Project description:Drosophila melanogaster adult flies fed on normal food (NF) containing 16 mg/ml of pentylenetetrazole (PTZ) in the food show a hyperkinetic behavior within 24 hours. Half of that concentration, i.e., 8 mg/ml, of the PTZ, if fed for seven days, though doesn’t cause seizure-like behavior, results in a decreased climbing speed in flies. This change in locomotor behavior is progressive and becomes significant only on seventh day of the treatment. This climbing deficit is ameliorated when flies are treated concomitantly with PTZ and either of the two antiepileptic drugs (AEDs), sodium valproate (NaVP) or levetiracetam (LEV). Further experiments based on different regimes of combination and singular PTZ treatment demonstrated that whereas NaVP show a weaker prophylactic and stronger symptomatic effect, LEV exhibit an opposite effect, i.e., stronger prophylactic and weaker symptomatic action. These observations are consistent with the therapeutic effect of antiepileptic drugs. Time series of microarray gene expression profiling (earlier GEO submission) during chronic PTZ provided evidence of underlying downregulation of three main categories of biological processes, synaptic remodeling, energy metabolism and transport, in that order, in fly head. Transcriptomic analysis secondary to NaVP and LEV (earlier GEO submission) was found to cause statistically significant upregulation of two biological process categories each, energy metabolism and transport in case of NaVP and synaptic remodeling and energy metabolism in case of LEV. Time series of genome wide expression profiling secondary to PTZ and LEV combination treatment (earlier GEO submission) showed neutralizing effect of LEV on PTZ induced expression changes. Mining of published transcriptomic and proteomic data pertaining to epilepsy or established rodent animal models of epileptogenesis supported the relevance of the fly model in understanding the underlying brain pathophysiology. Systems modeling using RNA interference and small molecules demonstrated the robustness of the fly model. In brief, the above results clearly showed that the fly model is valuable not only in screening of antiepileptic, antiepileptogenic, disease-modifying and neuroprotective agents, but also in advancing our knowledge of mechanisms of action of drugs used in treating human patients suffering from various neurological and neuropsychiatric conditions, pharmacogenomics of these drugs, identification of potential drug targets, and selection of potential candidate genes for association analysis in epilepsy. Considering the above fly locomotor behavior model as relevant in kindling attainment, it was of obvious interest to study the behavioral and transcriptomic changes post-kindling, i.e., after withdrawing PTZ following seven day long chronic PTZ administration. It was observed that when PTZ is discontinued and flies climbing speed is monitored for next seven days of PTZ discontinuation, climbing speed deficit initially disappears and then a progressive increase in climbing speed is detected. Behavioral pharmacology of AEDs in post-kindling regime, like fly kindling described above, showed its usefulness in screening of potential antiepileptic, antiepileptogenic, disease-modifying and neuroprotective agents. The present submission relates to transcriptomic changes in fly head secondary to ethosuximide (ETH) treatment following discontinuation of PTZ for seven days (after seven days of chronic PTZ treatment). To delineate possible prophylactic or symptomatic effect of ETH at behavioral level, flies were treated with ETH for first three days and then shifted to NF for next four days (3 + 4 day regime) or flies treated with NF for first four days and then drug treated for next three days (4 + 3 day regime), in that order. At transcriptomic level, we have now examined the effect of ETH in 3 + 4 day regime. Gene expression profiles have been generated at both time points, 3rd and 7th day, i.e., on 10th and 14th day from the beginning of PTZ treatment. Effect of three day long chronic ETH treatment on fly head microarray gene expression profile, in otherwise normally grown flies, has already been determined (earlier GEO submission). Similarly, transcriptomic changes after one day, three days and seven days of PTZ discontinuation (i.e., 8th, 10th and 14th day of the beginning of chronic PTZ treatment) have already been deciphered (earlier GEO submission). However, unlike the previous experiment in which flies were maintained in the same container during the post-kindling period of seven days, flies needed to be shifted in fresh vials once in the present experiment because of the demand of 3 + 4 day regime. Since change in housing conditions has the potential to influence head transcriptome, we are also submitting here microarray expression profile of fly head after treating flies with PTZ for seven days, maintaining the flies to NF containing vials for three days and then shifting and maintaining them in fresh NF containing vials for next four days. Repetition of expression profiling on 3rd day of withdrawal (i.e., 10th day from beginning of PTZ treatment) was not needed because both the previous and the present experiment were similar with respect to housing conditions. Repetition of expression profiling on 7th day (i.e., 14th day from the beginning of PTZ treatment) was however required in view of change in housing conditions. The present submission therefore includes this later expression profile also. Keywords: Drug response

