The Experts below are selected from a list of 5751 Experts worldwide ranked by ideXlab platform
Martin J Brodie - One of the best experts on this subject based on the ideXlab platform.
-
pharmacodynamic interaction studies with topiramate in the pentylenetetrazol and maximal electroshock Seizure models
Seizure-european Journal of Epilepsy, 2004Co-Authors: Graeme J Sills, Elaine Butler, G G Thompson, Martin J BrodieAbstract:There is emerging evidence to support the efficacy of some antiepileptic drug (AED) combinations in refractory epilepsy. Definitive clinical studies are, however, difficult to perform. Experimental Seizure models can be employed to identify potentially useful combinations for subsequent clinical evaluation. We have investigated the anticonvulsant effects of topiramate (TPM) in combination with 13 other AEDs in the pentylenetetrazol (PTZ) and maximal electroshock (MES) Seizure models. Single drugs and combinations were administered by intraperitoneal injection and anticonvulsant effects determined at 1-hour post-dosing. TPM was without significant effect in the PTZ test. In contrast, phenobarbital, primidone, ethosuximide, sodium valproate, felbamate and tiagabine all increased the latency to the first generalised Seizure. Combinations of TPM and active adjunctive drug were universally effective. Combinations of TPM with clobazam, lamotrigine and levetiracetam were also anticonvulsant, despite the inactivity of the constituent compounds when administered alone. TPM reduced the incidence of MES-induced Seizures in a dose-dependent manner, as did phenobarbital, phenytoin, primidone, carbamazepine, sodium valproate, clobazam, lamotrigine, felbamate and tiagabine. All combination treatments were similarly effective. These findings suggest that combinations of TPM with lamotrigine and levetiracetam may demonstrate anticonvulsant synergism and merit further investigation in additional model systems and with recourse to more quantitative mathematical analysis.
-
regional expression of multidrug resistance genes in genetically epilepsy prone rat brain after a single audiogenic Seizure
Epilepsia, 2002Co-Authors: Patrick Kwan, Brian S Meldrum, Timothy W Gant, Graeme J Sills, Elaine Butler, Martin J BrodieAbstract:Summary: Purpose: The multidrug resistance (mdr) gene family encodes the drug transport macromolecule P-glycoprotein (P-gp), which contributes to the functionality of the blood–brain barrier. Recent evidence suggests that P-gp–mediated drug extrusion may play a facilitatory role in refractory epilepsy. We investigated the regional expression of mdr genes in genetically epilepsy-prone rat (GEPR) brain after a single audiogenic Seizure. Methods: Three groups of adult male GEPRs (n = 5/group) were exposed to a Seizure-inducing audiogenic stimulus and killed at 4 h, 24 h, and 7 days thereafter. A further group (n = 5) served as a stimulus-naive control. Expression of mdr1a and mdr1b in distinct anatomic brain regions (cortex, midbrain, pons/medulla, hippocampus) was determined by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) in the presence of competitive internal standards. Results: When compared with control, mdr1a expression in cortex and midbrain was significantly (p < 0.05) increased at 24 h after a single audiogenic Seizure. Cortical mdr1a expression remained elevated at 7 days after stimulus. In contrast, mdr1a expression in pons/medulla and hippocampus was unchanged. The mdr1b isoform was quantifiable in hippocampus alone and not influenced by Seizure activity. Conclusions: These findings suggest that acute Seizures in the GEPR can induce the expression of mdr genes. The pattern of increased expression appears to follow the anatomic pathway of audiogenic Seizures in these animals, with initiation in the midbrain and propagation to the cortex. Further studies are required to investigate the effects of recurrent Seizure activity and to characterise mdr expression in other Experimental Seizure models.
