Translocator Protein Ligand Protects against Neurodegeneration in the MPTP Mouse Model of Parkinsonism.

Parkinson's disease is the second most common neurodegenerative disease, after Alzheimer's disease. Parkinson's disease is a movement disorder with characteristic motor features that arise due to the loss of dopaminergic neurons from the substantia nigra. Although symptomatic treatment by the dopamine precursor levodopa and dopamine agonists can improve motor symptoms, no disease-modifying therapy exists yet. Here, we show that Emapunil (AC-5216, XBD-173), a synthetic ligand of the translocator protein 18, ameliorates degeneration of dopaminergic neurons, preserves striatal dopamine metabolism, and prevents motor dysfunction in female mice treated with the MPTP, as a model of parkinsonism. We found that Emapunil modulates the inositol requiring kinase 1α (IRE α)/X-box binding protein 1 (XBP1) unfolded protein response pathway and induces a shift from pro-inflammatory toward anti-inflammatory microglia activation. Previously, Emapunil was shown to cross the blood-brain barrier and to be safe and well tolerated in a Phase II clinical trial. Therefore, our data suggest that Emapunil may be a promising approach in the treatment of Parkinson's disease.SIGNIFICANCE STATEMENT Our study reveals a beneficial effect of Emapunil on dopaminergic neuron survival, dopamine metabolism, and motor phenotype in the MPTP mouse model of parkinsonism. In addition, our work uncovers molecular networks which mediate neuroprotective effects of Emapunil, including microglial activation state and unfolded protein response pathways. These findings not only contribute to our understanding of biological mechanisms of translocator protein 18 (TSPO) function but also indicate that translocator protein 18 may be a promising therapeutic target. We thus propose to further validate Emapunil in other Parkinson's disease mouse models and subsequently in clinical trials to treat Parkinson's disease.

[Nephrolithiasis in patients with intestinal diseases]. / La nefrolitiasi nelle malattie intestinali.

Intestinal diseases may cause the formation of urinary stones through changes in the metabolism of oxalate, calcium, and uric acid. The oxalate that is excreted into urine comes from the catabolism of ascorbic acid and some amino acids or from intestinal absorption of food oxalate. Calcium is absorbed by the gut after the stimulation of active vitamin D and is excreted by the kidney under the control of the bone/parathyroid hormone axis. Uric acid is generated by the oxidation of exogenous and endogenous purine bases, is excreted by the kidney through glomerular filtration/tubular secretion, and is soluble in alkaline urine. Several data indicate that patients with inflammatory bowel diseases are at high risk of urinary stones containing calcium-oxalate salt or uric acid. Calcium-oxalate stones are caused by colonic oxalate hyperabsorption (secondary to intestinal dysfunction) or by parenteral nutrition. Uric acid stones are typical of patients with severe diarrhea and/or intestinal neostomy, that is, in patients with hyperconcentrated acidic urine. Relationships between malabsorptive intestinal diseases and urinary stones are less well defined. Preventive countermeasures are not the same for all disorders. Hyperoxaluria should be controlled by diets with a low content of lipids and oxalate but supplemented with calcium and probiotics. The presence of hyperconcentrated acidic urine should be controlled by correct hydration and administration of citrate.

Uric acid: role in cardiovascular disease and effects of losartan.

A substantial body of epidemiological and experimental evidence suggests that serum uric acid is an important, independent risk factor for cardiovascular and renal disease especially in patients with hypertension, heart failure, or diabetes. Elevated serum uric acid is highly predictive of mortality in patients with heart failure or coronary artery disease and of cardiovascular events in patients with diabetes. Further, patients with hypertension and hyperuricemia have a 3- to 5-fold increased risk of experiencing coronary artery disease or cerebrovascular disease compared with patients with normal uric acid levels. Although the mechanisms by which uric acid may play a pathogenetic role in cardiovascular disease is unclear, hyperuricemia is associated with deleterious effects on endothelial dysfunction, oxidative metabolism, platelet adhesiveness, hemorheology, and aggregation. Xanthine oxidase inhibitors (e.g., allopurinol) or a variety of uricosuric agents (e.g., probenecid, sulfinpyrazone, benzbromarone, and benziodarone) can lower elevated uric acid levels but it is unknown whether these agents reversibly impact cardiovascular outcomes. However, the findings of the recent LIFE study in patients with hypertension and left ventricular hypertrophy suggest the possibility that a treatment-induced decrease in serum uric acid may indeed attenuate cardiovascular risk. LIFE showed that approximately 29% (14% to 107%, p = 0.004) of the treatment benefit of a losartan-based versus atenolol-based therapy on the primary composite endpoint (death, myocardial infarction, or stroke) may be ascribed to differences in achieved serum uric acid levels. Overall, serum uric acid may be a powerful tool to help stratify risk for cardiovascular disease. At the very least, it should be carefully considered when evaluating overall cardiovascular risk.

