Exploring the effect of 6-BIO and sulindac in modulation of Wnt/ß-catenin signaling pathway in chronic phase of temporal lobe epilepsy.

The prospective involvement of the Wnt/ß-catenin signaling pathway in epilepsy, with the proposed therapeutic uses of its modulators, has been suggested; however, comprehensive knowledge in this regard is currently limited. Despite postulations about the pathway's significance and treatment potential, a systematic investigation is required to better understand its implications in chronic epilepsy. We investigated the role of key proteins like ß-catenin, GSK-3ß, and their modulators sulindac and 6-BIO, in Wnt/ß-catenin pathway during chronic phase of temporal lobe epilepsy. We also evaluated the role of modulators in seizure score, seizure frequency and neurobehavioral parameters in temporal lobe epilepsy. We developed status epilepticus model using lithium-pilocarpine. The assessment of neurobehavioral parameters was done followed by histopathological examination and immunohistochemistry staining of hippocampus as well as RT-qPCR and western blotting to analyse gene and protein expression. In SE rats, seizure score and frequency were significantly high compared to control rats, with notable changes in neurobehavioral parameters and neuronal damage observed in hippocampus. Our study also revealed a substantial upregulation of the Wnt/ß-catenin pathway in chronic epilepsy, as evidenced by gene and protein expression studies. Sulindac emerged as a potent modulator, reducing seizure score, frequency, neuronal damage, apoptosis, and downregulating the Wnt/ß-catenin pathway when compared to 6-BIO. Our findings emphasize the potential of GSK-3ß and ß-catenin as promising drug targets for chronic temporal lobe epilepsy, offering valuable treatment options for chronic epilepsy. The promising outcomes with sulindac encourages further exploration in clinical trials to assess its therapeutic potential.

Evaluation of Wnt/ß-catenin signaling and its modulators in repeated dose lithium-pilocarpine rat model of status epilepticus: An acute phase study.

The role of the Wnt/ß-catenin signaling pathway in epilepsy and the effects of its modulators as efficacious treatment options, though postulated, has not been sufficiently investigated. We evaluated the involvement of ß-catenin and GSK-3ß, the significant proteins in this pathway, in the lithium chloride-pilocarpine-induced status epilepticus model in rodents to study acute phase of temporal lobe epilepsy (TLE). The modulators studied were 6-BIO, a GSK-3ß inhibitor and Sulindac, a Dvl protein inhibitor. The disease group exhibited increased seizure score and seizure frequency, and the assessment of neurobehavioral parameters indicated notable alterations. Furthermore, histopathological examination of hippocampal brain tissues revealed significant neurodegeneration. Immunohistochemical study of hippocampus revealed neurogenesis in 6-BIO and sulindac groups. The gene and protein expression by RT-qPCR and western blotting studies indicated Wnt/ß-catenin pathway downregulation and increased apoptosis in the acute phase of TLE. 6-BIO was very efficient in upregulating the Wnt pathway, decreasing neuronal damage, increasing neurogenesis in hippocampus and decreasing seizure score and frequency in comparison to sulindac. This suggests that both GSK-3ß and ß-catenin are potential and novel drug targets for acute phase of TLE, and treatment options targeting these proteins could be beneficial in successfully managing acute epilepsy. Further evaluation of 6-BIO to explore its therapeutic potential in other models of epilepsy should be conducted.

Reelin Signaling Pathway and Mesial Temporal Lobe Epilepsy: A Causative Link.

Introduction: Mesial temporal lobe epilepsy (MTLE) is the most frequent form of partial epilepsy. Granule cell dispersion, resulting from aberrant neuronal migration in the hippocampus, is pathognomonic of MTLE. Reelin, a secreted neurodevelopmental glycoprotein has a crucial role in controlling the radial migration of neurons. Several animal studies have implicated Reelin in the MTLE pathogenesis Mesial temporal lobe epilepsy (MTLE) is the most frequent form of partial epilepsy. Granule cell dispersion, resulting from aberrant neuronal migration in the hippocampus, is pathognomonic of MTLE. Reelin, a secreted neurodevelopmental glycoprotein has a crucial role in controlling the radial migration of neurons. Several animal studies have implicated Reelin in the MTLE pathogenesis. Methods: The aim of this study was to investigate the Reelin signalling pathway in the MTLE patients. Therefore, we studied each step in the Reelin signalling pathway for the gene and protein expressions, in the hippocampal tissue obtained from patients undergoing surgery for MTLE and compared it with age matched normal autopsy cases. Results: We found statistically significant decrease (P<0.001) in the Reelin mRNA expression in MTLE patients. Among the two reelin receptors, apolipoprotein E receptor 2 (ApoER2) was significantly increased whereas very low density lipoprotein receptor (VLDLR) was decreased among the patients. Disabled 1 (Dab1), the downstream target of reelin, was found to be decreased. Dab1 in turn inhibits Cofilin, which is responsible for cytoskeletal reorganization, thus limiting aberrant neuronal migration. Statistically significant over expression of Cofilin protein was found in the patient group. Matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteases-1 (TIMP-1), both of which are involved in processing of Reelin, were down regulated in 70-85% of cases. Conclusion: The whole pathway was found to be deranged in MTLE. These results indicate that Reelin signalling pathway is disturbed at various points in the MTLE patients and might be involved in the pathogenesis & progression of MTLE. Our results extend the existing information regarding the components of the Reelin pathway and further, establish a link between pathway disturbance and MTLE.