-
regional expression of multidrug resistance genes in genetically epilepsy prone rat brain after a single audiogenic Seizure
Epilepsia, 2002Co-Authors: Patrick Kwan, Brian S Meldrum, Timothy W Gant, Graeme J Sills, Elaine Butler, Martin J BrodieAbstract:Summary: Purpose: The multidrug resistance (mdr) gene family encodes the drug transport macromolecule P-glycoprotein (P-gp), which contributes to the functionality of the blood–brain barrier. Recent evidence suggests that P-gp–mediated drug extrusion may play a facilitatory role in refractory epilepsy. We investigated the regional expression of mdr genes in genetically epilepsy-prone rat (GEPR) brain after a single audiogenic Seizure. Methods: Three groups of adult male GEPRs (n = 5/group) were exposed to a Seizure-inducing audiogenic stimulus and killed at 4 h, 24 h, and 7 days thereafter. A further group (n = 5) served as a stimulus-naive control. Expression of mdr1a and mdr1b in distinct anatomic brain regions (cortex, midbrain, pons/medulla, hippocampus) was determined by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) in the presence of competitive internal standards. Results: When compared with control, mdr1a expression in cortex and midbrain was significantly (p < 0.05) increased at 24 h after a single audiogenic Seizure. Cortical mdr1a expression remained elevated at 7 days after stimulus. In contrast, mdr1a expression in pons/medulla and hippocampus was unchanged. The mdr1b isoform was quantifiable in hippocampus alone and not influenced by Seizure activity. Conclusions: These findings suggest that acute Seizures in the GEPR can induce the expression of mdr genes. The pattern of increased expression appears to follow the anatomic pathway of audiogenic Seizures in these animals, with initiation in the midbrain and propagation to the cortex. Further studies are required to investigate the effects of recurrent Seizure activity and to characterise mdr expression in other Experimental Seizure models.
Zhe-shan Quan - One of the best experts on this subject based on the ideXlab platform.
-
synthesis and anticonvulsant activity evaluation of 7 alkoxy 2 4 dihydro 1h benzo b 1 2 4 triazolo 4 3 d 1 4 thiazin 1 ones in various murine Experimental Seizure models
Medicinal Chemistry Research, 2014Co-Authors: X Cao, Xianqing Deng, Shiben Wang, Dachuan Liu, Zhe-shan QuanAbstract:A novel series of 7-alkoxy-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]-thiazin-1-ones have been synthesized and tested for their anticonvulsant activity using the maximal electroshock (MES) method. The majority of the compounds prepared were effective in the MES screens at a dose level of 100 mg/kg. Of the compounds tested, the most promising was 7-[(4-fluorobenzyl)oxy]-2,4-dihydro-1H-[1,2,4]-triazolo[4,3-d][1,4]-benzothiazin-1-one (6m), which showed an ED50 value of 9.2 mg/kg in the MES test in mice. Furthermore, the compound exhibited a PI value of 15.4 which was superior to the standard drug carbamazepine (PI value of 6.4). As well as demonstrating the anti-MES efficacy of compound 6m, its potency against Seizures induced by pentylenetetrazole, 3-mercaptopropionic acid, and bicuculline were also established, with the results suggesting that several different mechanisms of action might be involved in its anticonvulsant activity, including the inhibition of voltage-gated ion channels and the modulation of GABAergic activity.
-
Synthesis and anticonvulsant activity evaluation of 4-(2-alkoxy-phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-ones in various Experimental Seizure models in mice.
Drug research, 2013Co-Authors: X Cao, X-q Deng, B Shu, S-b Wang, Zhe-shan QuanAbstract:A new series of 4-(2-alkoxy-phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-ones was synthesized using appropriate synthetic route. Their anticonvulsant activities were evaluated Experimentally against maximal electroshock test and their neurotoxicities were evaluated under the rotarod neurotoxicity test with intraperitoneally injected mice. The results showed that all target compounds exhibited anticonvulsant activity in varying degrees against maximal electroshock test. Among them, 4-(2-octyloxy-phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (5 g) was the most promising compound with the median effective dose (ED50) of 23.7 mg/kg, the median toxicity dose (TD50) of 611.0 mg/kg, and the protective index (PI) of 25.8. Compound 5 g showed the higher safety than the standard carbamazepine (PI=6.5). As well as demonstrating the anti-MES efficacy of compound 5 g, its potency against Seizures induced by pentylenetetrazole, 3-mercaptopropionic acid, and bicuculline were also established, with the results suggesting that GABA-mediated mechanisms might be involved in its anticonvulsant activity.
