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Updated: Mar 23, 2026
Modeling Neuronal Death and Degeneration in Mouse Primary Cerebellar Granule Neurons
Published on: November 6, 2017
Anticonvulsant drug-induced cell death in the developing white matter of the rodent brain
Suhasini Kaushal1, Zenab Tamer1, Freda Opoku1
1Department of Pharmacology & Physiology, Georgetown University School of Medicine, Washington, DC, U.S.A.
Objective:
During critical periods of brain development, both seizures and anticonvulsant medications can affect neurodevelopmental outcomes. In rodent models, many anticonvulsants trigger neuronal apoptosis. However, white matter apoptosis (WMA) has not been examined after anticonvulsant drug treatment. Herein, we sought to determine if anticonvulsant drugs induced apoptosis in the developing white matter (WM) in a rodent model.
Methods:
Postnatal day (P)7 rats were treated with phenobarbital (PB-75), MK-801 (dizocilpine, 0.5), lamotrigine (LTG-20), carbamazepine (CBZ-100), phenytoin (PHT-50), levetiracetam (LEV-250), or saline; all doses are mg/kg. Brain tissue collected 24 h after treatment was stained using the terminal deoxynucleotidyl transferase dUTP nick end labeling method. The number of degenerating cells within WM, that is, anterior commissure (AC), corpus callosum, cingulum, and hippocampus-associated WM tracts, was quantified.
Results:
Saline-treated rats showed low baseline level of apoptosis in developing WM on P8 in all the areas examined. PB, PHT, and MK-801 significantly increased apoptosis in all four brain areas examined. Exposure to CBZ, LTG, or LEV failed to increase apoptosis in all regions.
Significance:
Commonly used anticonvulsants (PB, PHT) cause apoptosis in the developing WM in a rat model; the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 has a similar effect. These results are consistent with reports of anesthesia-induced WMA during brain development. Consistent with the lack of neuronal apoptosis caused by LTG, LEV, and CBZ, these drugs did not cause WMA. Many infants treated with anticonvulsant drugs have underlying neurologic injury, including WM damage (e.g., following intraventricular hemorrhage [IVH] or hypoxic-ischemic encephalopathy [HIE]). The degree to which anticonvulsant drug treatment will alter outcomes in the presence of underlying injury remains to be examined, but avoiding drugs (when possible) that induce WMA may be beneficial.
Insights
Certain anticonvulsant drugs like phenobarbital and phenytoin induce white matter apoptosis in developing rat brains. Other anticonvulsants did not show this effect, suggesting potential benefits in specific clinical scenarios.
Area of Science:
- Neuroscience
- Developmental Neuroscience
- Pharmacology
Background:
- Seizures and anticonvulsant medications can impact neurodevelopment during critical brain growth periods.
- Anticonvulsants are known to induce neuronal apoptosis in rodent models.
- The effect of anticonvulsants on white matter apoptosis (WMA) in developing brains remains largely unexamined.
Purpose of the Study:
- To investigate whether specific anticonvulsant drugs induce apoptosis in the developing white matter (WM) of a rodent model.
- To compare the effects of various anticonvulsants on WM apoptosis.
Main Methods:
- Postnatal day 7 rats were administered phenobarbital, MK-801, lamotrigine, carbamazepine, phenytoin, levetiracetam, or saline.
- Brain tissue was collected 24 hours post-treatment and stained using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) method.
- Apoptosis was quantified in specific WM regions, including the anterior commissure, corpus callosum, cingulum, and hippocampus-associated tracts.
Main Results:
- Saline-treated rats exhibited low baseline WM apoptosis.
- Phenobarbital, phenytoin, and MK-801 significantly increased apoptosis in all examined WM areas.
- Carbamazepine, lamotrigine, and levetiracetam did not significantly increase WM apoptosis.
Conclusions:
- Commonly used anticonvulsants phenobarbital and phenytoin, along with the NMDA receptor antagonist MK-801, induce apoptosis in developing white matter in rats.
- Anticonvulsants lamotrigine, levetiracetam, and carbamazepine did not cause WMA, mirroring their lack of effect on neuronal apoptosis.
- Avoiding anticonvulsants that induce WMA may be beneficial for infants with underlying neurological injuries, such as those from intraventricular hemorrhage or hypoxic-ischemic encephalopathy.
