Limits...
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 human dentate gyrus. (A) The response of the DG (dentate gyrus) molecular layer evoked by 10 stimuli at 16 Hz of 500 μA (vertical gray lines) recorded in the stimulated (A1) and nonstimulated blade (A2) of the DG (the same slice as is shown in Fig. 1), for the control situation (“Control”), after 20 min incubation with 100 μmol/L CBZ (“CBZ”) and after 20 min wash‐out of CBZ (“Wash‐out”). (B) Spatial dynamics of the amplitude of the integrated response (IR) defined by the integral of the signal over the first 15 msec following each stimulus pulse (indicated by the black horizontal lines in A1) in the ROI (region of interest). The first two columns show the integrated response for the control and CBZ conditions described in A and for stimulus pulses (stim) 1, 5, and 10. The third column shows the normalized difference of the relative activity (RA) between the control and the CBZ condition (CBZ – Control/Control). (C) Distribution of the relative activity at 10 repeated stimuli, for six DG slices within a ROI, showing C1) the distribution for two slices of a patient with a lesion (16 Hz), C2) the distribution of four slices of two patients with MTS (8 Hz), and C3) the overall distribution of all slices (MTS + Lesion).
© Copyright Policy - creativeCommonsBy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4834359&req=5

brb3463-fig-0002: Effect of carbamazepine in human dentate gyrus. (A) The response of the DG (dentate gyrus) molecular layer evoked by 10 stimuli at 16 Hz of 500 μA (vertical gray lines) recorded in the stimulated (A1) and nonstimulated blade (A2) of the DG (the same slice as is shown in Fig. 1), for the control situation (“Control”), after 20 min incubation with 100 μmol/L CBZ (“CBZ”) and after 20 min wash‐out of CBZ (“Wash‐out”). (B) Spatial dynamics of the amplitude of the integrated response (IR) defined by the integral of the signal over the first 15 msec following each stimulus pulse (indicated by the black horizontal lines in A1) in the ROI (region of interest). The first two columns show the integrated response for the control and CBZ conditions described in A and for stimulus pulses (stim) 1, 5, and 10. The third column shows the normalized difference of the relative activity (RA) between the control and the CBZ condition (CBZ – Control/Control). (C) Distribution of the relative activity at 10 repeated stimuli, for six DG slices within a ROI, showing C1) the distribution for two slices of a patient with a lesion (16 Hz), C2) the distribution of four slices of two patients with MTS (8 Hz), and C3) the overall distribution of all slices (MTS + Lesion).

Mentions: The parameter “integrated response” is the mean of the signal over a 15‐msec window, starting from the onset of the stimulation pulse. The resulting integrated response value was color coded as well and plotted at the designated location of the photodiode array to visualize the spatial dynamics of the response (e.g., Figs. 2B, 5B). During repetitive stimulation, the response to each stimulus is superimposed on the decay phase of the previous response (e.g., Fig. 2A). In this case, the integrated response was determined with respect to the signal value immediately before each stimulus.


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 human dentate gyrus. (A) The response of the DG (dentate gyrus) molecular layer evoked by 10 stimuli at 16 Hz of 500 μA (vertical gray lines) recorded in the stimulated (A1) and nonstimulated blade (A2) of the DG (the same slice as is shown in Fig. 1), for the control situation (“Control”), after 20 min incubation with 100 μmol/L CBZ (“CBZ”) and after 20 min wash‐out of CBZ (“Wash‐out”). (B) Spatial dynamics of the amplitude of the integrated response (IR) defined by the integral of the signal over the first 15 msec following each stimulus pulse (indicated by the black horizontal lines in A1) in the ROI (region of interest). The first two columns show the integrated response for the control and CBZ conditions described in A and for stimulus pulses (stim) 1, 5, and 10. The third column shows the normalized difference of the relative activity (RA) between the control and the CBZ condition (CBZ – Control/Control). (C) Distribution of the relative activity at 10 repeated stimuli, for six DG slices within a ROI, showing C1) the distribution for two slices of a patient with a lesion (16 Hz), C2) the distribution of four slices of two patients with MTS (8 Hz), and C3) the overall distribution of all slices (MTS + Lesion).
© Copyright Policy - creativeCommonsBy
Related In: Results  -  Collection

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

brb3463-fig-0002: Effect of carbamazepine in human dentate gyrus. (A) The response of the DG (dentate gyrus) molecular layer evoked by 10 stimuli at 16 Hz of 500 μA (vertical gray lines) recorded in the stimulated (A1) and nonstimulated blade (A2) of the DG (the same slice as is shown in Fig. 1), for the control situation (“Control”), after 20 min incubation with 100 μmol/L CBZ (“CBZ”) and after 20 min wash‐out of CBZ (“Wash‐out”). (B) Spatial dynamics of the amplitude of the integrated response (IR) defined by the integral of the signal over the first 15 msec following each stimulus pulse (indicated by the black horizontal lines in A1) in the ROI (region of interest). The first two columns show the integrated response for the control and CBZ conditions described in A and for stimulus pulses (stim) 1, 5, and 10. The third column shows the normalized difference of the relative activity (RA) between the control and the CBZ condition (CBZ – Control/Control). (C) Distribution of the relative activity at 10 repeated stimuli, for six DG slices within a ROI, showing C1) the distribution for two slices of a patient with a lesion (16 Hz), C2) the distribution of four slices of two patients with MTS (8 Hz), and C3) the overall distribution of all slices (MTS + Lesion).
Mentions: The parameter “integrated response” is the mean of the signal over a 15‐msec window, starting from the onset of the stimulation pulse. The resulting integrated response value was color coded as well and plotted at the designated location of the photodiode array to visualize the spatial dynamics of the response (e.g., Figs. 2B, 5B). During repetitive stimulation, the response to each stimulus is superimposed on the decay phase of the previous response (e.g., Fig. 2A). In this case, the integrated response was determined with respect to the signal value immediately before each stimulus.

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