No abstract

Copper is a transition metal that has been linked to pathological and beneficial effects in neurodegenerative diseases. In Parkinson's disease, free copper is related to increased oxidative stress, alpha-synuclein oligomerization, and Lewy body formation. Decreased copper along with increased iron has been found in substantia nigra and caudate nucleus of Parkinson's disease patients. Copper influences iron content in the brain through ferroxidase ceruloplasmin activity; therefore decreased protein-bound copper in brain may enhance iron accumulation and the associated oxidative stress. The function of other copper-binding proteins such as Cu/Zn-SOD and metallothioneins is also beneficial to prevent neurodegeneration. Copper may regulate neurotransmission since it is released after neuronal stimulus and the metal is able to modulate the function of NMDA and GABA A receptors. Some of the proteins involved in copper transport are the transporters CTR1, ATP7A, and ATP7B and the chaperone ATOX1. There is limited information about the role of those biomolecules in the pathophysiology of Parkinson's disease; for instance, it is known that CTR1 is decreased in substantia nigra pars compacta in Parkinson's disease and that a mutation in ATP7B could be associated with Parkinson's disease. Regarding copper-related therapies, copper supplementation can represent a plausible alternative, while copper chelation may even aggravate the pathology.

PurposeThe aim of present study is to measure plasma clozapine (CLZ) and N-desmethyl clozapine (DMC) as biomarkers to correlate drug concentrations with the appearance of preclinical adverse hematic effects.MethodsA high-performance liquid chromatographic method, using a diode-array (ultraviolet) detector, was validated to obtain reliable concentrations of CLZ and DMC, its main metabolite, in plasma of 41 schizophrenic patients taking CLZ. Blood neutrophils and leucocytes counting were concurrently assessed as a proxy to subclinical adverse reactions.ResultsThe analytical method employed was linear, reproducible, and stable to measure concentrations of CLZ between 30 and 1000 ng/mL, while 12.5–560 ng/mL of the metabolite. The method allowed us to correlate CLZ plasma concentrations, the time taking CLZ and CLZ dose as determinants of neutrophils’ counting with a R2 = 0.447, using a multiple regression analysis model. Likewise, the correlation of leucocyte counting vs CLZ plasma levels and CLZ time, showed a R2 = 0.461. DMC correlated significantly with both neutrophils and leucocytes counting, but was excluded from the regression when CLZ concentration was included in the model. Finally, no other hematological adverse reactions were recorded. One patient presented a cardiovascular complication. The negative correlation between clozapine and neutrophil count observed in patients, suggest that CLZ itself, but not DMC, could be related to hematologic side-effects.ConclusionThe findings of this study, demonstrate for the first time, that plasma levels of CLZ and time taking the drug are independent determinants of blood neutrophils and leucocytes, so the monitoring of plasma CLZ may be useful in the clinic practice to determine safe dosing of the drug.

We found that clay pots, jars, and mugs leached on average 200 µg/l lead, and exposure to the lemonade resulted in 2.5 µg/dl of lead in the pregnant rats' blood. Neonates also showed increased lead content in the hippocampus and cerebellum. Caspase-3 activity was found to be statistically increased in the hippocampus in prenatally exposed neonates, suggesting increased apoptosis in that brain region. Glazed ceramics are still an important source of lead exposure in Mexico, and our results confirm that pregnancy is a vulnerable period for brain development.

Essential fatty acids have an important effect on oxidative stress-related diseases. The Huntington's disease (HD) is a hereditary neurologic disorder in which oxidative stress caused by free radicals is an important damage mechanism. The HD experimental model induced by quinolinic acid (QUIN) has been widely used to evaluate therapeutic effects of antioxidant compounds. The aim of this study was to test whether the fatty acid content in olive- or fish-oil-rich diet prevents against QUIN-related oxidative damage in rats. Rats were fed during 20 days with an olive- or a fish-oil-rich diet (15% w/w). Posterior to diet period, rats were striatally microinjected with QUIN (240 nmol/µl) or saline solution. Then, we evaluated the neurological damage, oxidative status, and gamma isoform of the peroxisome proliferator-activated receptor (PPARγ) expression. Results showed that fatty acid-rich diet, mainly by fish oil, reduced circling behavior, prevented the fall in GABA levels, increased PPARγ expression, and prevented oxidative damage in striatal tissue. In addition none of the enriched diets exerted changes neither on triglycerides or cholesterol blood levels, nor or hepatic function. This study suggests that olive- and fish-oil-rich diets exert neuroprotective effects.