Investigating a novel antioxidant approach to the treatment of tardive dyskinesia / Charise Joubert
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Extrapyramidal side effects are the most frequently experienced side effects associated with neuroleptic drug use, while tardive dyskinesia (TD) remains one of the most debilitating of these side-effects, TD is a serious motor disorder, especially of the orofacial region, caused by prolonged treatment with neuroleptic drugs. Various hypotheses exist to explain this severely disfiguring syndrome but the precise pathology remains unclear. in recent years, a growing body of evidence has been mounting in support of the free radical hypothesis. The striatum, the brain region associated with regulation and control of movement, is highly susceptible to oxidative stress, primarily because of the oxidative metabolism of dopamine in striatal neurons. Indeed, increased oxidative stress in the striatum has been implicated in various neurological disorders of movement including TD. There is currently no pharmacological treatment that has been found to be universally effective in the treatment of TD in clinical practice, although antioxidants have been purported to have possible therapeutic value in the treatment of the disorder. N-acetytcysteine (NAC) is an antioxidant and effective free radical scavenger, and is also able to increase the intracellular cysteine concentrations in order to maintain glutathione (GSH) synthesis. With regard to conditions in which oxidative stress and free radicals are implicated, two therapeutic strategies, utilizing antioxidants may be considered: Preventative: In this strategy patients are healthy and oxidative stress and free radicals are not abnormally increased. Healthy patients are supplemented with antioxidants in order to prevent the induction of oxidative stress that may occur later through some or other process. This can be related to the daily taking of vitamins by healthy individuals. Therapeutic: In this strategy anti-oxidants are utilized as treatment options. In these cases, oxidative stress has already been induced and antioxidant therapy is employed in order to minimize the effect of oxidative stress and possibly even reverse these effects. In the current study both of these strategies were examined. The purpose of the current study was, firstly, to establish a valid animal model of TD, followed by the evaluation of the behavioural and neurochemical effects of chronic NAC administration at various doses in a nonpathological state, i.e. in healthy rats, and, lastly, to assess the behavioural and neurochemical effects of various doses of NAC in rats also receiving chronic haloperidol treatment (TD model). The treatment of the rats with haloperidol was exploited as an in vivo animal model of striatal oxidative stress since numerous studies have not only suggested that TD is a condition of overt oxidative stress in striatal regions of the brain, but also that haloperidol has been found to increase oxidative stress both in vivo and in vitro. In the validation phase of the study, rats were treated with either haloperidol (1.5 mg/kg/day) of vehicle. In the non-pathological state, rats received either vehicle or NAC at doses of 10 mg/day, 100 mg/day or 300 mg/day orally for 21 days. In the pathological study utilizing the previously established animal model of TD, rats received either haloperidol and NAC vehicles (control), haloperidol (1.5 mg/kg/day) and NAC vehicle (TD model), or haloperidol (1.5 mg/kg/day) in combination with either 10 mg/day, 100 mg/day or 300 mg/day doses of NAC for 21 days. Behaviour was assessed by counting the number of vacuous chewing movements (VCMs) on days 0, 7, 14, 17, 19 and 21 during a 2 minute rating session. On day 21, after the final behavioural evaluation, animals were sacrificed by decapitation, and striatal tissue were dissected out and fixed in liquid N2 for later utilization in the neurochemical assays, namely the measurement of the degree of lipid peroxidation, levels of superoxide and the determination of oxidized versus reduced glutathione (GSSG:GSH). In the TD model, haloperidol treatment induced significant increases in VCMs, superoxide radicals and lipid peroxidation, supporting the hypothesis that TD and chronic neuroleptic administration is associated with increased free radical production and subsequent cell damage. However, haloperidol had no effect on the GSSG:GSH ratio. The current study demonstrated that in a non-pathological state 10 mg/day and 100mgIday NAC doses had no effect on either behaviour or neurochemical markers of oxidative stress. In contrast, at a dose of 300 mg/day, NAC induced a significant increase in the number of VCMs compared to control. This increase in VCMs, while initially increasing, showed a decrease with time, suggesting that these abnormal movements may only be temporary. At a dose of 300 mg/day, NAC also caused a significant increase in superoxide radicals in the striatum of the animals, indicating that NAC may act as a pro-oxidant at these doses by increasing free radicals such as superoxide. However, this increase in superoxide radicals was associated with a decrease in lipid peroxidation, and it is proposed that the increase in superoxide radicals may induce certain adaptive processes which may protect against excessive oxidative stress and damage and may also explain the reduction in VCMs seen in the last week of treatment. In the animal model of TD, only 100 mg/day NAC dose was able to significantly decrease VCMs when compared to the haloperidol group. However, all of the doses were able to significant reduce superoxide radicals which were induced by haloperidol administration. Only the 100 mg/day and 300 mg/day NAC doses were able to effect a decrease in lipid peroxidation levels comparable to basal values, while this decrease was also associated with an increase in the GSSG:GSH ratio that could possibly indicate that reduced glutathione was consumed through its scavenging effects on superoxide (and possibly other free radicals as well) and converted to oxidized glutathione and in this way mediating the decrease in lipid peroxidation. The results of the current study is thus in support of the free radical hypothesis of TD and indicates that NAC may have potential in protecting against hatoperidol-induced motor abnormalities. High doses of NAC were able to protect against lipid peroxidation, although the negative effect that high doses NAC exert on motor behaviour warrants further investigation to explore whether these behavioural deficits are only temporary or more permanent in character. The data also support the hypothesis that antioxidants may become pro-oxidative under certain circumstances, which may be dependant on the redox environment of the biological system in which it is administered or put another way, whether the organism is in a state of oxidative stress or not.
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