-
evaluation of the anticonvulsant activity of 6 4 chlorophenyoxy tetrazolo 5 1 a phthalazine in various Experimental Seizure models in mice
Pharmacological Reports, 2010Co-Authors: Xianqing Deng, Zhe-shan QuanAbstract:Abstract This study investigated the anticonvulsant activity of a new phthalazine tetrazole derivative, QUAN-0808 (6-(4-chlorophenoxy)-tetrazolo[5,1-a]phthalazine), in the mouse maximal electroshock (MES) Seizure model. The neurotoxicity of QUAN-0808 was investigated using the rotarod neurotoxicity test in mice. QUAN-0808 exhibited higher activity (median effective dose, ED 50 = 6.8 mg/ kg) and lower neurotoxicity (median toxic dose, TD 50 = 456.4 mg/kg), resulting in a higher protective index (PI = 67.1) compared with carbamazepine (PI = 6.4). In addition, QUAN-0808 exhibited significant oral anticonvulsant activity (ED 50 = 24 mg/kg) against MES-induced Seizure with low neurotoxicity (TD 50 > 4500 mg/kg) in mice, resulting in a PI value of more than 187.5. QUAN-0808 was also tested in chemically induced animal models of Seizure (pentylenetetrazole [PTZ], isoniazid [ISO], thiosemicarbazide [THIO] and 3-mercaptopropionic acid [3-MP]) to further investigate the anticonvulsant activity; QUAN-0808 produced significant anticonvulsant activity against Seizures induced by ISO, THIO and 3-MP.
-
Evaluation of the anticonvulsant activity of 6-(4-chlorophenyoxy)-tetrazolo[5,1-a]phthalazine in various Experimental Seizure models in mice
Pharmacological reports : PR, 2010Co-Authors: Xian-yu Sun, Xianqing Deng, Cheng-xi Wei, Zhi-gang Sun, Zhe-shan QuanAbstract:Abstract This study investigated the anticonvulsant activity of a new phthalazine tetrazole derivative, QUAN-0808 (6-(4-chlorophenoxy)-tetrazolo[5,1-a]phthalazine), in the mouse maximal electroshock (MES) Seizure model. The neurotoxicity of QUAN-0808 was investigated using the rotarod neurotoxicity test in mice. QUAN-0808 exhibited higher activity (median effective dose, ED 50 = 6.8 mg/ kg) and lower neurotoxicity (median toxic dose, TD 50 = 456.4 mg/kg), resulting in a higher protective index (PI = 67.1) compared with carbamazepine (PI = 6.4). In addition, QUAN-0808 exhibited significant oral anticonvulsant activity (ED 50 = 24 mg/kg) against MES-induced Seizure with low neurotoxicity (TD 50 > 4500 mg/kg) in mice, resulting in a PI value of more than 187.5. QUAN-0808 was also tested in chemically induced animal models of Seizure (pentylenetetrazole [PTZ], isoniazid [ISO], thiosemicarbazide [THIO] and 3-mercaptopropionic acid [3-MP]) to further investigate the anticonvulsant activity; QUAN-0808 produced significant anticonvulsant activity against Seizures induced by ISO, THIO and 3-MP.
-
Characterization of the anticonvulsant activity of doxepin in various Experimental Seizure models in mice
Pharmacological Reports, 2009Co-Authors: Lei Zhang, Hu-ri Piao, Zhe-shan QuanAbstract:Abstract In this paper, the anticonvulsant characteristics of doxepin were evaluated in numerous Experimental Seizure models, including maximal electroshock (MES)-, pentylenetetrazole (PTZ)-, isoniazid (ISO)-, 3-mercaptopropionic acid (3-MP)-, bicuculline (BIC)-, thiosemicarbazide (THIO)-, and strychnine (STR)-induced Seizures. In addition, the acute adverse-effect profile of doxepin with respect to impairment of motor coordination was assessed with a mouse rotarod test. The evaluation of the time-course and doseresponse relationships for doxepin provided evidence that the peak maximum anticonvulsant activity and acute adverse effects occurred 5 min after intraperitoneal ( ip ) administration. The results also revealed that doxepin had excellent anticonvulsant activity against maximal electroshock-induced Seizures in mice with a median effect value (ED 50 ) of 6.6 mg/kg. The assessment of acute adverse effects in the rotarod test revealed that doxepin induced acute neurotoxicity, and its median toxic dose (TD 50 ) was 26.4 mg/kg. Additionally, doxepin showed anticonvulsant activity in several chemically-induced Seizure models, including ISO, 3-MP, BIC, and THI. Based on this study, we can conclude that the antidepressant drug doxepin may be useful for treatment of depression in patients with epilepsy due to its short time to peak maximum anticonvulsant activity after ip administration (5 min) and remarkable anticonvulsant activity (6.6 mg/kg).
Patrick Kwan - One of the best experts on this subject based on the ideXlab platform.
