allopurinol and Astrocytoma

Methylmercury (MeHg) is a global pollutant that is affecting the health of millions of people worldwide. However, the mechanism of MeHg toxicity still remains somewhat elusive and there is no treatment. It has been known for some time that MeHg can be progressively converted to inorganic mercury (iHg) in various tissues including the brain. Recent work has suggested that cleavage of the carbon-metal bond in MeHg in a biological environment is facilitated by reactive oxygen species (ROS). However, the oxyradical species that actually mediates this process has not been identified. Here, we provide evidence that superoxide anion radical (O2(-)) can convert MeHg to iHg. The calculated second-order rate constant for the degradation of 1μM MeHg by O2(-) generated by xanthine/xanthine oxidase was calculated to be 2×10(5)M(-1)s(-1). We were also able to show that this bioconversion can proceed in intact CCF-STTG1 human astrocytoma cells exposed to paraquat (PQ), a O2(-) generating viologen. Notably, exposure of cells to increasing amounts of PQ led to a dose dependent increase in both MeHg and iHg. Indeed, a 24h exposure to 500μM PQ induced a ∼13-fold and ∼18-fold increase in intracellular MeHg and iHg respectively. These effects were inhibited by superoxide dismutase mimetic MnTBAP. In addition, we also observed that a 24h exposure to a biologically relevant concentration of MeHg (1μM) did not induce cell death, oxidative stress, or even changes in cellular O2(-) and H2O2. However, co-exposure to PQ enhanced MeHg toxicity which was associated with a robust increase in cell death and oxidative stress. Collectively our results show that O2(-) can bioconvert MeHg to iHg in vitro and in intact cells exposed to conditions that simulate high intracellular O2(-) production. In addition, we show for the first time that O2(-) mediated degradation of MeHg to iHg enhances the toxicity of MeHg by facilitating an accumulation of both MeHg and iHg in the intracellular environment.

Topics: Astrocytoma; Cell Death; Cell Line, Tumor; Central Nervous System Neoplasms; Humans; Hydrogen Peroxide; Mercury; Methylmercury Compounds; Oxidative Stress; Paraquat; Reactive Oxygen Species; Superoxide Dismutase; Superoxides; Xanthine; Xanthine Oxidase

Topics: Allopurinol; Antineoplastic Combined Chemotherapy Protocols; Astrocytoma; Biopsy, Needle; Brain Neoplasms; Cyclophosphamide; Epirubicin; Fluorouracil; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Palliative Care; Parotid Neoplasms

The impairment of the purinergic system, characterized by reduced adenosinergic activity, has been implicated in the neurobiology of aggressive behaviour. Since there are no direct adenosine agonists available for human use, inhibition of purine degradation by allopurinol was conceived as a possible strategy. We report two cases of adults with refractory aggressive behaviour due to a neurological condition (one mainly with self-inflicted behaviour) with dramatic response to therapy with allopurinol, 300 mg/day p.o. These preliminary results reinforce the involvement of the purinergic system in the neurobiology of aggression, warranting further testing of allopurinol as a new treatment for aggressive and self-inflicted behaviours.

Topics: Administration, Oral; Adult; Aggression; Allopurinol; Astrocytoma; Brain Neoplasms; Combined Modality Therapy; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Humans; Intellectual Disability; Male; Meningitis; Neurocognitive Disorders; Parietal Lobe; Postoperative Complications; Radiotherapy, Adjuvant; Self-Injurious Behavior

Xanthine oxidase is most recognized for its role as the rate-limiting enzyme in nucleic acid degradation through which all purines are channelled for terminal oxidation. The enzyme serves as a source of oxygen-derived free radicals which induce both cellular injury and edema as well as changes in vascular permeability. In the study we compared xanthine oxidase levels of human brain tumors with normal brain tissues. Statistical evaluation of our results shows significantly higher xanthine oxidase levels in tumoral brain tissues. However, xanthine oxidase has not any significance for the differentiation of tumor types among each others. The oncotypes studied were meningioma and astrocytoma.

Topics: Astrocytoma; Brain; Brain Neoplasms; Humans; Meningeal Neoplasms; Meningioma; Xanthine Oxidase