Alteration of the pro-oxidant xanthine oxidase (XO) in the thalamus and occipital cortex of patients with schizophrenia.

OBJECTIVES: Mounting evidence shows that oxidative stress (OS) and the purine/adenosine system play a key role in the pathophysiology of schizophrenia. Lately, our group pointed out that not only antioxidants, but also the prooxidant system plays an important role in neuro-psychiatric disorders. Xanthine oxidase (XO) is an enzyme of special interest in this context, since it acts as a prooxidant, but its main product is a vastly important antioxidant, uric acid (UA). Furthermore, XO plays major part in the purine/adenosine metabolism, which has been hypothesised to play a role in schizophrenia as well. METHODS: We examined the activity of XO in the striato-cortico-limbic system of schizophrenic patients (SP) and controls using a commercially available activity assay. RESULTS: We found decreased activity of XO in the occipital cortex and thalamus of patients with psychosis. Furthermore, XO shows a significant positive correlation with chlorpromazine equivalents in the putamen and the temporal cortex. CONCLUSIONS: Nevertheless, our results might suggest a downregulation of cellular defence mechanisms in schizophrenia in several brain regions, which could account for neuronal alterations which have been described before. This demonstrates that more research is needed to fully understand the role of the complex enzyme XO in the pathophysiology of schizophrenia.

Increased xanthine oxidase in the thalamus and putamen in depression.

A growing body of literature suggests persistent and selective structural changes in the cortico-limbic-thalamic-striatal system in patients with recurrent depressive disorder (DD). Oxidative stress is thought to play a key role in these processes. So far, the main scientific focus has been on antioxidant enzymes in this context. For the first time, this proof of concept study examines the activity of the free radicals producing the enzyme, xanthine oxidase (XO), directly in the cortico-limbic-thalamic-striatal system of patients with recurrent depression. The activity of XO was ascertained in the cortico-limbic-thalamic-striatal regions in post-mortem brain tissue of patients with recurrent depressive episodes and individuals without any neurological or psychiatric history (7/7). We measured the XO activity in following brain areas: hippocampus, regio entorhinalis, thalamus, putamen and caudate nucleus. In this study, we report a significant increase of XO activity in the thalamus and the putamen of patients with depression. Our findings contribute to the growing body of evidence suggesting that oxidative stress plays a pivotal role in certain brain areas in recurrent depressive disorder.

Effects of methylphenidate: the cellular point of view.

The psychostimulant methylphenidate (MPH) is the first choice of treatment in attention-deficit hyperactivity disorder and is based mainly on inhibition of dopamine transporter (DAT). Nonetheless, the complete cellular effects of MPH are still unknown. We attempted to determine whether MPH influences neurotransmitter levels, synaptic gene expression, and cell proliferation in a dose-dependent manner in rat pheochromocytoma cells (PC12) lacking DAT. PC12 were treated in a dose-dependent manner with MPH. Gene expression level of synaptotagmin (Syt) 1 and 4, syntaxin 1a (Stx1a), and synaptic vesicle glycoprotein 2C (SV2C) was measured using quantitative real-time RT-PCR. Different Neurotransmitter release was measured using high-performance liquid chromatography (HPLC). Differences in cell proliferation were evaluated via BrdU incorporation. Treatment with low-dose MPH (1-100 nM) altered intra-/extracellular neurotransmitter levels, down-regulated all investigated genes as well as enhanced cell proliferation significantly. These data point to diverse effects of MPH on cell metabolism independent of inhibiting DAT.

Neuroprotective strategies in Parkinson's disease : an update on progress.

In spite of the extensive studies performed on postmortem substantia nigra from Parkinson's disease patients, the aetiology of the disease has not yet been established. Nevertheless, these studies have demonstrated that, at the time of death, a cascade of events had been initiated that may contribute to the demise of the melanin-containing nigro-striatal dopamine neurons. These events include increased levels of iron and monoamine oxidase (MAO)-B activity, oxidative stress, inflammatory processes, glutamatergic excitotoxicity, nitric oxide synthesis, abnormal protein folding and aggregation, reduced expression of trophic factors, depletion of endogenous antioxidants such as reduced glutathione, and altered calcium homeostasis. To a large extent, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) animal models of Parkinson's disease confirm these findings. Furthermore, neuroprotection can be afforded in these models with iron chelators, radical scavenger antioxidants, MAO-B inhibitors, glutamate antagonists, nitric oxide synthase inhibitors, calcium channel antagonists and trophic factors. Despite the success obtained with animal models, clinical neuroprotection is much more difficult to accomplish. Although the negative studies obtained with the MAO-B inhibitor selegiline (deprenyl) and the antioxidant tocopherol (vitamin E) may have resulted from an inappropriate choice of drug (selegiline) or an inadequate dose (tocopherol), the niggling problem that still remains is why these drugs, and others, do work in animals while they fail in the clinic. One reason for this may be related to the fact that in normal human brains the number of dopaminergic neurons falls by around 3-5% every decade, while in Parkinson's disease this decline is greater. Brain autopsy studies have shown that by the time the disease is identified, some 70-75% of the dopamine-containing neurons have been lost. More sensitive reliable methods and clinical correlative markers are required to discern between confoundable symptomatic effects versus a possible neuroprotective action of drugs, namely, the ability to delay or forestall disease progression by protecting or rescuing the remaining dopamine neurons or even restoring those that have been lost.A number of other possibilities for the clinical failure of potential neuroprotectants also exist. First, the animal models of Parkinson's disease may not be totally reflective of the disease and, therefore, the chemical pathologies established in the animal models may not cause, or contribute to, the progression of the disease clinically. Second, because of the series of events occurring in neurodegeneration and our ignorance about which of these factors constitutes the primary event in the pathogenic process, a single drug may not be adequate to induce neuroprotection and, as a consequence, use of a cocktail of drugs may be more appropriate. The latter concept receives support from recent complementary DNA (cDNA) microarray gene expression studies, which show the existence of a gene cascade of events occurring in the nigrostriatal pathway of MPTP, 6-OHDA and methamphetamine animal models of Parkinson's disease. Even with the advent of powerful new tools such as genomics, proteomics, brain imaging, gene replacement therapy and knockout animal models, the desired end result of neuroprotection is still beyond our current capability.