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Carbamazepine modulates the spatiotemporal activity in the dentate gyrus of rats and pharmacoresistant humans in vitro.

Cappaert NL, Werkman TR, Benito N, Witter MP, Baayen JC, Wadman WJ - Brain Behav (2016)

Bottom Line: Bath applied CBZ (100 μmol/L) reduced the amplitude of the evoked responses in the human DG, albeit that no clear use-dependent effects were found at frequencies of 8 or 16 Hz.This study demonstrates that CBZ still reduced the activity in the DG, although the patients were clinically diagnosed as pharmacoresistant for CBZ.We also concluded that the effect of CBZ was found in the activated region of the DG, quite comparable to the observations in the nonepileptic rat.

View Article: PubMed Central - PubMed

Affiliation: Swammerdam Institute for Life Sciences - Center for NeuroScience University of Amsterdam Amsterdam The Netherlands.

ABSTRACT

Introduction: Human hippocampal tissue resected from pharmacoresistant epilepsy patients was investigated to study the effect of the antiepileptic drug CBZ (carbamazepine) and was compared to similar experiments in the hippocampus of control rats.

Methods: The molecular layer of the DG (dentate gyrus) of human epileptic tissue and rat nonepileptic tissue was electrically stimulated and the evoked responses were recorded with voltage-sensitive dye imaging to characterize the spatiotemporal properties.

Results: Bath applied CBZ (100 μmol/L) reduced the amplitude of the evoked responses in the human DG, albeit that no clear use-dependent effects were found at frequencies of 8 or 16 Hz. In nonepileptic control DG from rats, CBZ also reduced the amplitude of the evoked response in the molecular layer of the DG as well as the spatial extent of the response.

Conclusions: This study demonstrates that CBZ still reduced the activity in the DG, although the patients were clinically diagnosed as pharmacoresistant for CBZ. This suggests that in the human epileptic brain, the targets of CBZ, the voltage-gated Na(+) channels, are still sensitive to CBZ, although we used a relative high concentration and it is not possibility to assess the actual CBZ concentration that reached the target in the patient. We also concluded that the effect of CBZ was found in the activated region of the DG, quite comparable to the observations in the nonepileptic rat.

No MeSH data available.


Related in: MedlinePlus

Input–output response of rat dentate gyrus. (A) Image of a recorded rat hippocampal slice. The black solid line indicates the outline of the molecular layer of the dentate gyrus and the outline of the Cornu ammonis. The dotted lines mark the granule cell layer and the pyramidal cell layer of CA3 and CA1. The polymorphic layer or hilus is indicated with PML. The red hexagonal overlay represents the outline of the photodiode array. The magenta circle and blue diamond indicate the VSDi recording sites represented in B. The position of the bipolar stimulation electrode is indicated by a black arrow. Scale bar indicates 1 mm. (B) Optical responses recorded in the DG of the rat hippocampal slice shown in A to a single pulse stimulus of 0–100% stimulus intensity. The traces are recorded in the ML layer of the DG and are an average of three channels which location is indicated with a magenta circle (B1; stimulated blade of DG) and a blue diamond (B2; nonstimulated blade of DG) in A. The gray vertical lines indicate the time of the electrical stimulation. (C) The responses presented in B are integrated from 0 to 15 msec after the start of the stimulus pulse for every VSDi recording site. These integrated values are represented in color code at the corresponding location of these recording sites in the photodiode array and are depicted for 25, 50, and 75% stimulation. The black and red shapes are the outlines of the anatomical regions and photodiode array, respectively, as in A.
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brb3463-fig-0003: Input–output response of rat dentate gyrus. (A) Image of a recorded rat hippocampal slice. The black solid line indicates the outline of the molecular layer of the dentate gyrus and the outline of the Cornu ammonis. The dotted lines mark the granule cell layer and the pyramidal cell layer of CA3 and CA1. The polymorphic layer or hilus is indicated with PML. The red hexagonal overlay represents the outline of the photodiode array. The magenta circle and blue diamond indicate the VSDi recording sites represented in B. The position of the bipolar stimulation electrode is indicated by a black arrow. Scale bar indicates 1 mm. (B) Optical responses recorded in the DG of the rat hippocampal slice shown in A to a single pulse stimulus of 0–100% stimulus intensity. The traces are recorded in the ML layer of the DG and are an average of three channels which location is indicated with a magenta circle (B1; stimulated blade of DG) and a blue diamond (B2; nonstimulated blade of DG) in A. The gray vertical lines indicate the time of the electrical stimulation. (C) The responses presented in B are integrated from 0 to 15 msec after the start of the stimulus pulse for every VSDi recording site. These integrated values are represented in color code at the corresponding location of these recording sites in the photodiode array and are depicted for 25, 50, and 75% stimulation. The black and red shapes are the outlines of the anatomical regions and photodiode array, respectively, as in A.

Mentions: To corroborate this CBZ effect for all six tested slices, we first defined the ROI (region of interest) by selecting the channels in the DG that responded to the stimulus in the control situation. Second, the integrated response to every stimulus pulse was calculated for all ROI channels of all slices in the control and CBZ condition. Finally, the relative activity for all the ROI channels was calculated and its distribution is plotted in Figure 2 (MTS/8 Hz – Fig. 2C1; Lesion/16 Hz – Fig. 2C2; all slices/lesion + MTS: Figs. 2C, 3C). All distributions are shifted to the left, which indicates that CBZ reduced the evoked response in the ROI of all tested slices. This CBZ effect on the integrated area was significant on all 10 pulses (Two‐way ANOVA with repeated measures performed on the data from the MTS + lesion, P < 0.01).


