Neuroinflammation in inflammatory bowel disease

Inflammatory bowel disease is a chronic intestinal inflammatory condition, the pathology of which is incompletely understood. Gut inflammation causes significant changes in neurally controlled gut functions including cramping, abdominal pain, fecal urgency, and explosive diarrhea. These symptoms are caused, at least in part, by prolonged hyperexcitability of enteric neurons that can occur following the resolution of colitis. Mast, enterochromaffin and other immune cells are increased in the colonic mucosa in inflammatory bowel disease and signal the presence of inflammation to the enteric nervous system. Inflammatory mediators include 5-hydroxytryptamine and cytokines, as well as reactive oxygen species and the production of oxidative stress. This review will discuss the effects of inflammation on enteric neural activity and potential therapeutic strategies that target neuroinflammation in the enteric nervous system.     

Association of alpha subunit of GABAA receptor subtype gene polymorphisms with epilepsy susceptibility and drug resistance in north Indian population

GABA (γ-amino butyric acid) receptors have always been an inviting target in the etiology and treatment of epilepsy because of its role as a major inhibitory neurotransmitter in the brain. The aim of our study was to find out the possible role of single nucleotide polymorphisms (SNPs) present in GABRA1 IVS11 + 15 A > G (rs2279020) and GABRG2 588C > T (rs211037) genes in seizure susceptibility and pharmaco-resistance in northern Indian patients with epilepsy. A total of 395 epilepsy patients and 199 control subjects were enrolled for present study. The genotyping was done by PCR-RFLP methods. The GABRA1 IVS11 + 15 A > G polymorphism conferred high risk for epilepsy susceptibility at genotype ‘AG’ (P = 0.004, OR = 1.77, 95% CI = 1.20–2.63), ‘GG’ (P = 0.01, OR = 1.80, 95% CI = 1.15–2.80) and G allele level (P = 0.001, OR = 1.50, 95% CI = 1.16–1.92). Moreover this polymorphism was also associated with multiple drug resistance in patients with epilepsy for homozygous variant ‘GG’ genotype (P = 0.031, OR = 1.84, 95% CI = 1.05–3.23) and G allele (P = 0.020, OR = 1.43, 95% CI = 1.05–1.95). However GABRG2 588C > T polymorphism was not found to be associated either with epilepsy susceptibility or with drug resistance. Overall results indicate differential role of different subunits of GABA_A receptor subtypes in epilepsy susceptibility and pharmacotherapy.     

Differential role of sodium channels SCN1A and SCN2A gene polymorphisms with epilepsy and multiple drug resistance in the north Indian population

AIMS

To evaluate sodium channel genes as candidates for epilepsy susceptibility and their role in therapeutic efficacy, we screened coding single-nucleotide polymorphism of SCN1A p. Thr 1067 Ala or c.3184 A→G (rs2298771) and SCN2A p.Arg19Lys or c.56 G→A (rs17183814) in north Indian epilepsy patients.

METHODS

The genotyping was performed in 160 control subjects and 336 patients with epilepsy, of whom 117 were drug resistant and 219 were drug responsive. Therapeutic drug monitoring for phenytoin, carbamazepine, phenobarbital and valproate was also performed in 20% of the patients to confirm compliance.

RESULTS

AG genotype of SCN1A 3184 A→G polymorphism was significantly higher and associated in epilepsy patients [P= 0.005; odds ratio (OR) 1.76, 95% confidence interval (CI) 1.19, 2.61], whereas A variant of SCN2A c.56 G→A was associated with multiple drug resistance in north Indian patients with epilepsy (P= 0.03; OR 1.62, 95% CI 1.03, 2.56).

CONCLUSIONS

Overall, results indicate a differential role of genetic polymorphisms of sodium channels SCN1A and SCN2A in epilepsy susceptibility and drug response.     

