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COX-2 downregulation in response to valproic acid
Epilepsy is a chronic neurological disease affecting COX-2 inhibitors in adjunction to prescribed AEDs
1% of the world population. Antiepileptic drug in large-sample, randomized, controlled trials with
(AED) therapy is the initial choice for treatment. a parallel assessment of plasma PGE2 levels to
Despite the market availability of various AEDs, substantiate the potential adjunctive application
nearly 40-50% of the individuals fail to respond to of COX-2 inhibitors for epilepsy treatment.
first AED monotherapy with 30% patients not
responding to even multidrug therapy. The vast PGx panels to predict antiepileptic drug response
heterogeneity associated with epilepsy and Every individual responds differently to different
multifactorial nature of the disease involving both drugs. These differences in drug response are
genetic and environmental factors have resulted primarily attributable to individual genetic
in inconsistencies in genetic findings predictive of differences, called pharmacogenomic (PGx)
AED response. This entails the need to adopt an variants. Our group aims to comprehend the genes
approach different from pharmacogenetic involved in drug response like the metabolising
approach in determining AED response. Our lab enzymes, transporters and drug targets and
conducted a microarray-based gene expression identify its PGx variants to formulate clinically
profiling study in blood samples of patients with actionable pharmacogenetic tests. Furthermore,
epilepsy (PWE). The project firstly aimed to the technology assessment based on predictive
investigate the heterogeneity in blood value of each test and cost-effectiveness of testing
transcriptomic profiles of patients with different patients for an entire panel of relevant markers at
epilepsy etiologies. Comparing the profiles of once will be evaluated. The focus is on highly
patients with different epilepsy subtypes showed curated epilepsy patients and control samples, in
patients with idiopathic epilepsy to have the most which a total of 1063 epilepsy patient samples and
distinct and differential profiles compared to that 498 age-matched healthy controls were recruited
with cryptogenic and symptomatic epilepsies. In in earlier research projects. For each of the
the second part of the study, a comparison was recruited cohort, genotype-phenotype
made between the peripheral blood gene correlations were estimated to identify
expression profiles of patients with idiopathic statistically significant genetic variants. To confirm
epilepsy responding and non-responding to the findings from the previous studies, in this
valproic acid (VA), a broad-spectrum AED to look project, we have performed a large-scale
for genes associated with variable response. The validation study in the complete cohort. Here, we
proinflammatory gene, PTGS2 (encoding COX-2) evaluated the correlation of the genotype marker
was found to be downregulated in PWE with a specific drug phenotype to assess its
responding efficaciously to VA. VA responder reproducibility/replicability, validated the
patients also showed lower plasma levels of PGE2 statistical models and finally determined the
(major prostaglandin synthesized by COX-2). credibility of the genetic marker to be
Functional studies were carried out in human recommended as a genetic test for clinical practice
cerebral microvascular endothelial cells, by determining the strength of the association.
hCMEC/D3 to validate the effect of VA on the Genetic markers like HLA-A*31:01:02, HLA-
expression and activity of COX-2, EP1 B*15:02:01 are primary determinant of
(prostaglandin receptor) and drug efflux carbamazepine induced hypersensitivity and
transporter, P-glycoprotein. The results suggested rs113994095 (POLG), rs113994097 (POLG),
that VA downregulates COX-2 to suppress P- rs1047891 (CPS1) for valproic acid induced
glycoprotein expression. The findings of the adverse effects like liver injury and
project provided insights in identifying the hyperammonemia. Likewise, CYP2C9*2 and *3 for
markers of VA response and suggested COX-2 phenytoin metabolism, and CYP2C19*2 and *3 for
inhibition as a potential strategy to increase AED poor metabolism of diazepam, clobazam,
efficacy. Future work anticipates the effect of lacosamide metabolism are significant outcomes
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