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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 concentration–response effect of carbamazepine in the rat dentate gyrus. (A) Example of a field potential in response to the 10th pulse of a 16 Hz pulse train recorded in the granule cell layer of the DG. The green trace is control condition, red trace is after 20‐min bath application of 100 μmol/L carbamazepine. Scale: 5 msec, 0.1 mV. (B) The concentration–response effect of carbamazepine (20, 50, and 100 μmol/L) on the relative amplitude of the field potential amplitude (fEPSP) in the granule cell layer of the dentate gyrus tested at the 10th pulse of frequency trains of 8, 16, and 50 Hz. * indicate a significant difference between the control and the CBZ condition.
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brb3463-fig-0004: The concentration–response effect of carbamazepine in the rat dentate gyrus. (A) Example of a field potential in response to the 10th pulse of a 16 Hz pulse train recorded in the granule cell layer of the DG. The green trace is control condition, red trace is after 20‐min bath application of 100 μmol/L carbamazepine. Scale: 5 msec, 0.1 mV. (B) The concentration–response effect of carbamazepine (20, 50, and 100 μmol/L) on the relative amplitude of the field potential amplitude (fEPSP) in the granule cell layer of the dentate gyrus tested at the 10th pulse of frequency trains of 8, 16, and 50 Hz. * indicate a significant difference between the control and the CBZ condition.

Mentions: The concentration–response relation of CBZ was investigated in the rat DG with field potential recordings. Stimulus trains of 10 pulses at 8, 16, and 5 Hz at 100% of the maximum stimulus intensity were applied to the outer molecular layer of the DG. Stimulus‐evoked field potentials (fEPSP) were recorded in granule cell layer of the DG from healthy rats. The fEPSP were obtained in the control situation and after 20 min wash‐in of CBZ at 20, 50, and 100 μmol/L (Fig. 4A). The concentration–response relationship for CBZ was explored by determining the % inhibition of the fEPSP peak amplitude at the 10th pulse after CBZ application (Fig. 4B). Paired t‐tests were conducted to compare the fEPSP amplitude between the control situation and CBZ, for all tested frequencies. Bonferroni correction was performed to correct for multiple testing and the α‐level was set at 0.017. Significant effects of CBZ were detected for 50 μmol/L CBZ at 16 Hz (P = 0.0065 – t = −5.6) and for 100 μmol/L CBZ at 8, 16, and 50 Hz (P < 0.0005 – t = 16.3, P = 0.007 – t = 6.8 and P = 0.01 – t = 9.2, respectively).


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 concentration–response effect of carbamazepine in the rat dentate gyrus. (A) Example of a field potential in response to the 10th pulse of a 16 Hz pulse train recorded in the granule cell layer of the DG. The green trace is control condition, red trace is after 20‐min bath application of 100 μmol/L carbamazepine. Scale: 5 msec, 0.1 mV. (B) The concentration–response effect of carbamazepine (20, 50, and 100 μmol/L) on the relative amplitude of the field potential amplitude (fEPSP) in the granule cell layer of the dentate gyrus tested at the 10th pulse of frequency trains of 8, 16, and 50 Hz. * indicate a significant difference between the control and the CBZ condition.
© Copyright Policy - creativeCommonsBy
Related In: Results  -  Collection

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

brb3463-fig-0004: The concentration–response effect of carbamazepine in the rat dentate gyrus. (A) Example of a field potential in response to the 10th pulse of a 16 Hz pulse train recorded in the granule cell layer of the DG. The green trace is control condition, red trace is after 20‐min bath application of 100 μmol/L carbamazepine. Scale: 5 msec, 0.1 mV. (B) The concentration–response effect of carbamazepine (20, 50, and 100 μmol/L) on the relative amplitude of the field potential amplitude (fEPSP) in the granule cell layer of the dentate gyrus tested at the 10th pulse of frequency trains of 8, 16, and 50 Hz. * indicate a significant difference between the control and the CBZ condition.
Mentions: The concentration–response relation of CBZ was investigated in the rat DG with field potential recordings. Stimulus trains of 10 pulses at 8, 16, and 5 Hz at 100% of the maximum stimulus intensity were applied to the outer molecular layer of the DG. Stimulus‐evoked field potentials (fEPSP) were recorded in granule cell layer of the DG from healthy rats. The fEPSP were obtained in the control situation and after 20 min wash‐in of CBZ at 20, 50, and 100 μmol/L (Fig. 4A). The concentration–response relationship for CBZ was explored by determining the % inhibition of the fEPSP peak amplitude at the 10th pulse after CBZ application (Fig. 4B). Paired t‐tests were conducted to compare the fEPSP amplitude between the control situation and CBZ, for all tested frequencies. Bonferroni correction was performed to correct for multiple testing and the α‐level was set at 0.017. Significant effects of CBZ were detected for 50 μmol/L CBZ at 16 Hz (P = 0.0065 – t = −5.6) and for 100 μmol/L CBZ at 8, 16, and 50 Hz (P < 0.0005 – t = 16.3, P = 0.007 – t = 6.8 and P = 0.01 – t = 9.2, respectively).

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