-
regional expression of multidrug resistance genes in genetically epilepsy prone rat brain after a single audiogenic Seizure
Epilepsia, 2002Co-Authors: Patrick Kwan, Brian S Meldrum, Timothy W Gant, Graeme J Sills, Elaine Butler, Martin J BrodieAbstract:Summary: Purpose: The multidrug resistance (mdr) gene family encodes the drug transport macromolecule P-glycoprotein (P-gp), which contributes to the functionality of the blood–brain barrier. Recent evidence suggests that P-gp–mediated drug extrusion may play a facilitatory role in refractory epilepsy. We investigated the regional expression of mdr genes in genetically epilepsy-prone rat (GEPR) brain after a single audiogenic Seizure. Methods: Three groups of adult male GEPRs (n = 5/group) were exposed to a Seizure-inducing audiogenic stimulus and killed at 4 h, 24 h, and 7 days thereafter. A further group (n = 5) served as a stimulus-naive control. Expression of mdr1a and mdr1b in distinct anatomic brain regions (cortex, midbrain, pons/medulla, hippocampus) was determined by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) in the presence of competitive internal standards. Results: When compared with control, mdr1a expression in cortex and midbrain was significantly (p < 0.05) increased at 24 h after a single audiogenic Seizure. Cortical mdr1a expression remained elevated at 7 days after stimulus. In contrast, mdr1a expression in pons/medulla and hippocampus was unchanged. The mdr1b isoform was quantifiable in hippocampus alone and not influenced by Seizure activity. Conclusions: These findings suggest that acute Seizures in the GEPR can induce the expression of mdr genes. The pattern of increased expression appears to follow the anatomic pathway of audiogenic Seizures in these animals, with initiation in the midbrain and propagation to the cortex. Further studies are required to investigate the effects of recurrent Seizure activity and to characterise mdr expression in other Experimental Seizure models.
-
regional expression of multidrug resistance genes in genetically epilepsy prone rat brain after a single audiogenic Seizure
Epilepsia, 2002Co-Authors: Patrick Kwan, Brian S Meldrum, Timothy W Gant, Graeme J Sills, Elaine Butler, Martin J BrodieAbstract:Summary: Purpose: The multidrug resistance (mdr) gene family encodes the drug transport macromolecule P-glycoprotein (P-gp), which contributes to the functionality of the blood–brain barrier. Recent evidence suggests that P-gp–mediated drug extrusion may play a facilitatory role in refractory epilepsy. We investigated the regional expression of mdr genes in genetically epilepsy-prone rat (GEPR) brain after a single audiogenic Seizure. Methods: Three groups of adult male GEPRs (n = 5/group) were exposed to a Seizure-inducing audiogenic stimulus and killed at 4 h, 24 h, and 7 days thereafter. A further group (n = 5) served as a stimulus-naive control. Expression of mdr1a and mdr1b in distinct anatomic brain regions (cortex, midbrain, pons/medulla, hippocampus) was determined by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) in the presence of competitive internal standards. Results: When compared with control, mdr1a expression in cortex and midbrain was significantly (p < 0.05) increased at 24 h after a single audiogenic Seizure. Cortical mdr1a expression remained elevated at 7 days after stimulus. In contrast, mdr1a expression in pons/medulla and hippocampus was unchanged. The mdr1b isoform was quantifiable in hippocampus alone and not influenced by Seizure activity. Conclusions: These findings suggest that acute Seizures in the GEPR can induce the expression of mdr genes. The pattern of increased expression appears to follow the anatomic pathway of audiogenic Seizures in these animals, with initiation in the midbrain and propagation to the cortex. Further studies are required to investigate the effects of recurrent Seizure activity and to characterise mdr expression in other Experimental Seizure models.
Graeme J Sills - One of the best experts on this subject based on the ideXlab platform.