Carbamazepine modulates the spatiotemporal activity in the dentate gyrus of rats and pharmacoresistant humans in vitro.

Cappaert NL, Werkman TR, Benito N, Witter MP, Baayen JC, Wadman WJ - Brain Behav (2016)

Input–output response of rat dentate gyrus. (A) Image of a recorded rat hippocampal slice. The black solid line indicates the outline of the molecular layer of the dentate gyrus and the outline of the Cornu ammonis. The dotted lines mark the granule cell layer and the pyramidal cell layer of CA3 and CA1. The polymorphic layer or hilus is indicated with PML. The red hexagonal overlay represents the outline of the photodiode array. The magenta circle and blue diamond indicate the VSDi recording sites represented in B. The position of the bipolar stimulation electrode is indicated by a black arrow. Scale bar indicates 1 mm. (B) Optical responses recorded in the DG of the rat hippocampal slice shown in A to a single pulse stimulus of 0–100% stimulus intensity. The traces are recorded in the ML layer of the DG and are an average of three channels which location is indicated with a magenta circle (B1; stimulated blade of DG) and a blue diamond (B2; nonstimulated blade of DG) in A. The gray vertical lines indicate the time of the electrical stimulation. (C) The responses presented in B are integrated from 0 to 15 msec after the start of the stimulus pulse for every VSDi recording site. These integrated values are represented in color code at the corresponding location of these recording sites in the photodiode array and are depicted for 25, 50, and 75% stimulation. The black and red shapes are the outlines of the anatomical regions and photodiode array, respectively, as in A.
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brb3463-fig-0003: Input–output response of rat dentate gyrus. (A) Image of a recorded rat hippocampal slice. The black solid line indicates the outline of the molecular layer of the dentate gyrus and the outline of the Cornu ammonis. The dotted lines mark the granule cell layer and the pyramidal cell layer of CA3 and CA1. The polymorphic layer or hilus is indicated with PML. The red hexagonal overlay represents the outline of the photodiode array. The magenta circle and blue diamond indicate the VSDi recording sites represented in B. The position of the bipolar stimulation electrode is indicated by a black arrow. Scale bar indicates 1 mm. (B) Optical responses recorded in the DG of the rat hippocampal slice shown in A to a single pulse stimulus of 0–100% stimulus intensity. The traces are recorded in the ML layer of the DG and are an average of three channels which location is indicated with a magenta circle (B1; stimulated blade of DG) and a blue diamond (B2; nonstimulated blade of DG) in A. The gray vertical lines indicate the time of the electrical stimulation. (C) The responses presented in B are integrated from 0 to 15 msec after the start of the stimulus pulse for every VSDi recording site. These integrated values are represented in color code at the corresponding location of these recording sites in the photodiode array and are depicted for 25, 50, and 75% stimulation. The black and red shapes are the outlines of the anatomical regions and photodiode array, respectively, as in A.
Mentions: To corroborate this CBZ effect for all six tested slices, we first defined the ROI (region of interest) by selecting the channels in the DG that responded to the stimulus in the control situation. Second, the integrated response to every stimulus pulse was calculated for all ROI channels of all slices in the control and CBZ condition. Finally, the relative activity for all the ROI channels was calculated and its distribution is plotted in Figure 2 (MTS/8 Hz – Fig. 2C1; Lesion/16 Hz – Fig. 2C2; all slices/lesion + MTS: Figs. 2C, 3C). All distributions are shifted to the left, which indicates that CBZ reduced the evoked response in the ROI of all tested slices. This CBZ effect on the integrated area was significant on all 10 pulses (Two‐way ANOVA with repeated measures performed on the data from the MTS + lesion, P < 0.01).

Bottom Line: Bath applied CBZ (100 μmol/L) reduced the amplitude of the evoked responses in the human DG, albeit that no clear use-dependent effects were found at frequencies of 8 or 16 Hz.This study demonstrates that CBZ still reduced the activity in the DG, although the patients were clinically diagnosed as pharmacoresistant for CBZ.We also concluded that the effect of CBZ was found in the activated region of the DG, quite comparable to the observations in the nonepileptic rat.

View Article: PubMed Central - PubMed

Affiliation: Swammerdam Institute for Life Sciences - Center for NeuroScience University of Amsterdam Amsterdam The Netherlands.

ABSTRACT

Introduction: Human hippocampal tissue resected from pharmacoresistant epilepsy patients was investigated to study the effect of the antiepileptic drug CBZ (carbamazepine) and was compared to similar experiments in the hippocampus of control rats.

Methods: The molecular layer of the DG (dentate gyrus) of human epileptic tissue and rat nonepileptic tissue was electrically stimulated and the evoked responses were recorded with voltage-sensitive dye imaging to characterize the spatiotemporal properties.

Results: Bath applied CBZ (100 μmol/L) reduced the amplitude of the evoked responses in the human DG, albeit that no clear use-dependent effects were found at frequencies of 8 or 16 Hz. In nonepileptic control DG from rats, CBZ also reduced the amplitude of the evoked response in the molecular layer of the DG as well as the spatial extent of the response.

Conclusions: This study demonstrates that CBZ still reduced the activity in the DG, although the patients were clinically diagnosed as pharmacoresistant for CBZ. This suggests that in the human epileptic brain, the targets of CBZ, the voltage-gated Na(+) channels, are still sensitive to CBZ, although we used a relative high concentration and it is not possibility to assess the actual CBZ concentration that reached the target in the patient. We also concluded that the effect of CBZ was found in the activated region of the DG, quite comparable to the observations in the nonepileptic rat.

No MeSH data available.


Related in: MedlinePlus