Change in antiepileptic drug prescription patterns for pregnant women with epilepsy over the years: Impact on pregnancy and fetal outcomes.

AIMS AND OBJECTIVES: The objectives of the study were: (1) to determine if there is a change in pattern of antiepileptic drug (AED) prescription during pregnancy in women with epilepsy (WWE) attending a tertiary care institute in North India and (2) to determine if change in AED prescription pattern has resulted in improved fetal and maternal outcomes in WWE. PATIENTS AND METHODS: The current study was a retrospective analysis of records of WWE attending a medical and surgical disorder clinic of obstetrics and gynecology department of a tertiary care teaching hospital in North India. We retrospectively collected data of all the patients during the 5-year period from 2011 to 2015 (Group A) (n = 177) and compared it with our previously published data during the years 1987-1994 (Group B) (n = 219). RESULTS: There was significantly higher use of (i) levetiracetam (LEV) in Group A compared to Group B when women on monotherapy were compared (P<0.0001) and (ii) LEV (P<0.0001), clobazam (P<0.0001) and lamotrigine (P=0.0004) in Group A compared to Group B when women on polytherapy were compared. A significantly higher (P=0.02) number of women were using more than two antiepileptic drugs simultaneously in Group A compared to Group B. There was a significantly higher incidence (P = 0.001) of small for gestational age babies in Group A. CONCLUSION: Although there is an increase in the use of newer AEDs in WWE during pregnancy in North Indian population, it has not resulted in improved maternal and fetal outcomes. (2) to determine if change in AED prescription pattern has resulted in improved fetal and maternal outcomes in WWE.

Neurocysticercosis: An uncommon cause of drug-refractory epilepsy in North Indian population.

OBJECTIVE: Being a common cause of epilepsy in endemic areas, neurocysticercosis (NCC) is expected to account for a sizable proportion of patients with drug-refractory epilepsy (DRE) as well. However, data regarding prevalence of DRE in NCC are sparse. This study aimed to determine the prevalence of DRE as well as identification of clinical and radiologic factors that lead to DRE in patients with NCC. METHODS: This study was conducted in a tertiary-care postgraduate teaching institute in Northern India from July 2011 to July 2013. Two hundred patients with epilepsy due to NCC (definite [n = 59, 29.5%] or probable [n = 141, 70.5%]) based on diagnostic criteria by Del Brutto et al. were enrolled in the study in both a prospective (n = 51 [25.5%]) and a retrospective manner (n = 149 [74.5%]), and were followed for a minimum period of 1 year. RESULTS: Thirteen patients with NCC were found to be refractory to drug therapy. Prevalence of DRE was found to be 65 of 1,000 NCC patients with epilepsy in the present study. The risk factors associated with high risk of DRE were male sex (p = 0.035), older age (p = 0.016), pig-raising practices (p = 0.003), pork eating (p = 0.04), and presence of multiple (>2) (p = 0.0001) or mixed stage lesions (p = 0.007) on neuroimaging. On multivariate analysis, it was found that residing in an area where pig raising is prevalent (p = 0.01) and presence of multiple (>2) (p = 0.004) lesions on neuroimaging are associated with increased risk of DRE. SIGNIFICANCE: NCC is only rarely associated with the development of DRE. The common risk factors associated with increased chance of DRE include pig-rearing practices and presence of multiple (>2) lesions on neuroimaging.

Sodium valproate, hyperandrogenism and altered ovarian function in Indian women with epilepsy: a prospective study.

PURPOSE: To assess the association of long-term sodium valproate therapy with reproductive endocrine disorders in Indian women with generalized epilepsy. METHODS: Clinical parameters, ovarian morphology, and serum reproductive hormone concentrations were evaluated in 30 clinically normal and eumenorrheic reproductive age women with generalized epilepsy who were newly initiated on valproate. Longitudinal evaluations were done in 25 of these women after 1 year, and in some of them after 2 and 3 years of therapy. RESULTS: Of the 25 women who completed 1 year follow-up, we observed clinically relevant weight gain in 40%, hirsutism in 20%, menstrual abnormalities in 24%, polycystic ovaries (PCO) in 16%, polycystic ovarian syndrome (PCOS) in 20%, and a significant increase in mean serum testosterone (p=0.046). A significant positive correlation existed between weight gain and the development of menstrual abnormalities (r=0.66, p<0.0001), hirsutism (r=0.53, p=0.006) and PCO (r=0.51, p=0.012). No correlation existed between weight change and serum reproductive hormonal changes. Yearly follow-up for next 2 years in some of these women revealed persistence of menstrual abnormalities, hirsutism and PCO, a significant linear increase in mean body weight, body mass index, and serum testosterone concentrations, and an increase in serum LH levels from second year onwards. LIMITATIONS: Limitations include small sample size and a high dropout rate on follow-up. CONCLUSIONS: Long-term valproate therapy in Indian women with generalized epilepsy is associated with development of hirsutism, significant weight gain, stable or progressive alterations in reproductive hormonal function, and ultimately a higher occurrence of PCOS.