-
pharmacodynamic interaction studies with topiramate in the pentylenetetrazol and maximal electroshock Seizure models
Seizure-european Journal of Epilepsy, 2004Co-Authors: Graeme J Sills, Elaine Butler, G G Thompson, Martin J BrodieAbstract:There is emerging evidence to support the efficacy of some antiepileptic drug (AED) combinations in refractory epilepsy. Definitive clinical studies are, however, difficult to perform. Experimental Seizure models can be employed to identify potentially useful combinations for subsequent clinical evaluation. We have investigated the anticonvulsant effects of topiramate (TPM) in combination with 13 other AEDs in the pentylenetetrazol (PTZ) and maximal electroshock (MES) Seizure models. Single drugs and combinations were administered by intraperitoneal injection and anticonvulsant effects determined at 1-hour post-dosing. TPM was without significant effect in the PTZ test. In contrast, phenobarbital, primidone, ethosuximide, sodium valproate, felbamate and tiagabine all increased the latency to the first generalised Seizure. Combinations of TPM and active adjunctive drug were universally effective. Combinations of TPM with clobazam, lamotrigine and levetiracetam were also anticonvulsant, despite the inactivity of the constituent compounds when administered alone. TPM reduced the incidence of MES-induced Seizures in a dose-dependent manner, as did phenobarbital, phenytoin, primidone, carbamazepine, sodium valproate, clobazam, lamotrigine, felbamate and tiagabine. All combination treatments were similarly effective. These findings suggest that combinations of TPM with lamotrigine and levetiracetam may demonstrate anticonvulsant synergism and merit further investigation in additional model systems and with recourse to more quantitative mathematical analysis.
-
regional expression of multidrug resistance genes in genetically epilepsy prone rat brain after a single audiogenic Seizure
Epilepsia, 2002Co-Authors: Patrick Kwan, Brian S Meldrum, Timothy W Gant, Graeme J Sills, Elaine Butler, Martin J BrodieAbstract:Summary: Purpose: The multidrug resistance (mdr) gene family encodes the drug transport macromolecule P-glycoprotein (P-gp), which contributes to the functionality of the blood–brain barrier. Recent evidence suggests that P-gp–mediated drug extrusion may play a facilitatory role in refractory epilepsy. We investigated the regional expression of mdr genes in genetically epilepsy-prone rat (GEPR) brain after a single audiogenic Seizure. Methods: Three groups of adult male GEPRs (n = 5/group) were exposed to a Seizure-inducing audiogenic stimulus and killed at 4 h, 24 h, and 7 days thereafter. A further group (n = 5) served as a stimulus-naive control. Expression of mdr1a and mdr1b in distinct anatomic brain regions (cortex, midbrain, pons/medulla, hippocampus) was determined by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) in the presence of competitive internal standards. Results: When compared with control, mdr1a expression in cortex and midbrain was significantly (p < 0.05) increased at 24 h after a single audiogenic Seizure. Cortical mdr1a expression remained elevated at 7 days after stimulus. In contrast, mdr1a expression in pons/medulla and hippocampus was unchanged. The mdr1b isoform was quantifiable in hippocampus alone and not influenced by Seizure activity. Conclusions: These findings suggest that acute Seizures in the GEPR can induce the expression of mdr genes. The pattern of increased expression appears to follow the anatomic pathway of audiogenic Seizures in these animals, with initiation in the midbrain and propagation to the cortex. Further studies are required to investigate the effects of recurrent Seizure activity and to characterise mdr expression in other Experimental Seizure models.
-
regional expression of multidrug resistance genes in genetically epilepsy prone rat brain after a single audiogenic Seizure
Epilepsia, 2002Co-Authors: Patrick Kwan, Brian S Meldrum, Timothy W Gant, Graeme J Sills, Elaine Butler, Martin J BrodieAbstract:Summary: Purpose: The multidrug resistance (mdr) gene family encodes the drug transport macromolecule P-glycoprotein (P-gp), which contributes to the functionality of the blood–brain barrier. Recent evidence suggests that P-gp–mediated drug extrusion may play a facilitatory role in refractory epilepsy. We investigated the regional expression of mdr genes in genetically epilepsy-prone rat (GEPR) brain after a single audiogenic Seizure. Methods: Three groups of adult male GEPRs (n = 5/group) were exposed to a Seizure-inducing audiogenic stimulus and killed at 4 h, 24 h, and 7 days thereafter. A further group (n = 5) served as a stimulus-naive control. Expression of mdr1a and mdr1b in distinct anatomic brain regions (cortex, midbrain, pons/medulla, hippocampus) was determined by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) in the presence of competitive internal standards. Results: When compared with control, mdr1a expression in cortex and midbrain was significantly (p < 0.05) increased at 24 h after a single audiogenic Seizure. Cortical mdr1a expression remained elevated at 7 days after stimulus. In contrast, mdr1a expression in pons/medulla and hippocampus was unchanged. The mdr1b isoform was quantifiable in hippocampus alone and not influenced by Seizure activity. Conclusions: These findings suggest that acute Seizures in the GEPR can induce the expression of mdr genes. The pattern of increased expression appears to follow the anatomic pathway of audiogenic Seizures in these animals, with initiation in the midbrain and propagation to the cortex. Further studies are required to investigate the effects of recurrent Seizure activity and to characterise mdr expression in other Experimental Seizure models.
