Association of serotonin receptor 2a haplotypes with obsessive–compulsive disorder and its treatment response in Iranian patients: a genetic and pharmacogenetic study

Marzie Sina,1 Abolhassan Ahmadiani,1 Sareh Asadi,2 Jamal Shams3 1Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 2NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 3Behavioral Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Introduction: Obsessive–compulsive disorder (OCD) is a debilitating psychiatric disorder causing intrusive thoughts or repetitive behaviors. Serotonin reuptake inhibitors are used for OCD treatment, but 40%–60% of patients do not respond to them adequately. In this study, the associations of serotonin receptor 2a polymorphisms rs6311 and rs6313 with OCD, its familial form and fluvoxamine treatment response in Iranian population were investigated. Patients and methods: Association analyses were conducted in 293 OCD cases fulfilling the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV-TR and 245 controls. Pharmacotherapy was defined as 12 weeks of treatment with fluvoxamine (150–300 mg). Treatment response was considered as >25% reduction in Yale–Brown Obsessive Compulsive Scale score. Genotyping was performed by means of PCR-RFLP. Results: The results showed no association of rs6311 or rs6313 with OCD, but their haplotypes had different distribution patterns in cases and controls. Moreover, rs6313 was associated with the familial form of OCD in females significantly (P=0.005) under the recessive genetic model. Moreover, rs6311–rs6313 haplotypes were associated with fluvoxamine treatment response in OCD patients with more AC and less AT in responders. Conclusion: HTR2A haplotypes are associated with OCD and its treatment response with a fluvoxamine in Iranian patients. Furthermore, the observed association of rs6313 with the familial form of OCD in females suggests different genetic background of OCD familial and non-familial forms, which needs further investigation. Keywords: family history, fluvoxamine, treatment response, rs6311, rs631

PKC Mediates endogenous inhibition of myelin repair in the context of local demyelination induced in mice optic chiasm

Background: Axon regeneration in adult CNS is limited by the presence of inhibitory proteins associated with myelin. Although blocking PKC activity attenuates the ability of CNS myelin to inhibit neurite outgrowth, the role as well as mechanisms underlying the remyelination inhibition in CNS are still largely unknown. Considering the role of PKC in axonal regeneration and the vulnerability of optic chiasm in multiple sclerosis (MS), we assessed the effect of PKC inhibition on remyelination of lysolecithin induced demyelinated optic chiasm.Materials and Methods: Demyelination was induced by stereotaxic intra-chiasmatic injection of 1µl lysolecithin (1) in male mice. Intracerebroventricular daily injection of a PKC inhibitor (GO6976) was done for 14 days post-lesion. Demyelination and remyelination patterns in optic chiasm were confirmed through histological verification and electrophysiological study using Luxol fast blue staining and visual evoked potentials (VEP) recording, respectively.Results: In lysolecithin treated animals, demyelination was mostly marked at days 3 and 7 post-lesion and an incomplete remyelination occurred at day 14 post-lesion. VEP recording showed increased P-latency at the days 3 and 7 post-lesion while it partially decreased at day 14. Following the inhibition of PKC, while the extent of demyelination and P-latency slightly decreased at the days 3 and 7 post-lesion, it recovered at day 14. VEP recording data were confirmed by histological verification. Conclusion: Inhibition of PKC activity could represent a potential therapeutic approach for stimulating the remyelination process in the context of multiple sclerosis

Fluvoxamine treatment response prediction in obsessive-compulsive disorder: association rule mining approach

Hesam Hasanpour,1 Ramak Ghavamizadeh Meibodi,1 Keivan Navi,1 Jamal Shams,2 Sareh Asadi,3 Abolhassan Ahmadiani4 1Faculty of Computer Science and Engineering, Shahid Beheshti University, Tehran, Iran; 2Behavioral Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 3Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 4Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Background: Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder characterized by intrusive thoughts or repetitive behaviors. Clinicians use serotonin reuptake inhibitors (SRIs) for OCD treatment, but 40%–60% of the patients do not respond to them adequately. Here, we described an association rule mining approach for treatment response prediction using an Iranian OCD data set.Patients and methods: Three hundred and thirty OCD patients fulfilling DSM-5 criteria were initially included, but 151 subjects completed their pharmacotherapy which was defined as 12-week treatment with fluvoxamine (150–300 mg). Treatment response was considered as >35% reduction in the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score. Apriori algorithm was applied to the OCD data set for extraction of the association rules predicting response to fluvoxamine pharmacotherapy in OCD patients. We considered the association of each attribute with treatment response using interestingness measures and found important attributes that associated with treatment response.Results: Results showed that low obsession and compulsion severities, family history of mental illness, illness duration less than 5 years, being married, and female were the most associated variables with responsiveness to fluvoxamine pharmacotherapy. Meanwhile, if an OCD patient reported a family history of mental illness and his/her illness duration was less than 5 years, he/she responded to 12-week fluvoxamine pharmacotherapy with the probability of 91%. We also found useful and applicable rules for resistant and refractory patients.Conclusion: This is the first study where association rule mining approach was used to extract predicting rules for treatment response in OCD. Application of this method in personalized medicine may help clinicians in taking the right therapeutic decision. Keywords: data mining, apriori algorithm, family history, refractory patient

Brain Lipopolysaccharide Preconditioning-Induced Gene Reprogramming Mediates a Tolerance State in Electroconvulsive Shock Model of Epilepsy

There is increasing evidence pointing toward the role of inflammatory processes in epileptic seizures, and reciprocally, prolonged seizures induce more inflammation in the brain. In this regard, effective strategies to control epilepsy resulting from neuroinflammation could be targeted. Based on the available data, preconditioning (PC) with low dose lipopolysaccharide (LPS) through the regulation of the TLR4 signaling pathway provides neuroprotection against subsequent challenge with injury in the brain. To test this, we examined the effects of a single and chronic brain LPS PC, which is expected to lead to reduction of inflammation against epileptic seizures induced by electroconvulsive shock (ECS). A total of 60 male Sprague Dawley rats were randomly assigned to five groups: control, vehicle (single and chronic), and LPS PC (single and chronic). We first recorded the data regarding the behavioral and histological changes. We further investigated the alterations of gene and protein expression of important mediators in relation to TLR4 and inflammatory signaling pathways. Interestingly, significant increased presence of NFκB inhibitors [Src homology 2-containing inositol phosphatase-1 (SHIP1) and Toll interacting protein (TOLLIP)] was observed in LPS-preconditioned animals. This result was also associated with over-expression of IRF3 activity and anti-inflammatory markers, along with down-regulation of pro-inflammatory mediators. Summarizing, the analysis revealed that PC with LPS prior to seizure induction may have a neuroprotective effect possibly by reprogramming the signaling response to injury