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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

Effect of carbamazepine in rat dentate gyrus. (A) Spatial dynamics of the integrated response recorded in the molecular layer of the DG in response to a stimulus train at 16 Hz (500 μA) in the control condition (first column, “Control”) and 100 μmol/L CBZ (second, “CBZ”). The RA (relative activity) between the CBZ and control response is represented in the third column, RA = (CBZ – Control)/Control. (B) The distribution of the relative activity in the molecular layer of the dentate gyrus for all slices (n = 7), for 8 Hz (B1) and 16 Hz (B2) stimulus frequencies.
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brb3463-fig-0005: Effect of carbamazepine in rat dentate gyrus. (A) Spatial dynamics of the integrated response recorded in the molecular layer of the DG in response to a stimulus train at 16 Hz (500 μA) in the control condition (first column, “Control”) and 100 μmol/L CBZ (second, “CBZ”). The RA (relative activity) between the CBZ and control response is represented in the third column, RA = (CBZ – Control)/Control. (B) The distribution of the relative activity in the molecular layer of the dentate gyrus for all slices (n = 7), for 8 Hz (B1) and 16 Hz (B2) stimulus frequencies.

Mentions: Stimulus trains of 10 pulses at 8 and 16 Hz were applied to the outer molecular layer of the rat DG and the evoked responses were measured with VSD imaging in the control situation, 20 min after wash‐in of 100 μmol/L CBZ and 20 min after wash‐out of CBZ. A typical example of the spatial dynamics of the integrated VSD response is shown in Figure 5A in response to stimulus pulses 1, 5, and 10 applied at 16 Hz (500 μA). In the control condition (ACSF), all pulses of the stimulus train activated the entire molecular layer of the DG, while application of 100 μmol/L CBZ decreased the integrated responses. Typically, the relative activity integrated response (CBZ – control/control) showed a decrease in the integrated response in the entire molecular layer of the DG in the typical example (Fig. 5A – third column). This relative activity was calculated for all diode channels in the molecular layer of all seven rat slices (Fig. 5B). The distribution of the relative activity is shifted toward negative values, indicating that CBZ reduced the size of the integrated response for 8 and 16 Hz (Fig. 5B). There was a significant effect of CBZ on the relative activity on all 10 pulses for 8 as well as 16 Hz (Two‐way ANOVA with repeated measures performed on the data from all channels in the molecular layer; 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)

Effect of carbamazepine in rat dentate gyrus. (A) Spatial dynamics of the integrated response recorded in the molecular layer of the DG in response to a stimulus train at 16 Hz (500 μA) in the control condition (first column, “Control”) and 100 μmol/L CBZ (second, “CBZ”). The RA (relative activity) between the CBZ and control response is represented in the third column, RA = (CBZ – Control)/Control. (B) The distribution of the relative activity in the molecular layer of the dentate gyrus for all slices (n = 7), for 8 Hz (B1) and 16 Hz (B2) stimulus frequencies.
© Copyright Policy - creativeCommonsBy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4834359&req=5

brb3463-fig-0005: Effect of carbamazepine in rat dentate gyrus. (A) Spatial dynamics of the integrated response recorded in the molecular layer of the DG in response to a stimulus train at 16 Hz (500 μA) in the control condition (first column, “Control”) and 100 μmol/L CBZ (second, “CBZ”). The RA (relative activity) between the CBZ and control response is represented in the third column, RA = (CBZ – Control)/Control. (B) The distribution of the relative activity in the molecular layer of the dentate gyrus for all slices (n = 7), for 8 Hz (B1) and 16 Hz (B2) stimulus frequencies.
Mentions: Stimulus trains of 10 pulses at 8 and 16 Hz were applied to the outer molecular layer of the rat DG and the evoked responses were measured with VSD imaging in the control situation, 20 min after wash‐in of 100 μmol/L CBZ and 20 min after wash‐out of CBZ. A typical example of the spatial dynamics of the integrated VSD response is shown in Figure 5A in response to stimulus pulses 1, 5, and 10 applied at 16 Hz (500 μA). In the control condition (ACSF), all pulses of the stimulus train activated the entire molecular layer of the DG, while application of 100 μmol/L CBZ decreased the integrated responses. Typically, the relative activity integrated response (CBZ – control/control) showed a decrease in the integrated response in the entire molecular layer of the DG in the typical example (Fig. 5A – third column). This relative activity was calculated for all diode channels in the molecular layer of all seven rat slices (Fig. 5B). The distribution of the relative activity is shifted toward negative values, indicating that CBZ reduced the size of the integrated response for 8 and 16 Hz (Fig. 5B). There was a significant effect of CBZ on the relative activity on all 10 pulses for 8 as well as 16 Hz (Two‐way ANOVA with repeated measures performed on the data from all channels in the molecular layer; 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