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Alterations in bcl-2 and caspase gene family protein expression in human temporal lobe epilepsy
D C Henshall1, R S Clark, P D Adelson
1Department of Neurology, University of Pittsburgh, PA, USA.
Objective:
To address the role of cell death regulatory genes of the bcl-2 and caspase families in the neuropathology of human epilepsy using tissue extracted from patients undergoing temporal lobectomy for intractable seizures.
Methods:
Using Western blotting and immunohistochemistry, the authors investigated the expression of bcl-2, bcl-xL, bax, caspase-1,and caspase-3 in temporal cortex samples from patients who had undergone temporal lobectomy surgery for intractable epilepsy (n = 19). Nonepileptic postmortem tissue from a brain bank served as control (n = 6).
Results:
Western blot analysis demonstrated significant increases in levels of bcl-2 and bcl-xL protein in seizure brain compared to control. Cleavage of caspase-1 was evidenced by a reduction in levels of the 45 kDa proenzyme form and an increase in levels of the p10 fragment. Levels of the 32 kDa proenzyme form of caspase-3 were elevated in seizure patients, as were levels of the 12 kDa cleaved fragment. Bcl-2, bax, and caspase-3 immunoreactivity was increased predominantly in cells with the morphologic appearance of neurons, whereas bcl-xL immunoreactivity was increased in cells with the appearance of glia. DNA fragmentation was detected in some but not all sections from epileptic brain samples.
Conclusions:
Cell death regulatory genes of the bcl-2 and caspase families may play a role in ongoing neuropathologic processes in human epilepsy, and offer novel targets as an adjunct to anticonvulsant therapy.
Insights
Cell death genes bcl-2 and caspase families are upregulated in human epilepsy brain tissue, suggesting their role in neuropathology and potential as therapeutic targets beyond anticonvulsant drugs.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Epilepsy is a neurological disorder characterized by recurrent seizures.
- Understanding the underlying neuropathology is crucial for developing effective treatments.
- Cell death pathways, regulated by bcl-2 and caspase families, are implicated in various neurological conditions.
Purpose of the Study:
- To investigate the expression of bcl-2 and caspase family genes in the neuropathology of human epilepsy.
- To determine the role of these cell death regulatory genes in intractable seizures.
Main Methods:
- Western blotting and immunohistochemistry were used to analyze temporal cortex samples.
- Expression levels of bcl-2, bcl-xL, bax, caspase-1, and caspase-3 were quantified.
- Samples from epilepsy patients (n=19) were compared to non-epileptic postmortem brain tissue (n=6).
Main Results:
- Significant increases in bcl-2 and bcl-xL protein levels were observed in epilepsy brain tissue.
- Evidence of caspase-1 and caspase-3 cleavage indicated activation of these cell death proteases.
- Increased immunoreactivity for bcl-2, bax, and caspase-3 was found in neurons, while bcl-xL was increased in glial cells.
- DNA fragmentation was detected in some epileptic brain samples.
Conclusions:
- Cell death regulatory genes from the bcl-2 and caspase families are implicated in the neuropathological processes of human epilepsy.
- These genes represent potential novel therapeutic targets for epilepsy management, complementing existing anticonvulsant therapies.