolism of valproic acid by P-oxidation can be increased by prioritizing the inclusion of the most common risk allele characteristic of a particular population (country).
PubMed: 38790997
DOI: 10.3390/biomedicines12051036 -
Antioxidants (Basel, Switzerland) May 2024Valproic acid (VPA) is a common anti-epileptic drug and known neurodevelopmental toxicant. Although the exact mechanism of VPA toxicity remains unknown, recent findings...
Valproic acid (VPA) is a common anti-epileptic drug and known neurodevelopmental toxicant. Although the exact mechanism of VPA toxicity remains unknown, recent findings show that VPA disrupts redox signaling in undifferentiated cells but has little effect on fully differentiated neurons. Redox imbalances often alter oxidative post-translational protein modifications and could affect embryogenesis if developmentally critical proteins are targeted. We hypothesize that VPA causes redox-sensitive post-translational protein modifications that are dependent upon cellular differentiation states. Undifferentiated P19 cells and P19-derived neurons were treated with VPA alone or pretreated with D3T, an inducer of the nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant pathway, prior to VPA exposure. Undifferentiated cells treated with VPA alone exhibited an oxidized glutathione redox couple and increased overall protein oxidation, whereas differentiated neurons were protected from protein oxidation via increased -glutathionylation. Pretreatment with D3T prevented the effects of VPA exposure in undifferentiated cells. Taken together, our findings support redox-sensitive post-translational protein alterations in undifferentiated cells as a mechanism of VPA-induced developmental toxicity and propose NRF2 activation as a means to preserve proper neurogenesis.
PubMed: 38790665
DOI: 10.3390/antiox13050560 -
Pharmacoepidemiology and Drug Safety Jun 2024The purpose was to examine the correlation of antiseizure medication drug dose estimated from prescription fill records from prescription registers with blood levels...
PURPOSE
The purpose was to examine the correlation of antiseizure medication drug dose estimated from prescription fill records from prescription registers with blood levels during pregnancy.
METHODS
We conducted a Nation-wide study of mothers who gave birth in Denmark between 1 January 2014 and 31 December 2018 using data from Danish Prescription and Laboratory Registers. We identified mothers with blood level measurements of antiseizure medication. The main exposure was estimated antiseizure medication dosage estimated from pregnancy-filled prescriptions in the Danish Prescription Register. The main outcome was the correlation of estimated dose with mean blood level of antiseizure medication in pregnancy. For privacy reasons, the number of blood level measurement and prescription fills were rounded to nearest 10, but proportions reported as exact values.
RESULTS
Among 298 560 pregnancies, we identified pregnancies with recorded prescription fill from the prescription register for valproate (N = 90), lamotrigine (N = 1360), levetiracetam (N = 340), topiramate (N = 100), and carbamazepine (N = 60). In these pregnancies, blood level measurements were available in 50 (53%) pregnancies for valproate, 850 (62%) pregnancies for lamotrigine, 320 (93%) pregnancies for levetiracetam, 50 (68%) pregnancies for carbamazepine, and 40 (35%) pregnancies for topiramate. Pearsons's correlation coefficients for the correlation of estimated antiseizure medication dose with mean blood levels were 0.67 (p < 0.0001) for valproate, 0.63 (p < 0.0001) for lamotrigine, 0.63 (p < 0.0001) for levetiracetam, 0.76 (<0.0001) for carbamazepine and 0.89 (<0.0001) for topiramate.
CONCLUSIONS
Dose of antiseizure medication estimated from prescription fills was a good proxy for blood levels and thus for biological exposure in pregnancy, suggesting that administrative prescription fill records may be a valuable resource for estimating exposure to antiseizure medication in pregnancy.
Topics: Humans; Female; Anticonvulsants; Pregnancy; Registries; Denmark; Adult; Pregnancy Complications; Drug Prescriptions; Young Adult; Carbamazepine; Valproic Acid; Epilepsy; Lamotrigine; Levetiracetam; Topiramate
PubMed: 38783423
DOI: 10.1002/pds.5811 -
Behavioural Brain Research Jul 2024Autism spectrum disorder (ASD) is a pervasive developmental disorder with gender differences. Oxytocin (OXT) is currently an important candidate drug for autism, but the...
Autism spectrum disorder (ASD) is a pervasive developmental disorder with gender differences. Oxytocin (OXT) is currently an important candidate drug for autism, but the lack of data on female autism is a big issue. It has been reported that the effect of OXT is likely to be different between male and female ASD patients. In the study, we specifically explored the role of the OXT signaling pathway in a VPA-induced female rat's model of autism. The data showed that there was an increase of either oxytocin or its receptor expressions in both the hippocampus and the prefrontal cortex of VPA-induced female offspring. To determine if the excess of OXT signaling contributed to autism symptoms in female rats, exogenous oxytocin and oxytocin receptor antagonists Atosiban were used in the experiment. It was found that exogenous oxytocin triggered autism-like behaviors in wild-type female rats by intranasal administration. More interestingly, several autism-like deficits including social interaction, anxiety, and repeat stereotypical sexual behavior in the VPA female offspring were significantly attenuated by oxytocin receptor antagonists Atosiban. Moreover, Atosiban also effectively improved the synaptic plasticity impairment induced by VPA in female offspring. Our results suggest that oxytocin receptor antagonists significantly improve autistic-like behaviors in a female rat model of valproic acid-induced autism.
Topics: Animals; Valproic Acid; Female; Receptors, Oxytocin; Disease Models, Animal; Oxytocin; Rats; Vasotocin; Autistic Disorder; Prefrontal Cortex; Autism Spectrum Disorder; Hippocampus; Behavior, Animal; Rats, Sprague-Dawley; Neuronal Plasticity; Social Interaction; Sexual Behavior, Animal; Anxiety; Pregnancy
PubMed: 38782096
DOI: 10.1016/j.bbr.2024.115052