The effect of mexiletine on the level of lipid peroxidation and apoptosis of endothelium following experimental subarachnoid hemorrhage.
OBJECTIVE
The role of apoptosis in etiopathogenesis of vasospasm is not clearly understood yet. It is widely accepted that protection of the endothelial cells from the process of apoptosis could have beneficial effects on cerebral vasospasm after subarachnoid hemorrhage (SAH). Mexiletine blocks sodium and calcium channels and activates ATP-sensitive K(+) channels. Moreover, mexiletine is known to have potent antioxidant effects through inhibiting free-radical production.


METHODS
Twenty-one rabbits were allocated into three groups randomly. Group I was sham operated group (n=7). SAH occurred but no medication was given to the Group II rabbits (SAH only group) (n=7). Mexiletine (50 mg/kg, b.i.d., i.p.) was administered just before SAH and continued until 48 hours following SAH to the Group III rabbits (Mexiletine treated group) (n=7). The ApopTag peroxidase in situ apoptosis detection kit (Serologicals Corporation, former Intergen) was used to demonstrate apoptosis in a cross section of basillary arteries. Thiobarbituric acid reactive material was used to determine the lipid peroxidation levels.


RESULTS
There was a statistically significant difference between lipid peroxidation product levels of the control and SAH only groups (p<0.05). The level of lipid peroxidation production in Mexiletine treated group was significantly lower compared with SAH only group (p<0.05) but not significantly higher than the control group (p>0.05).


CONCLUSIONS
In the present study we investigated the antioxidant action of mexiletine on apoptosis of endothelium following a rabbit SAH model. This experimental study directly suggested that lipid peroxidation is an important step in development of apoptosis in endothelial cells and prevention of structural integrity of endothelial cell should play a beneficial role in attenuation of cerebral vasospasm. Mexiletine treatment prevented the increase in lipid peroxidation and cerebral vasospasm. Examination of endothelial cells by staining specific for apoptosis demonstrated significant protection of cell integrity in the treated group.
Sen
Orhan
O
Department of Neurosurgery, Baskent University, Ankara, Turkey. oraysen@yahoo.com
Caner
Hakan
H
Aydin
M Volkan
MV
Ozen
Ozlem
O
Atalay
Basar
B
Altinors
Nur
N
Bavbek
Murad
M
D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001158:Arteries / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004727:Endothelium / Q000187:drug effects*; D020287:In Situ Nick-End Labeling / Q000379:methods; D015227:Lipid Peroxidation / Q000187:drug effects*; D008801:Mexiletine / Q000627:therapeutic use*; D011817:Rabbits; D011897:Random Allocation; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; D008801:Mexiletine