Project description:Drosophila melanogaster adult flies fed on normal food (NF) containing 16 mg/ml of pentylenetetrazole (PTZ) in the food show a hyperkinetic behavior within 24 hours. Half of that concentration, i.e., 8 mg/ml, of the PTZ, if fed for seven days, though doesn’t cause seizure-like behavior, results in a decreased climbing speed in flies. This change in locomotor behavior is progressive and becomes significant only on seventh day of the treatment. This climbing deficit is ameliorated when flies are treated concomitantly with PTZ and either of the two antiepileptic drugs (AEDs), sodium valproate (NaVP) or levetiracetam (LEV). Further experiments based on different regimes of combination and singular PTZ treatment demonstrated that whereas NaVP show a weaker prophylactic and stronger symptomatic effect, LEV exhibit an opposite effect, i.e., stronger prophylactic and weaker symptomatic action. These observations are consistent with the therapeutic effect of antiepileptic drugs. Time series of microarray gene expression profiling (earlier GEO submission) during chronic PTZ provided evidence of underlying downregulation of three main categories of biological processes, synaptic remodeling, energy metabolism and transport, in that order, in fly head. Transcriptomic analysis secondary to NaVP and LEV (earlier GEO submission) was found to cause statistically significant upregulation of two biological process categories each, energy metabolism and transport in case of NaVP and synaptic remodeling and energy metabolism in case of LEV. Time series of genome wide expression profiling secondary to PTZ and LEV combination treatment (earlier GEO submission) showed neutralizing effect of LEV on PTZ induced expression changes. Mining of published transcriptomic and proteomic data pertaining to epilepsy or established rodent animal models of epileptogenesis supported the relevance of the fly model in understanding the underlying brain pathophysiology. Systems modeling using RNA interference and small molecules demonstrated the robustness of the fly model. In brief, the above results clearly showed that the fly model is valuable not only in screening of antiepileptic, antiepileptogenic, disease-modifying and neuroprotective agents, but also in advancing our knowledge of mechanisms of action of drugs used in treating human patients suffering from various neurological and neuropsychiatric conditions, pharmacogenomics of these drugs, identification of potential drug targets, and selection of potential candidate genes for association analysis in epilepsy. Considering the above fly locomotor behavior model as relevant in kindling attainment, it was of obvious interest to study the behavioral and transcriptomic changes post-kindling, i.e., after withdrawing PTZ following seven day long chronic PTZ administration. It was observed that when PTZ is discontinued and flies climbing speed is monitored for next seven days of PTZ discontinuation, climbing speed deficit initially disappears and then a progressive increase in climbing speed is detected. Behavioral pharmacology of AEDs in post-kindling regime, like fly kindling described above, showed its usefulness in screening of potential antiepileptic, antiepileptogenic, disease-modifying and neuroprotective agents. The present submission relates to transcriptomic changes in fly head secondary to gabapentin (GBP) treatment following discontinuation of PTZ for seven days (after seven days of chronic PTZ treatment). To delineate possible prophylactic or symptomatic effect of GBP at behavioral level, flies were treated with GBP for first three days and then shifted to NF for next four days (3 + 4 day regime) or flies treated with NF for first four days and then drug treated for next three days (4 + 3 day regime), in that order. At transcriptomic level, we have now examined the effect of GBP in 3 + 4 day regime. Gene expression profiles have been generated at both time points, 3rd and 7th day, i.e., on 10th and 14th day from the beginning of PTZ treatment. Effect of three day long chronic GBP treatment on fly head microarray gene expression profile, in otherwise normally grown flies, has already been determined (earlier GEO submission). Similarly, transcriptomic changes after one day, three days and seven days of PTZ discontinuation (i.e., 8th, 10th and 14th day of the beginning of chronic PTZ treatment) have already been deciphered (earlier GEO submission). Unlike the previous experiment in which flies were maintained in the same container during the post-kindling period of seven days, flies needed to be shifted in fresh vials once in the present experiment because of the demand of 3 + 4 day regime. Since change in housing conditions has the potential to influence head transcriptome, we have also generated microarray expression profile of fly head after treating flies with PTZ for seven days, maintaining the flies to NF containing vials for three days and then shifting and maintaining them in fresh NF containing vials for next four days (submitted in GEO previously). Keywords: Drug Response

