Atomoxetine Decreases Mitochondrial Biogenesis, Fission and Fusion In Human Neuron-like Cells But Does Not Alter Antioxidant Defences.

Atomoxetine (ATX) is a presynaptic norepinephrine transporter (NET) inhibitor widely prescribed for attention-deficit/hyperactivity disorder (ADHD) due to its low abuse potential and absence of psychostimulant effects. While NET inhibition is implicated in the clinical response, several additional pharmacoactivities may contribute to clinical efficacy or unwanted side effects. We recently reported that ATX can dose-dependently alter mitochondrial function and cellular redox status. Here, we assessed potential alterations in mitochondrial biogenesis, mitochondrial dynamics and cellular antioxidant capacity following high- and low-dose ATX treatment of differentiated human neuroblastoma cells. Human SH-SY5Y neuroblastoma cells were treated with ATX (1, 5, 10, 20 and 50 µM) for 7 days under differentiation culture conditions. Changes in the expression levels of protein markers for mitochondrial biogenesis, fusion and fission as well as of antioxidant proteins were analysed by Western blot. High-dose ATX (50 µM) reduced while low-dose ATX (10 µM) increased mitochondrial biogenesis as evidenced by parallel changes in SDHA, COX-I, PGC1α and TFAM expression. High-dose ATX also reduced mitochondrial fusion as evidenced by OPA1 and MFN2 downregulation, and mitochondrial fission as indicated by DRP1 and Fis1 downregulation. In contrast, ATX did not alter expression of the antioxidant enzymes SOD1 and catalase, the phase II transcription factor Nfr2, or the Nfr2-regulated antioxidant enzyme NQO1. Clinical responses and side effects of ATX may be mediated by dose-dependent modulation of mitochondrial biogenesis and dynamics as well as NET inhibition.

Antitumor Effects of Natural Compounds Derived from Allium sativum on Neuroblastoma: An Overview.

Garlic (Allium sativum) has been used in alternative medicine to treat several diseases, such as cardiovascular and neurodegenerative diseases, cancer, and hepatic diseases. Several publications have highlighted other features of garlic, including its antibacterial, antioxidative, antihypertensive, and antithrombotic properties. The properties of garlic result from the combination of natural compounds that act synergistically and cause different effects. Some garlic-derived compounds have been studied for the treatment of several types of cancer; however, reports on the effects of garlic on neuroblastoma are scarce. Neuroblastoma is a prevalent childhood tumor for which the search for therapeutic alternatives to improve treatment without affecting the patients' quality of life continues. Garlic-derived compounds hold potential for the treatment of this type of cancer. A review of articles published to date on some garlic compounds and their effect on neuroblastoma was undertaken to comprehend the possible therapeutic role of these compounds. This review aimed to analyze the impact of some garlic compounds on cells derived from neuroblastoma.

Neuroprotective Effects of Quercetin in Pediatric Neurological Diseases.

Oxidative stress is a crucial event underlying several pediatric neurological diseases, such as the central nervous system (CNS) tumors, autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Neuroprotective therapy with natural compounds used as antioxidants has the potential to delay, ameliorate or prevent several pediatric neurological diseases. The present review provides an overview of the most recent research outcomes following quercetin treatment for CNS tumors, ASD and ADHD as well as describes the potential in vitro and in vivo ameliorative effect on oxidative stress of bioactive natural compounds, which seems like a promising future therapy for these diseases. The neuroprotective effects of quercetin against oxidative stress can also be applied in the management of several neurodegenerative disorders with effects such as anti-cancer, anti-inflammatory, anti-viral, anti-obesity and anti-microbial. Therefore, quercetin appears to be a suitable adjuvant for therapy against pediatric neurological diseases.

Paraptosis in human glioblastoma cell line induced by curcumin.

Curcumin is a polyphenol compound extracted from Curcuma longa plant, is a molecule with pleiotropic effects that suppresses transformation, proliferation and metastasis of malignant tumors. Curcumin can cause different kinds of cell death depending of its concentration on the exposed cell type. Here we show that exposure of the glioblastoma cell line A172 to curcumin at 50 µM, the IC50, causes morphological change characteristic of paraptosis cell-death. Vesicles derived from the endoplasmic reticulum (ER) and low membrane potential of the mitochondria were constantly found in the exposed cells. Furthermore, changes in expression of the ER Stress Response (ERSR) genes IRE1 and ATF6, and the microRNAs (miRNAs) miR-27a, miR-222, miR-449 was observed after exposure to curcumin. AKT-Insulin and p53-BCL2 networks were predicted being modulated by the affected miRNAs. Furthermore, AKT protein levels reduction was confirmed. Our data, strongly suggest that curcumin exerts its cell-death properties by affecting the integrity of the reticulum, leading to paraptosis in the glioblastoma cells. These data unveils the versatility of curcumin to control cancer progression.

PPARγ activation rescues mitochondrial function from inhibition of complex I and loss of PINK1.

Parkinson's disease has long been associated with impaired mitochondrial complex I activity, while several gene defects associated with familial Parkinson's involve defects in mitochondrial function or 'quality control' pathways, causing an imbalance between mitochondrial biogenesis and removal of dysfunctional mitochondria by autophagy. Amongst these are mutations of the gene for PTEN-induced kinase 1 (PINK1) in which mitochondrial function is abnormal. Peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor and ligand-dependent transcription factor, regulates pathways of inflammation, lipid and carbohydrate metabolism, antioxidant defences and mitochondrial biogenesis. We have found that inhibition of complex I in human differentiated SHSY-5Y cells by the complex I inhibitor rotenone irreversibly decrease mitochondrial mass, membrane potential and oxygen consumption, while increasing free radical generation and autophagy. Similar changes are seen in PINK1 knockdown cells, in which potential, oxygen consumption and mitochondrial mass are all decreased. In both models, all these changes were reversed by pre-treatment of the cells with the PPARγ agonist, rosiglitazone, which increased mitochondrial biogenesis, increased oxygen consumption and suppressed free radical generation and autophagy. Thus, rosiglitazone is neuroprotective in two different models of mitochondrial dysfunction associated with Parkinson's disease through a direct impact on mitochondrial function.

Calpain inhibition protects spinal motoneurons from the excitotoxic effects of AMPA in vivo.

Microdialysis perfusion of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) in rat lumbar spinal cord produces severe motoneuron damage and consequently hindlimb paralysis. Here we studied the time course of the AMPA-induced neurodegenerative changes and motor alterations, and the protective effect of leupeptin, an inhibitor of calpain, a Ca(2+)-activated protease. Paralysis occurs at 4-6 h after AMPA perfusion, but cresyl violet staining showed that motoneuron damage starts at about 3 h and progresses until reaching 50% neuronal loss at 6 h and 90% loss at 12 h. In contrast, choline acetyltransferase (ChAT) immunohistochemistry revealed that the enzyme is already decreased at 30 min after AMPA perfusion and practically disappears at 3 h. Microdialysis coperfusion of leupeptin with AMPA prevented the motor alterations and paralysis and remarkably reduced both the decrement in ChAT immunoreactivity and the loss of motoneurons. We conclude that an increased Ca(2+) influx through Ca(2+)-permeable AMPA receptors activates calpain, and as a consequence ChAT content decreases earlier than other Ca(2+)-dependent processes, including the proteolytic activity of calpain, cause the death of motoneurons.