A randomized, double-blind, placebo controlled trial of melatonin add-on therapy in epileptic children on valproate monotherapy: effect on glutathione peroxidase and glutathione reductase enzymes.
OBJECTIVE
To compare the effect of add-on melatonin with placebo on the antioxidant enzymes (glutathione peroxidase and glutathione reductase) in epileptic children on valproate monotherapy.


METHODS
In a double-blind, randomized, placebo controlled trial, the effect of add-on melatonin administration on the antioxidant enzymes in epileptic children on valproate (VPA) monotherapy was assessed. A total of 31 patients met the entry criteria. 16 patients were randomly allocated to receive add-on melatonin, and 15 to receive add-on placebo. Blood samples (5 ml) were collected just before the morning dose of valproate for baseline values of glutathione peroxidase and glutathione reductase enzymes, and then after 14 days of add-on melatonin/placebo. Blood was then centrifuged at 3500 r.p.m., serum separated and stored in deep freezer at -20 degrees C until assay of glutathione reductase. Heparinized blood was collected and stored at -20 degrees C in eppendorfs in the deep freezer for assay of glutathione peroxidase. All activity assays were performed on the Ames (Technicon) RA 50 chemistry analyser.


RESULTS
Fifteen patients in the add-on melatonin group and 14 patients in the add-on placebo group were finally assessed. There was an increase in the activity of antioxidant enzymes, glutathione peroxidase (GSH-Px) and glutathione reductase (GSSG-Rd), in the add-on melatonin (MEL) group as compared with a reduction in the same in the add-on placebo group (P). After the addition of melatonin/placebo in the respective groups, there was a 7.5% decrease in GSH-Px in the valproate + placebo group, whereas a 11.9% increase in the valproate + melatonin group was observed, the difference between the groups being not statistically significant (P = 0.29). On administration of melatonin/placebo, the post-treatment concentrations of GSSG-Rd in the valproate + placebo group decreased from 92.0 U l(-1) to 67.0 U l(-1) and increased from 82.0 U l(-1) to 113.0 U l(-1), in the valproate + melatonin group, respectively, the difference between them being statistically significant (P = 0.05). The percentage change in the values of GSSG-Rd in the two groups was statistically significant (P = 0.005).


CONCLUSIONS
Melatonin exerts neuroprotection due to its antioxidant, antiexcitotoxic and free radical scavenging properties within the central nervous system. Melatonin, thus, as an adjunct, can be a putative neuroprotector in conditions involving oxidative stress like epilepsies.
Gupta
Madhur
M
Department of Pharmacology, Lady Hardinge Medical College and associated hospitals, New Delhi, India. madhurgupta@hotmail.com
Gupta
Yogendra Kumar
YK
Agarwal
Sarita
S
Aneja
Satinder
S
Kohli
Kamlesh
K
D000927:Anticonvulsants / Q000627:therapeutic use*; D000975:Antioxidants / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000188:drug therapy* / Q000201:enzymology; D005260:Female; D005979:Glutathione Peroxidase / Q000378:metabolism*; D005980:Glutathione Reductase / Q000378:metabolism*; D006801:Humans; D008297:Male; D008550:Melatonin / Q000627:therapeutic use*; D014635:Valproic Acid / Q000627:therapeutic use*
D000927:Anticonvulsants; D000975:Antioxidants; D014635:Valproic Acid; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D008550:Melatonin