-
Experimental Seizure models and new antiepileptic drugs
1994Co-Authors: Graeme J SillsAbstract:The objective of this programme of work was to study Experimental Seizure models and new antiepileptic drugs. Initial investigations addressed the contribution of basic animal models of epilepsy to its Experimental study. Next, an attempt was made to emphasise the crucial role of neuronal inhibition and excitation in epileptogenesis and to relate these phenomena to the study of novel antiepileptic agents. Finally, the future of epilepsy research, in terms of appropriate strategies for AED development and innovative Experimental paradigms was examined. Investigation of basic animal Seizure models Of all the Experimental Seizure models in current laboratory employment, the pentylenetetrazol (PTZ) test, and the maximal (MES) and minimal (Min-ES) electroshock tests are among the most popular by virtue of their simplicity and economy. The primary aim of these studies was to afford a familiarity with these three basic animal Seizure models and to validate them as techniques for subsequent use. These studies also incorporated an investigation of concentration-effect relationships with PTZ which attempted to delineate previously observed efficacy problems with this compound in our laboratory. Validation of all three Experimental models was satisfactory, with results reflecting those reported in the literature. Although the concentration-effect studies with PTZ afforded a degree of insight into its pharmacokinetics, attempts to provide a suitable explanation for its lack of convulsant action in some animals proved unsuccessful. Antiepileptic drug enhancement of neuronal inhibition Impairment of gamma-aminobutyric acid (GABA)-mediated neuronal inhibition is believed to be one of the fundamental aetiological mechanisms of epileptogenesis. These investigations compared and contrasted the Experimental anticonvulsant profiles and mechanisms of action of vigabatrin (VGB) and tiagabine (TGB), two novel AEDs which have been proposed to enhance GABA-mediated inhibition. VGB raised the threshold for induction of tonic Seizures, determined by the Min-ES test, but was without effect in the PTZ and MES tests. TGB, in contrast, exhibited anticonvulsant effects against both PTZ- and MES-induced Seizures. Drug mechanisms were investigated in isolated brain tissue and in primary cultures of cerebral cortical astrocytes and neurones. Previously reported mechanisms of action of the two drugs were confirmed, with VGB inhibiting GAB A metabolism by an action on GABA-aminotransferase (GABA-T), and TGB blocking GAB A uptake in a non-cell-specific manner. An inhibitory effect of VGB on glutamic acid decarboxylase (GAD) was also verified, and an additional, previously unreported action of the drug on GABA uptake was proposed. Antiepileptic drug attenuation of neuronal excitation Glutamate-induced neuronal excitability and voltage-sensitive calcium influx are believed to be inexorably entwined at all stages of epileptogenesis. These studies compared and contrasted the Experimental anticonvulsant profiles and mechanisms of action of nimodipine (NMD) and amlodipine (AML), members of the dihydropyridine (DHP) class of calcium channel blockers which have been proposed as putative AEDs. In single dose, NMD was effective against MES-induced Seizures and also raised the tonic Seizure threshold, determined by the Min-ES test. Its effects in the MES test appeared to extend Novel strategies for antiepileptic drug development It has been proposed that to satisfactorily address the problem of refractory epilepsy the development of novel antiepileptic agents with similarly novel mechanisms of action is required. Nicotinylalanine (NA) is a newly-synthesised neuroactive compound which is believed to exert its effects by inhibition of the kynurenine pathway, resulting in increased brain concentrations of kynurenic acid, an endogenous antagonist at the glycine recognition site on the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. This study explored the anticonvulsant profile of NA in three standard animal models of Seizure. NA protected against PTZ induced Seizures in mice in a dose and time dependent manner and was also active in the maximal and minimal electroshock tests. These preliminary results would suggest that NA warrants further investigation as a putative AED. Development of a novel animal model of epilepsy It is now recognised that few, if any, of the existing "animal models of the epilepsies" mirror the condition of chronically recurrent spontaneous Seizures which is characteristic of human epilepsy. This study followed the preliminary development of an innovative model of partial epilepsy, proposed to more closely mimic the human condition. This model was characterised by a laser-induced lesion in the rat somatosensory cortex. Production of cortical laser lesions in the rat proved to be a feasible procedure. Histological investigation proposed the lesions to be highly reproducible and to possess cellular characteristics similar to those of disruptive brain insults in man. The lesion did not appear to be intrinsically epileptogenic, nor did the procedure influence the latency to generalised PTZ-induced Seizures. Preliminary autoradiographical studies suggested that brain damage associated with the procedure was confined to the lesion tract itself, and that cerebral glucose metabolism was additionally altered in adjacent, otherwise healthy, tissue. Despite possessing several attractive features, the full potential of this model for use in epilepsy research remains to be evaluated.
