Nitric Oxide, Superoxide, and Hydrogen Peroxide Production in Brain Mitochondria after Haloperidol Treatment

Arnaiz, Silvia Lores; Coronel, Marı́a Florencia; Boveris, Alberto

doi:10.1006/niox.1999.0229

Cited by 108 publications

(59 citation statements)

References 27 publications

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“…It is known that impairment of respiratory chain in mitochondria leads to free radicals production. If oxidative stress occurs, oxidative damage to proteins, lipids and DNA may be present [25,34,35]. These data support the hypothesis that antipsychotics may cause oxidative stress that damage proteins/enzymes involved in mitochondrial metabolism.…”

Section: Discussionsupporting

confidence: 69%

Effect of Antipsychotics on Creatine Kinase Activity in Rat Brain

Assis¹,

Scaini²,

Di-Pietro³

et al. 2007

Basic Clin Pharma Tox

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Typical and atypical antipsychotic drugs have different clinical and behavioural profiles. It is well described that inhibition of creatine kinase activity has been implicated in the pathogenesis of a number of diseases, especially in the brain. In this work, we evaluate the effect of haloperidol, clozapine, olanzapine or aripiprazole chronic administration on creatine kinase activity in brain of rats. Adult male Wistar rats received daily injections of haloperidol (1.5 mg/kg), clozapine (25 mg/kg), olanzapine (2.5, 5 or 10 mg/kg) or aripiprazole (2, 10 or 20 mg/kg). Our results demonstrate that haloperidol did not affect the enzyme activity in brain of rats. Clozapine inhibited the enzyme activity only in cerebellum and prefrontal cortex of rats. Aripiprazole did not affect creatine kinase in hippocampus, cerebellum and prefrontal cortex. The administration of 2.0 mg/kg aripiprazole did not alter creatine kinase activity, but 10.0 and 20.0 mg/kg aripiprazole activated the enzyme in striatum and cerebral cortex. Finally, the higher dose of olanzapine (10.0 mg/kg) activated the enzyme in striatum of rats. In hippocampus and cerebral cortex, we could not verify any effect of olanzapine on creatine kinase activity. The inhibitory effect of clozapine and olanzapine on creatine kinase activity in cerebellum and prefrontal cortex suggest that these drugs may impair energy metabolism in these brain areas.Creatine kinase (EC 2.7.3.2) is a crucial enzyme for high energy-consuming tissues like brain, skeletal muscle and heart. This enzyme works as a buffering system of cellular ATP levels, playing a central role in energy metabolism. Creatine kinase catalyses the reversible transfer of the phosphoryl group from phosphocreatine to ADP, regenerating ATP [1][2][3]. It is also known that a decrease in creatine kinase activity is associated with neurodegenerative pathways that result in neuronal death in brain ischaemia [4], neurodegenerative diseases [5,6], bipolar disorder [7] and other pathological states [8,9].Brain and other high energy tissues are more susceptible to reduction of energy metabolism. In this context, neuropsychiatry disorders, such as schizophrenia, depression and bipolar disorder, have been related to dysfunction in brain metabolism [10,11]. The metabolism dysfunction includes mitochondrial impairment [12,13], increase in reactive oxygen species production and expression of biochemical markers of cellular degeneration [14 -16].The therapeutic efficacy of antipsychotic drugs is generally believed to be due to their ability to block central dopamine D 2 receptor [17,18]. The older generation of antipsychotics, known as typical antipsychotics, showed great promise to control acute positive symptomatology and the induction of extrapyramidal side effects, which often lead to persistent tardive dyskinesia and termination of treatment, limiting the long-term use of these agents. In addition, the long-term use of typical antipsychotics was often found to be associated with increased core negative sympto...

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Section: Discussionsupporting

confidence: 69%

Effect of Antipsychotics on Creatine Kinase Activity in Rat Brain

Assis¹,

Scaini²,

Di-Pietro³

et al. 2007

Basic Clin Pharma Tox

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show abstract

“…Control experiments adding 1 mM NG-methyl--arginine (-NMMA) were performed to confirm that hemoglobin oxidation occurred only by NO formation. Addition of -NMMA inhibited the rate of hemoglobin oxidation by 90% (Arnaiz et al 1999).…”

Section: Detection Of Nitric Oxide (No): Total Nitrite and Oxidation mentioning

confidence: 95%

Oxidative and nitrosative stress in brain mitochondria of diabetic rats

Mastrocola¹,

Restivo²,

Vercellinatto³

et al. 2005

Journal of Endocrinology

244

123

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Diabetic encephalopathy, characterized by impaired cognitive functions and neurochemical and structural abnormalities, may involve direct neuronal damage caused by intracellular glucose. The study assesses the direct effect of chronic hyperglycemia on the function of brain mitochondria, the major site of reactive species production, in diabetic streptozotocin (STZ) rats. Oxidative stress plays a central role in diabetic tissue damage. Alongside enhanced reactive oxygen species (ROS) levels, both nitric oxide (NO) levels and mitochondrial nitric oxide synthase expression were found to be increased in mitochondria, whereas glutathione (GSH) peroxidase activity and manganese superoxide dismutase protein content were reduced. GSH was reduced and GSH disulfide (GSSG) was increased in STZ rats. Oxidative and nitrosative stress, by reducing the activity of complexes III, IV and V of the respiratory chain and decreasing ATP levels, might contribute to mitochondrial dysfunction. In summary, this study offers fresh evidence that, besides the vasculardependent mechanisms of brain dysfunction, oxidative and nitrosative stress, by damaging brain mitochondria, may cause direct injury of neuronal cells.

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“…Despite these observations suggesting CLO's benefits, there have been several case reports of TD associated with CLO as well as other typical neuroleptics [43]. The inherent biochemical and physiological characteristics of the brain, with high unsaturated phospholipid content and energy requirement, make it particularly susceptible to free-radical-mediated damage [44]. We showed here that HAL treatment caused an increase in lipid peroxidation levels in the ST.…”

Section: Discussionmentioning

confidence: 49%

Effects of Chronic Haloperidol and/or Clozapine on Oxidative Stress Parameters in Rat Brain

et al. 2007

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Decreased antioxidant activity is considered as one of the causes of tardive dyskinesia in schizophrenic patients in a prolonged neuroleptic treatment course. Haloperidol (HAL) has been hypothesized to increase oxidative stress, while clozapine (CLO) would produce less oxidative damage. The objective was to determine whether CLO for 28 days could reverse or attenuate HAL-induced oxidative damage in animals previously treated with HAL for 28 days. HAL significantly increased thiobarbituric acid reactive substances levels in the cortex (CX) and striatum and increased protein carbonyls in hippocampus (HP) and CX and this was not attenuated by CLO treatment. In the total radical trapping antioxidant parameter assay there was a decrease in the HP total antioxidant potential induced by HAL and by treatment with HAL + CLO. Our findings demonstrated that the atypical antipsychotic CLO could not revert oxidative damage caused by HAL.

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Nitric Oxide, Superoxide, and Hydrogen Peroxide Production in Brain Mitochondria after Haloperidol Treatment

Cited by 108 publications

References 27 publications

Effect of Antipsychotics on Creatine Kinase Activity in Rat Brain

Effect of Antipsychotics on Creatine Kinase Activity in Rat Brain

Oxidative and nitrosative stress in brain mitochondria of diabetic rats

Effects of Chronic Haloperidol and/or Clozapine on Oxidative Stress Parameters in Rat Brain

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