Association of intronic polymorphism rs3773364 A>G in synapsin‐2 gene with idiopathic epilepsy

In epilepsy, there is a tendency towards recurrent unprovoked seizures. Seizures result due to the excessive electrical misfiring in the brain between neurons and disturbance in neurotransmitter release. Several gene products affect the behavior of these neurons by regulating neurotransmission via several mechanisms. One such gene, Synapsin‐2 (SYN2), involved in synaptogenesis is also reported to regulate the neurotransmitter release. We hypothesized that SYN2 gene and its polymorphisms could affect the process of epileptogenesis and therapeutic response in humans. In this hospital‐based study, we enrolled 372 patients with epilepsy and 199 control subjects. We selected rs3773364 A>G polymorphism in SYN2 gene and analyzed its distribution in north Indian patients with epilepsy and control subjects. Genotyping was carried out by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) method. According to the results obtained, SYN2 “AG” genotype frequency was significantly higher in patients with epilepsy versus control subjects in north Indian population (P = 0.02, OR = 1.55, 95% CI = 1.06–2.26). After subclassification, we observed higher frequency of AG genotype in idiopathic patients as compared to control subjects (P = 0.01, OR = 1.67, 95% CI = 1.08–2.56). There were no significant differences in genotypic (AG: OR = 0.80, P = 0.377; GG: P = 0.628, OR = 1.17) or allelic (P = 0.86, OR = 1.03) frequency distributions in patients with multiple drug resistance versus patients with drug‐responsive epilepsy. Results from our study indicate the involvement of SYN2 gene polymorphism in conferring risk to epilepsy; however, the genetic variant does not seem to modulate drug‐response in epilepsy pharmacotherapy. Synapse 64:403–408, 2010. © 2009 Wiley‐Liss, Inc.     

Predicting epileptic seizures with a mental simulation task: a prospective study

The unpredictability of seizures is one of the most disabling aspects of epilepsy. We assessed the possibility of forecasting seizure onset by means of a behavioral task using mental simulation of biological and nonbiological movements. Four patients with epilepsy were included in a longitudinal study. In two patients with right temporal lobe epilepsy (RTLE), performance of the task changed depending on the epileptic cycle. In the preictal phase, timing precision decreased during simulation of biological movements and increased during simulation of nonbiological movements. In two other patients, the timing precision during simulation of biological movements was chronically decreased. The observed phase dependency of performance in patients with RTLE may indicate changes in brain states hours in advance of seizure onset. We suggest that our paradigm might be a simple and accurate method for the prediction of epileptic seizures. The validity of the approach for different types of epilepsy should be assessed in future studies.     

Effect of prenatal exposure of deltamethrin on the ontogeny of xenobiotic metabolizing cytochrome P450s in the brain and liver of offsprings

Prenatal exposure to low doses (0.25 or 0.5 or 1.0 mg/kg, p.o.) of deltamethrin, a type II pyrethroid insecticide, to pregnant dams from gestation days 5 to 21 (GD5-21) produced dose-dependent alterations in the ontogeny of xenobiotic metabolizing cytochrome P450 (CYP) isoforms in brain and liver of the offsprings. RT-PCR analysis revealed dose-dependent increase in the mRNA expression of cerebral and hepatic CYP1A1, 1A2, 2B1, 2B2, and 2E1 isoenzymes in the offsprings exposed prenatally to deltamethrin. Similar increase in the activity of the marker enzymes of these CYP isoforms has indicated that placental transfer of the pyrethroid, a mixed type of CYP inducer, even at these low doses may be sufficient to induce the CYPs in brain and liver of the offsprings. Our data have further revealed persistence in the increase in expression of xenobiotics metabolizing CYPs up to adulthood in brain and liver of the exposed offsprings, suggesting the potential of deltamethrin to imprint the expression of CYPs in brain and liver of the offsprings following its in utero exposure. Furthermore, though the levels of CYPs were several fold lower in brain, almost equal magnitude of induction in cerebral and hepatic CYPs has further suggested that brain CYPs are responsive to the induction by environmental chemicals. The present data indicating alterations in the expression of xenobiotic metabolizing CYPs during development following prenatal exposure to deltamethrin may be of significance as these CYP enzymes are not only involved in the neurobehavioral toxicity of deltamethrin but have a role in regulating the levels of ligands that modulate growth, differentiation, and neuroendocrine functions.