Timothy W Gant - One of the best experts on this subject based on the ideXlab platform.
-
regional expression of multidrug resistance genes in genetically epilepsy prone rat brain after a single audiogenic Seizure
Epilepsia, 2002Co-Authors: Patrick Kwan, Brian S Meldrum, Timothy W Gant, Graeme J Sills, Elaine Butler, Martin J BrodieAbstract:Summary: Purpose: The multidrug resistance (mdr) gene family encodes the drug transport macromolecule P-glycoprotein (P-gp), which contributes to the functionality of the blood–brain barrier. Recent evidence suggests that P-gp–mediated drug extrusion may play a facilitatory role in refractory epilepsy. We investigated the regional expression of mdr genes in genetically epilepsy-prone rat (GEPR) brain after a single audiogenic Seizure. Methods: Three groups of adult male GEPRs (n = 5/group) were exposed to a Seizure-inducing audiogenic stimulus and killed at 4 h, 24 h, and 7 days thereafter. A further group (n = 5) served as a stimulus-naive control. Expression of mdr1a and mdr1b in distinct anatomic brain regions (cortex, midbrain, pons/medulla, hippocampus) was determined by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) in the presence of competitive internal standards. Results: When compared with control, mdr1a expression in cortex and midbrain was significantly (p < 0.05) increased at 24 h after a single audiogenic Seizure. Cortical mdr1a expression remained elevated at 7 days after stimulus. In contrast, mdr1a expression in pons/medulla and hippocampus was unchanged. The mdr1b isoform was quantifiable in hippocampus alone and not influenced by Seizure activity. Conclusions: These findings suggest that acute Seizures in the GEPR can induce the expression of mdr genes. The pattern of increased expression appears to follow the anatomic pathway of audiogenic Seizures in these animals, with initiation in the midbrain and propagation to the cortex. Further studies are required to investigate the effects of recurrent Seizure activity and to characterise mdr expression in other Experimental Seizure models.
-
regional expression of multidrug resistance genes in genetically epilepsy prone rat brain after a single audiogenic Seizure
Epilepsia, 2002Co-Authors: Patrick Kwan, Brian S Meldrum, Timothy W Gant, Graeme J Sills, Elaine Butler, Martin J BrodieAbstract:Summary: Purpose: The multidrug resistance (mdr) gene family encodes the drug transport macromolecule P-glycoprotein (P-gp), which contributes to the functionality of the blood–brain barrier. Recent evidence suggests that P-gp–mediated drug extrusion may play a facilitatory role in refractory epilepsy. We investigated the regional expression of mdr genes in genetically epilepsy-prone rat (GEPR) brain after a single audiogenic Seizure. Methods: Three groups of adult male GEPRs (n = 5/group) were exposed to a Seizure-inducing audiogenic stimulus and killed at 4 h, 24 h, and 7 days thereafter. A further group (n = 5) served as a stimulus-naive control. Expression of mdr1a and mdr1b in distinct anatomic brain regions (cortex, midbrain, pons/medulla, hippocampus) was determined by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) in the presence of competitive internal standards. Results: When compared with control, mdr1a expression in cortex and midbrain was significantly (p < 0.05) increased at 24 h after a single audiogenic Seizure. Cortical mdr1a expression remained elevated at 7 days after stimulus. In contrast, mdr1a expression in pons/medulla and hippocampus was unchanged. The mdr1b isoform was quantifiable in hippocampus alone and not influenced by Seizure activity. Conclusions: These findings suggest that acute Seizures in the GEPR can induce the expression of mdr genes. The pattern of increased expression appears to follow the anatomic pathway of audiogenic Seizures in these animals, with initiation in the midbrain and propagation to the cortex. Further studies are required to investigate the effects of recurrent Seizure activity and to characterise mdr expression in other Experimental Seizure models.
