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A novel brain-targeted antioxidant (AD4) attenuates haloperidol-induced abnormal movement in rats: implications for
Ofer Sadan1, Merav Bahat-Stromza, Yossi Gilgun-Sherki
1Department of Neurology and Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, 49100 Israel.
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.
Conclusion:
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.
Insights
N-acetyl cysteine amide (AD4), a novel antioxidant, shows promise in treating tardive dyskinesia (TD) by reducing oxidative stress and abnormal movements in rat models. This brain-penetrant compound may offer a new therapeutic avenue for antipsychotic-induced TD.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Tardive dyskinesia (TD) is a significant side effect of antipsychotic medications, affecting approximately 30% of patients.
- Oxidative stress and free radical release are implicated in the pathophysiology of TD.
- Currently, no brain-targeted antioxidants have been investigated for TD treatment.
Purpose of the Study:
- To evaluate the neuroprotective effects of N-acetyl cysteine amide (AD4), a novel brain-penetrating antioxidant, in experimental models of TD.
- To assess AD4's potential as a therapeutic agent for TD.
Main Methods:
- Rats were administered haloperidol to induce vacuous chewing movements, a behavioral model for TD.
- AD4 was administered orally to rats treated with haloperidol.
- Oxidative stress markers, including thiobarbituric acid reactive substances and anticarbonyl antibodies, were measured in brain tissue.
Main Results:
- Haloperidol significantly increased vacuous chewing movements and markers of lipid peroxidation and protein oxidation in rat brains.
- Co-administration of AD4 with haloperidol notably reduced vacuous chewing movements.
- AD4 treatment preserved normal levels of oxidative stress markers in the brain.
Conclusions:
- Haloperidol induces behavioral changes and oxidative stress in rats, mirroring human TD symptoms.
- AD4, a potent brain-targeted antioxidant, effectively reduces cellular oxidation and improves behavioral abnormalities.
- AD4 represents a promising novel therapeutic candidate for antipsychotic-induced TD.
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