Evaluation of okadaic acid, dinophysistoxin-1 and dinophysistoxin-2 toxicity on Neuro-2a, NG108-15 and MCF-7 cell lines

10.1016/j.tiv.2014.09.002Marine dinoflagelates from the genus Dynophisis are important producers of Diarrhetic Shellfish Poisoning (DSP) toxins which are responsible for human intoxications. The present work is an approach to study the relative toxicity of DSP toxins effects on Neuro-2a, NG108-15 and MCF-7 cell-lines. Certified standards of okadaic acid (OA), dinophysistoxin-1 (DTX-1) and dinophysistoxin-2 (DTX-2) were used. Our results show that the three toxins exhibit similar cytotoxicity in Neuro-2a and NG108-15 cell lines. Conversely, MCF-7 cells were the least sensitive to these toxins. DTX-1 displayed the most toxic effect in the three tested cell lines

Tryptophanol-derived oxazolopiperidone lactams: Identification of a hit compound as NMDA receptor antagonist

10.1016/j.bmcl.2014.05.105N-Methyl-d-aspartate receptors (NMDAR) exacerbated activation leads to neuron death through a phenomenon called excitotoxicity. These receptors are implicated in several neurological diseases (e.g., Alzheimer and Parkinson) and thus represent an important therapeutic target. We herein describe the study of enantiopure tryptophanol-derived oxazolopiperidone lactams as NMDA receptor antagonists. The most active hit exhibited an IC50 of 63.4 µM in cultured rat cerebellar granule neurons thus being 1.5 fold more active than clinically approved NMDA antagonist amantadine (IC50 = 92 µM

Synthesis of phenylalaninol-derived oxazolopyrrolidone lactams and evaluation as NMDA receptor antagonists

10.1007/s00706-012-0880-8N-Methyl-d-aspartate (NMDA) receptor antagonists are known to rescue neuronal cell death caused by excessive activation of glutamate receptors. This phenomenon, known as excitotoxicity, is implicated in the pathogenesis of several neurodegenerative disorders including ischemia, Alzheimer's disease, Parkinson's disease, and Huntington's disease. Unfortunately, some NMDA receptor antagonists have shown discouraging results when tested in clinical trials. However, recent advances in the physiology and pharmacology of the NMDA receptor have kept interest alive in modulating NMDA receptors for therapeutic intervention. We present here the synthesis of a small library of phenylalaninol-derived oxazolopyrrolidone lactams and their evaluation as NMDA receptor antagonists. The compounds were easily synthesized in yields up to 92 %. In addition, one of the compounds has a 50 % inhibitory concentration (IC50) of 62 µM and offers potential to develop more potent NMDA receptor antagonists

An overview of investigational antiapoptotic drugs with potential application for the treatment of neurodegenerative disorders

Importance of the field: The increase in life expectancy in developed countries has given rise to several emerging social problems. Of particular note is the dramatic rise in the incidence of neurodegenerative diseases. Given this new social scenario, there is a need to identify therapeutic strategies to delay the advance of these pathologies, for which no effective treatment is currently available. Areas covered in this review: The present review discusses some of the drugs that are now under development with antiapoptotic activity or currently on the market that may have a potential application for the treatment of neurodegenerative diseases. Moreover, we also comment on potential compounds such as resveratrol and melatonin. Despite the lack of information from clinical trials on these two compounds, they are attracting considerable attention because of their natural origin and antioxidant and antiapoptotic action. Furthermore, they do not show toxicity in humans. In addition, we discuss the potential application of several compounds, such as NMDA antagonists, JNK inhibitors and GSK-3 inhibitors, for the treatment of neurodegenerative disorders. What the reader will gain: This article will review recent developments in the field of apoptosis inhibitors, which might provide future tools for the treatment of the neurodegenerative diseases. Take home message: The treatment of neurodegenerative diseases is a major challenge in medicine. This is partly because the incidence of these disorders is expected to rise in the coming years. New developments in the field of apoptosis inhibitors may provide future tools for the treatment of the aforementioned neurodegenerative diseases. © 2010 Informa UK Ltd

Sirtuin activators: Designing molecules to extend life span

Resveratrol (RESV) exerts important pharmacological effects on human health: in addition to its beneficial effects on type 2 diabetes and cardiovascular diseases, it also modulates neuronal energy homeostasis and shows antiaging properties. Although it clearly has free radical scavenger properties, the mechanisms involved in these beneficial effects are not fully understood. In this regard, one area of major interest concerns the effects of RESV on the activity of sirtuin 1 (SIRT1), an NAD+-dependent histone deacetylase that has been implicated in aging. Indeed, the role of SIRT1 is currently the subject of intense research due to the antiaging properties of RESV, which increases life span in various organisms ranging from yeast to rodents. In addition, when RESV is administered in experimental animal models of neurological disorders, it has similar beneficial effects to caloric restriction. SIRT1 activation could thus constitute a potential strategic target in neurodegenerative diseases and in disorders involving disturbances in glucose homeostasis, as well as in dyslipidaemias or cardiovascular diseases. Therefore, small SIRT1 activators such as SRT501, SRT2104, and SRT2379, which are currently undergoing clinical trials, could be potential drugs for the treatment of type 2 diabetes, obesity, and metabolic syndrome, among other disorders. This review summarises current knowledge about the biological functions of SIRT1 in aging and aging-associated diseases and discusses its potential as a pharmacological target. © 2010 Elsevier B.V