Project description:Drosophila melanogaster adult flies fed on normal food (NF) containing 16 mg/ml of pentylenetetrazole (PTZ) in the food show a hyperkinetic behavior within 24 hours. Half of that concentration, i.e., 8 mg/ml, of the PTZ, if fed for seven days, though doesn’t cause seizure-like behavior, results in a decreased climbing speed in flies. This change in locomotor behavior is progressive and becomes significant only on seventh day of the treatment. This climbing deficit is ameliorated when flies are treated concomitantly with PTZ and either of the two antiepileptic drugs (AEDs), sodium valproate (NaVP) or levetiracetam (LEV). Further experiments based on different regimes of combination and singular PTZ treatment demonstrated that whereas NaVP show a weaker prophylactic and stronger symptomatic effect, LEV exhibit an opposite effect, i.e., stronger prophylactic and weaker symptomatic action. These observations are consistent with the therapeutic effect of antiepileptic drugs. Time series of microarray gene expression profiling (earlier GEO submission) during chronic PTZ provided evidence of underlying downregulation of three main categories of biological processes, synaptic remodeling, energy metabolism and transport, in that order, in fly head. Transcriptomic analysis secondary to NaVP and LEV (earlier GEO submission) was found to cause statistically significant upregulation of two biological process categories each, energy metabolism and transport in case of NaVP and synaptic remodeling and energy metabolism in case of LEV. Time series of genome wide expression profiling secondary to PTZ and LEV combination treatment (earlier GEO submission) showed neutralizing effect of LEV on PTZ induced expression changes. Mining of published transcriptomic and proteomic data pertaining to epilepsy or established rodent animal models of epileptogenesis supported the relevance of the fly model in understanding the underlying brain pathophysiology. Systems modeling using RNA interference and small molecules demonstrated the robustness of the fly model. In brief, the above results clearly showed that the fly model is valuable not only in screening of antiepileptic, antiepileptogenic, disease-modifying and neuroprotective agents, but also in advancing our knowledge of mechanisms of action of drugs used in treating human patients suffering from various neurological and neuropsychiatric conditions, pharmacogenomics of these drugs, identification of potential drug targets, and selection of potential candidate genes for association analysis in epilepsy. Considering the above fly locomotor behavior model as relevant in kindling attainment, it was of obvious interest to study the behavioral and transcriptomic changes post-kindling, i.e., after withdrawing PTZ following seven day long chronic PTZ administration. It was observed that when PTZ is discontinued and flies climbing speed is monitored for next seven days of PTZ discontinuation, climbing speed deficit initially disappears and then a progressive increase in climbing speed is detected. Behavioral pharmacology of AEDs in post-kindling regime, like fly kindling described above, showed its usefulness in screening of potential antiepileptic, antiepileptogenic, disease-modifying and neuroprotective agents. The present submission relates to transcriptomic changes in fly head secondary to levetiracetam (LEV) treatment following discontinuation of PTZ for seven days (after seven days of chronic PTZ treatment). To delineate possible prophylactic or symptomatic effect of LEV at behavioral level, flies were treated with LEV for first three days and then shifted to NF for next four days (3 + 4 day regime) or flies treated with NF for first four days and then drug treated for next three days (4 + 3 day regime), in that order. At transcriptomic level, we have now examined the effect of LEV in 3 + 4 day regime. Gene expression profiles have been generated at both time points, 3rd and 7th day, i.e., on 10th and 14th day from the beginning of PTZ treatment. Effect of three day long chronic LEV treatment on fly head microarray gene expression profile, in otherwise normally grown flies, has already been determined (earlier GEO submission). Similarly, transcriptomic changes after one day, three days and seven days of PTZ discontinuation (i.e., 8th, 10th and 14th day of the beginning of chronic PTZ treatment) have already been deciphered (earlier GEO submission). Unlike the previous experiment in which flies were maintained in the same container during the post-kindling period of seven days, flies needed to be shifted in fresh vials once in the present experiment because of the demand of 3 + 4 day regime. Since change in housing conditions has the potential to influence head transcriptome, we have also generated microarray expression profile of fly head after treating flies with PTZ for seven days, maintaining the flies to NF containing vials for three days and then shifting and maintaining them in fresh NF containing vials for next four days (submitted in GEO previously). Keywords: Drug Response