Oncologic emergencies I. Metabolic and space-occupying consequences of cancer and cancer treatment.

Proper management of the consequences of cancer and cancer treatment is necessary to give affected children the increased chances of survival that recent therapeutic advances offer them. This article discusses the pathophysiology, diagnosis, and management of those metabolic and space-occupying consequences that are likely to face the primary care physician.

The role of thiopurine metabolites in inflammatory bowel disease and rheumatological disorders.

Thiopurines have been a cornerstone of medical management of patients with inflammatory bowel disease(IBD) and many rheumatological disorders. The thiopurines are metabolized to their end products, 6-methymercaptopurine (6MMP) and the 6-thioguanine nucleotides (6TGN), with 6TGN being responsible for thiopurine efficacy by causing apoptosis and preventing activation and proliferation of T-lymphocytes. In IBD, conventional weight-based dosing with thiopurines leads to an inadequate response in many patients. Utilizing measurement of these metabolites and then employing dose optimization strategies has led to markedly improved outcomes in IBD. Switching between thiopurines as well as the addition of low-dose allopurinol can overcome adverse events and elevate 6TGN levels into the therapeutic window. There is a paucity of data on thiopurine metabolites in rheumatological diseases and further research is required.

Pathophysiological roles for purines: adenosine, caffeine and urate.

The motor symptoms of Parkinson's disease (PD) are primarily due to the degeneration of the dopaminergic neurons in the nigrostriatal pathway. However, several other brain areas and neurotransmitters other than dopamine such as noradrenaline, 5-hydroxytryptamine and acetylcholine are affected in the disease. Moreover, adenosine because of the extensive interaction of its receptors with the dopaminergic system has been implicated in the pathophysiology of the disease. Based on the involvement of these non-dopaminergic neurotransmitters in PD and the sometimes severe adverse effects that limit the mainstay use of dopamine-based anti-parkinsonian treatments, recent assessments have called for a broadening of therapeutic options beyond the traditional dopaminergic drug arsenal. In this review we describe the interactions between dopamine and adenosine receptors that underpin the pre-clinical and clinical rationale for pursuing adenosine A(2A) receptor antagonists as symptomatic and potentially neuroprotective treatment of PD. The review will pay particular attention to recent results regarding specific A(2A) receptor-receptor interactions and recent findings identifying urate, the end product of purine metabolism, as a novel prognostic biomarker and candidate neuroprotectant in PD.

[Prevention and therapy of disorders of purine metabolism]. / Prophylaxe und Therapie der Störungen des Purinstoffwechsels.

To the most important prophylactic measures for the prevention of a disturbance of the purine metabolism belong the normalisation of the body-weight, a mixed diet without protein carriers containing much purine, a regular physical activity, a life without hectic conditions as well as without an excess of conflict situations and a moderate taking of alcohol. These recommendations are of particular importance for patients endangered by gout. In patients with hyperuricaemia they form the basic treatment for the prevention of a uric arthritis, a urate nephrolithiasis and a gouty nephropathy. The clinical and paraclinical results of the directives must be continuously tested with regard to the effectiveness. To the comprehensive prophylaxis also belong the preventive measures against an associated disturbance of an associated disturbance of metabolism or concomitant disease. An additional medicamentous therapy is necessary, when the success of the basic therapy is insufficient and there are already organ manifestations of a disturbance of the purine metabolism. The application of antihyperuraemic drugs corresponding to types should be performed by uricostatic drugs, uricosuric drugs and citric acid-citrate mixtures. The approach according to a 3-step-programme is most useful. In the treatment of the concomitant diseases certain preventive measures are to be taken into consideration. The therapy of an acute attack of gout is at present without any essential problems. Patients with disturbances of the purine metabolism need a permanent care by the physician.