The neuroprotective activity of group-II metabotropic glutamate receptors requires new protein synthesis and involves a glial-neuronal signaling

The group-II metabotropic glutamate (mGlu) receptor agonists (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), S-4-carboxy-3-hydroxyphenylglycine (4C3HPG), and (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I) protected mouse cortical neurons grown in mixed cultures against excitotoxic degeneration induced by a 10 min pulse with NMDA. Protection was observed not only when agonists were added in combination with NMDA but also when they were transiently applied to cultures 6-20 hr before the NMDA pulse. In both cases, neuroprotection was reduced by the group-II mGlu receptor antagonist (2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-phenylcyclopropyl)glycine (PCCG-IV), as well as by the protein synthesis inhibitor cycloheximide (CHX). Both neurons and astrocytes in mixed cultures were immunostained with an antibody that recognized mGlu2 and mGlu3 receptors in recombinant cells. To determine whether astrocytes played any role in the neuroprotection mediated by group-II mGlu receptors, we exposed pure cultures of cortical astrocytes to DCG-IV, 4C3HPG, or L-CCG-I for 10 min. The astrocyte medium collected 2-20 hr after the exposure to any of these drugs was highly neuroprotective when transferred to mixed cultures treated with NMDA. This protective activity was reduced when CHX was applied to astrocyte cultures immediately after the transient exposure to group-II mGlu receptor agonists. We conclude that neuroprotection mediated by group-II mGlu receptors in cultured cortical cells requires new protein synthesis and involves an interaction between neurons and astrocytes

Antiapoptotic drugs: A therapautic strategy for the prevention of neurodegenerative diseases

The purpose of this review is to discuss potential pathways involved in the pathogenesis of neurodegenerative diseases, highlighting current pharmacological drug targets in neuronal apoptosis prevention. The incidence of these disorders is expected to rise in the coming years and so finding effective treatments represents a significant challenge for medicine. Alzheimer's disease and Parkinson's disease were both described almost a century ago and are the most important neurodegenerative disorders in the developed world. However, the molecular mechanisms that lead to the development of the neuronal pathology in both diseases are unclear. For this reason, despite substantial research in the area, an effective treatment for these diseases does not yet exist. In the present study we discuss in depth the pathways involved in apoptosis and neuronal death in neurodegenerative diseases. We also examine drugs that may have a neuroprotective effect. Inhibition of apoptosis mediated by oxidative stress generation and mitochondrial alteration or by the blockade of NMDA receptors could constitute a suitable therapeutic strategy for Alzheimer's disease. A multiple therapy with antioxidants, cell cycle inhibitors, GSK3β inhibitors, and STATINS could, in the future, represent a suitable strategy for delaying the progression of neurodegenerative diseases. This research contributes to the development of new methods in the field of apoptosis inhibitors that could provide the future tools for the treatment of Alzheimer's and Parkinson's disease, as well as other neurodegenerative diseases. © 2011 Bentham Science Publishers Ltd

Prosurvival role of JAK/STAT and Akt signaling pathways in MPP +-induced apoptosis in neurons

In the present study the role of JAK/STAT and Akt in apoptosis was evaluated in cerebellar granule cells after treatment with the mitochondrial toxin MPP +. Firstly, we evaluated the role of the prosurvival Akt pathway in MPP +-induced apoptosis and found that MPP + rapidly reduced the phosphorylation of Akt at Ser473. Since PTEN is an upstream regulator of Akt, its inhibition with bpV(pic) (1-30?M) should activate Akt, however, it did not attenuate CGC cell death mediated by MPP + but protected CGC from apoptosis mediated by S/K deprivation. We also demonstrated that after the treatment with the complex I inhibitor, the expression levels of STAT1 increased and the levels of STAT3 decreased at the time points tested (0.5-8h). Meanwhile, pharmacological inhibition of the JAK/STAT pathway with AG490 (10-40?M) was neuroprotective, probably due to its antioxidant properties, the Jak2-inhibitor-II potentiated MPP + neurotoxicity. Collectively, our data indicate that the treatment of CGC with the neurotoxin MPP + decreased two prosurvival pathways: STAT3 and Akt. Meanwhile Akt activation, using a PTEN inhibitor, did not play a prominent role in neuroprotection; loss of STAT3 could be a signal pathway involved in neuroprotection against the Parkinsonian neurotoxin MPP +. © 2010 Elsevier Ltd