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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

The spatial effect of carbamazepine in the rat dentate gyrus. (A) Image of a rat hippocampal slice. The small white squares represent the location of the 464 photodiode channels; the position of the bipolar stimulation electrode is indicated by the white arrow. The molecular layer of the dentate gyrus is divided into seven fields. The numbers of the fields represent the: 1. Inner blade – tip; 2. Inner blade – middle part; 3. Inner blade – bottom part; 4. Crest; 5. Outer blade – bottom part; 6. Outer blade – middle part; and 7. Outer blade – tip. For the analysis, the channels included within one field were averaged and these values were used for averaging over slices and schematically represented (“V”‐shape – inset). (B) The average of the integrated responses (IR) within each of the seven defined fields (A) was calculated and averaged over seven slices for each evoked response following the 10 pulses applied at 8 Hz (B1) or 16 Hz (B2). The columns represent the control condition (“Control”), 100 μmol/L CBZ application for 20 min (“CBZ”) and the relative activity (RA) between control and CBZ. The averaged integrated response values (column 1–2) are represented in color code at the corresponding field in the DG. The black arrow in the top left panel in B1 shows the location of the stimulation electrode. The numbers represent the fields shown in A.
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brb3463-fig-0006: The spatial effect of carbamazepine in the rat dentate gyrus. (A) Image of a rat hippocampal slice. The small white squares represent the location of the 464 photodiode channels; the position of the bipolar stimulation electrode is indicated by the white arrow. The molecular layer of the dentate gyrus is divided into seven fields. The numbers of the fields represent the: 1. Inner blade – tip; 2. Inner blade – middle part; 3. Inner blade – bottom part; 4. Crest; 5. Outer blade – bottom part; 6. Outer blade – middle part; and 7. Outer blade – tip. For the analysis, the channels included within one field were averaged and these values were used for averaging over slices and schematically represented (“V”‐shape – inset). (B) The average of the integrated responses (IR) within each of the seven defined fields (A) was calculated and averaged over seven slices for each evoked response following the 10 pulses applied at 8 Hz (B1) or 16 Hz (B2). The columns represent the control condition (“Control”), 100 μmol/L CBZ application for 20 min (“CBZ”) and the relative activity (RA) between control and CBZ. The averaged integrated response values (column 1–2) are represented in color code at the corresponding field in the DG. The black arrow in the top left panel in B1 shows the location of the stimulation electrode. The numbers represent the fields shown in A.

Mentions: The similarities in the rat DG shape enabled us to average the integrated responses over slices and investigate the spatial dynamics of CBZ (Fig. 6). The mean value of the integrated response for each field were averaged over all tested slices (Fig. 6B). The highest value of the integrated response was always observed near the stimulation electrode (field 3 of the DG in Fig. 6A). To determine the CBZ effect, the relative activity was calculated. Application of 100 μmol/L CBZ significantly reduced the response amplitude for 8 and 16 Hz (Three‐way ANOVA with repeated measures, P < 0.05 for both 8 and 16 Hz) in all fields (P < 0.01 for both 8 and 16 Hz). A significant effect of pulse number was only observed for 16 Hz (P < 0.01; Fig. 6B), although a significant interaction between DG field and pulse number was observed for both 8 and 16 Hz (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)

The spatial effect of carbamazepine in the rat dentate gyrus. (A) Image of a rat hippocampal slice. The small white squares represent the location of the 464 photodiode channels; the position of the bipolar stimulation electrode is indicated by the white arrow. The molecular layer of the dentate gyrus is divided into seven fields. The numbers of the fields represent the: 1. Inner blade – tip; 2. Inner blade – middle part; 3. Inner blade – bottom part; 4. Crest; 5. Outer blade – bottom part; 6. Outer blade – middle part; and 7. Outer blade – tip. For the analysis, the channels included within one field were averaged and these values were used for averaging over slices and schematically represented (“V”‐shape – inset). (B) The average of the integrated responses (IR) within each of the seven defined fields (A) was calculated and averaged over seven slices for each evoked response following the 10 pulses applied at 8 Hz (B1) or 16 Hz (B2). The columns represent the control condition (“Control”), 100 μmol/L CBZ application for 20 min (“CBZ”) and the relative activity (RA) between control and CBZ. The averaged integrated response values (column 1–2) are represented in color code at the corresponding field in the DG. The black arrow in the top left panel in B1 shows the location of the stimulation electrode. The numbers represent the fields shown in A.
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Related In: Results  -  Collection

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brb3463-fig-0006: The spatial effect of carbamazepine in the rat dentate gyrus. (A) Image of a rat hippocampal slice. The small white squares represent the location of the 464 photodiode channels; the position of the bipolar stimulation electrode is indicated by the white arrow. The molecular layer of the dentate gyrus is divided into seven fields. The numbers of the fields represent the: 1. Inner blade – tip; 2. Inner blade – middle part; 3. Inner blade – bottom part; 4. Crest; 5. Outer blade – bottom part; 6. Outer blade – middle part; and 7. Outer blade – tip. For the analysis, the channels included within one field were averaged and these values were used for averaging over slices and schematically represented (“V”‐shape – inset). (B) The average of the integrated responses (IR) within each of the seven defined fields (A) was calculated and averaged over seven slices for each evoked response following the 10 pulses applied at 8 Hz (B1) or 16 Hz (B2). The columns represent the control condition (“Control”), 100 μmol/L CBZ application for 20 min (“CBZ”) and the relative activity (RA) between control and CBZ. The averaged integrated response values (column 1–2) are represented in color code at the corresponding field in the DG. The black arrow in the top left panel in B1 shows the location of the stimulation electrode. The numbers represent the fields shown in A.
Mentions: The similarities in the rat DG shape enabled us to average the integrated responses over slices and investigate the spatial dynamics of CBZ (Fig. 6). The mean value of the integrated response for each field were averaged over all tested slices (Fig. 6B). The highest value of the integrated response was always observed near the stimulation electrode (field 3 of the DG in Fig. 6A). To determine the CBZ effect, the relative activity was calculated. Application of 100 μmol/L CBZ significantly reduced the response amplitude for 8 and 16 Hz (Three‐way ANOVA with repeated measures, P < 0.05 for both 8 and 16 Hz) in all fields (P < 0.01 for both 8 and 16 Hz). A significant effect of pulse number was only observed for 16 Hz (P < 0.01; Fig. 6B), although a significant interaction between DG field and pulse number was observed for both 8 and 16 Hz (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