A novel brain-targeted antioxidant (AD4) attenuates haloperidol-induced abnormal movement in rats: implications for tardive dyskinesia.
BACKGROUND
Tardive dyskinesia (TD), characterized by abnormal movements, is the major late-onset chronic side effect of antipsychotic treatment found in about 30% of those patients. The association of oxidative stress and the release of free radicals is one of the hallmarks of dopaminergic malfunctions and is one of the leading theories suggested for the pathophysiology of TD. To this day, no brain-targeted antioxidant has been tested as a potential treatment of TD. In light of this assumption, the authors chose a novel, low-molecular weight thiol antioxidant, N-acetyl cysteine amide (AD4), that crosses the blood-brain barrier as a possible treatment of TD.


OBJECTIVE
To examine the protective effects of the novel brain-penetrating antioxidant AD4 on TD experimental models.


METHODS
The typical vacuous chewing movement occurs in rats following chronic haloperidol injections (1.5 mg/kg/day intraperitoneally for 21 days). This purposeless mouth opening in the vertical plane is similar to TD symptoms in humans. The authors tested rats treated with haloperidol without or with AD4 in the drinking water (1 g/kg orally). Thiobarbituric acid reactive substances and anticarbonyl antibodies were used to measure oxidation of membranes and proteins.


RESULTS
Haloperidol increased the vacuous chewing movements to 66.5 +/- 7.6 movements/5 minutes compared with 16.4 +/- 2.4 movements/5 minutes in untreated rats (P < 0.01). Coadministration of haloperidol and AD4 decreased the vacuous chewing movements level to 42.1 +/- 6.7 movements/5 minutes (P < 0.05). Haloperidol also increased the level of lipid peroxidation and protein oxidation in the rat brain, whereas coadministration with AD4 preserved their normal levels.


CONCLUSIONS
Haloperidol causes behavioral abnormalities associated with oxidative stress in rats, similar to TD. AD4, the brain-targeted potent antioxidant, reduces the cellular oxidation markers and improves the typical clinical behavior. Hence, AD4 is a potential new treatment of antipsychotic-induced TD.
Sadan
Ofer
O
Department of Neurology and Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, 49100 Israel.
Bahat-Stromza
Merav
M
Gilgun-Sherki
Yossi
Y
Atlas
Daphne
D
Melamed
Eldad
E
Offen
Daniel
D
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D004195:Disease Models, Animal; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000209:etiology; D020820:Dyskinesias / Q000188:drug therapy* / Q000209:etiology; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D006220:Haloperidol; D015227:Lipid Peroxidation / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D000975:Antioxidants; D017392:Thiobarbituric Acid Reactive Substances; C487056:N-Acetylcysteinamide; D006220:Haloperidol; D000111:Acetylcysteine