Project description:Drosophila melanogaster adult flies fed on normal food (NF) containing 16 mg/ml of pentylenetetrazole (PTZ) in the food show a hyperkinetic behavior within 24 hours. Half of that concentration, i.e., 8 mg/ml, of the PTZ, if fed for seven days, though doesn’t cause seizure-like behavior, results in a decreased climbing speed in flies. This change in locomotor behavior is progressive and becomes significant only on seventh day of the treatment. This climbing deficit is ameliorated when flies are treated concomitantly with PTZ and either of the two antiepileptic drugs (AEDs), sodium valproate (NaVP) or levetiracetam (LEV). Further experiments based on different regimes of combination and singular PTZ treatment demonstrated that whereas NaVP show a weaker prophylactic and stronger symptomatic effect, LEV exhibit an opposite effect, i.e., stronger prophylactic and weaker symptomatic action. These observations are consistent with the therapeutic effect of antiepileptic drugs. Time series of microarray gene expression profiling (earlier GEO submission) during chronic PTZ provided evidence of underlying downregulation of three main categories of biological processes, synaptic remodeling, energy metabolism and transport, in that order, in fly head. Transcriptomic analysis secondary to NaVP and LEV (earlier GEO submission) was found to cause statistically significant upregulation of two biological process categories each, energy metabolism and transport in case of NaVP and synaptic remodeling and energy metabolism in case of LEV. Time series of genome wide expression profiling secondary to PTZ and LEV combination treatment (earlier GEO submission) showed neutralizing effect of LEV on PTZ induced expression changes. Mining of published transcriptomic and proteomic data pertaining to epilepsy or established rodent animal models of epileptogenesis supported the relevance of the fly model in understanding the underlying brain pathophysiology. Systems modeling using RNA interference and small molecules demonstrated the robustness of the fly model. In brief, the above results clearly showed that the fly model is valuable not only in screening of antiepileptic, antiepileptogenic, disease-modifying and neuroprotective agents, but also in advancing our knowledge of mechanisms of action of drugs used in treating human patients suffering from various neurological and neuropsychiatric conditions, pharmacogenomics of these drugs, identification of potential drug targets, and selection of potential candidate genes for association analysis in epilepsy. Considering the above fly locomotor behavior model as relevant in kindling attainment, it was of obvious interest to study the behavioral and transcriptomic changes post-kindling, i.e., after withdrawing PTZ following seven day long chronic PTZ administration. It was observed that when PTZ is discontinued and flies climbing speed is monitored for next seven days of PTZ discontinuation, climbing speed deficit initially disappears and then a progressive increase in climbing speed is detected. Behavioral pharmacology of AEDs in post-kindling regime, like fly kindling described above, showed its usefulness in screening of potential antiepileptic, antiepileptogenic, disease-modifying and neuroprotective agents. The present submission relates to transcriptomic changes in fly head secondary to vigabatrin (VGB) treatment following discontinuation of PTZ for seven days (after seven days of chronic PTZ treatment). To delineate possible prophylactic or symptomatic effect of VGB at behavioral level, flies were treated with VGB for first three days and then shifted to NF for next four days (3 + 4 day regime) or flies treated with NF for first four days and then drug treated for next three days (4 + 3 day regime), in that order. At transcriptomic level, we have now examined the effect of VGB in 3 + 4 day regime. Gene expression profiles have been generated at both time points, 3rd and 7th day, i.e., on 10th and 14th day from the beginning of PTZ treatment. Effect of three day long chronic VGB treatment on fly head microarray gene expression profile, in otherwise normally grown flies, has already been determined (earlier GEO submission). Similarly, transcriptomic changes after one day, three days and seven days of PTZ discontinuation (i.e., 8th, 10th and 14th day of the beginning of chronic PTZ treatment) have already been deciphered (earlier GEO submission). Unlike the previous experiment in which flies were maintained in the same container during the post-kindling period of seven days, flies needed to be shifted in fresh vials once in the present experiment because of the demand of 3 + 4 day regime. Since change in housing conditions has the potential to influence head transcriptome, we have also generated microarray expression profile of fly head after treating flies with PTZ for seven days, maintaining the flies to NF containing vials for three days and then shifting and maintaining them in fresh NF containing vials for next four days (submitted in GEO previously). Keywords: Drug Response

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Effect of ethosuximide on gene expression in Drosophila head

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