24-Epibrassinolide, a Phytosterol from the Brassinosteroid Family, Protects Dopaminergic Cells against MPP+-Induced Oxidative Stress and Apoptosis

Oxidative stress and apoptosis are frequently cited to explain neuronal cell damage in various neurodegenerative disorders, such as Parkinson' s disease. Brassinosteroids (BRs) are phytosterols recognized to promote stress tolerance of vegetables via modulation of the antioxidative enzyme cascade. However, their antioxidative effects on mammalian neuronal cells have never been examined so far. We analyzed the ability of 24-epibrassinolide (24-Epi), a natural BR, to protect neuronal PC12 cells from 1-methyl-4-phenylpyridinium- (MPP+-) induced oxidative stress and consequent apoptosis in dopaminergic neurons. Our results demonstrate that 24-Epi reduces the levels of intracellular reactive oxygen species and modulates superoxide dismutase, catalase, and glutathione peroxidase activities. Finally, we determined that the antioxidative properties of 24-Epi lead to the inhibition of MPP+-induced apoptosis by reducing DNA fragmentation as well as the Bax/Bcl-2 protein ratio and cleaved caspase-3. This is the first time that the potent antioxidant and neuroprotective role of 24-Epi has been shown in a mammalian neuronal cell line

Sesamin modulates tyrosine hydroxylase, superoxide dismutase, catalase, inducible NO synthase and interleukin-6 expression in dopaminergic cells under MPP+-induced oxidative stress

Oxidative stress is regarded as a mediator of nerve cell death in several neurodegenerative disorders, such as Parkinson's disease. Sesamin, a lignan mainly found in sesame oil, is currently under study for its anti-oxidative and possible neuroprotective properties. We used 1-methyl-4-phenyl-pyridine (MPP+) ion, the active metabolite of the potent parkinsonism-causing toxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, to produce oxidative stress and neurodegeneration in neuronal PC12 cells, which express dopamine, as well as neurofilaments. Our results show that picomolar doses of sesamin protected neuronal PC12 cells from MPP+-induced cellular death, as revealed by colorimetric measurements and production of reactive oxygen species. We also demonstrated that sesamin acted by rescuing tyrosine hydroxylase levels from MPP+-induced depletion. Sesamin, however, did not modulate dopamine transporter levels, and estrogen receptor-alpha and -beta protein expression. By examining several parameters of cell distress, we found that sesamin also elicited a strong increase in superoxide dismutase activity as well as protein expression and decreased catalase activity and the MPP+ stimulated inducible nitric oxide synthase protein expression, in neuronal PC12 cells. Finally, sesamin possessed significant anti-inflammatory properties, as disclosed by its potential to reduce MPP+-induced interleukin-6 mRNA levels in microglia. From these studies, we determined the importance of the lignan sesamin as a neuroprotective molecule and its possible role in complementary and/or preventive therapies of neurodegenerative diseases

Cucurbitacin E has neuroprotective properties and autophagic modulating activities on dopaminergic neurons

Natural molecules are under intensive study for their potential as preventive and/or adjuvant therapies for neurodegenerative disorders such as Parkinson’s disease (PD). We evaluated the neuroprotective potential of cucurbitacin E (CuE), a tetracyclic triterpenoid phytosterol extracted from the Ecballium elaterium (Cucurbitaceae), using a known cellular model of PD, NGF-differentiated PC12. In our postmitotic experimental paradigm, neuronal cells were treated with the parkinsonian toxin 1-methyl-4-phenylpyridinium (MPP+) to provoke significant cellular damage and apoptosis or with the potent N,N-diethyldithiocarbamate (DDC) to induce superoxide () production, and CuE was administered prior to and during the neurotoxic treatment. We measured cellular death and reactive oxygen species to evaluate the antioxidant and antiapoptotic properties of CuE. In addition, we analyzed cellular macroautophagy, a bulk degradation process involving the lysosomal pathway. CuE showed neuroprotective effects on MPP+-induced cell death. However, CuE failed to rescue neuronal cells from oxidative stress induced by MPP+ or DDC. Microscopy and western blot data show an intriguing involvement of CuE in maintaining lysosomal distribution and decreasing autophagy flux. Altogether, these data indicate that CuE decreases neuronal death and autophagic flux in a postmitotic cellular model of PD.peer-reviewe

Diabetes, a Contemporary Risk for Parkinson’s Disease: Epidemiological and Cellular Evidences

Diabetes mellitus (DM), a group of diseases characterized by defective glucose metabolism, is the most widespread metabolic disorder affecting over 400 million adults worldwide. This pathological condition has been implicated in the pathogenesis of a number of central encephalopathies and peripheral neuropathies. In further support of this notion, recent epidemiological evidence suggests a link between DM and Parkinson’s disease (PD), with hyperglycemia emerging as one of the culprits in neurodegeneration involving the nigrostriatal pathway, the neuroanatomical substrate of the motor symptoms affecting parkinsonian patients. Indeed, dopaminergic neurons located in the mesencephalic substantia nigra appear to be particularly vulnerable to oxidative stress and degeneration, likely because of their intrinsic susceptibility to mitochondrial dysfunction, which may represent a direct consequence of hyperglycemia and hyperglycemia-induced oxidative stress. Other pathological pathways induced by increased intracellular glucose levels, including the polyol and the hexosamine pathway as well as the formation of advanced glycation end-products, may all play a pivotal role in mediating the detrimental effects of hyperglycemia on nigral dopaminergic neurons. In this review article, we will examine the epidemiological as well as the molecular and cellular clues supporting the potential susceptibility of nigrostriatal dopaminergic neurons to hyperglycemia

La neuro-inflammation

Enchâssé dans une cage osseuse, peuplé de cellules qui ont peu de pouvoir de régénération, le système nerveux central (SNC) ne peut supporter une réaction inflammatoire telle qu’elle se déroule en périphérie sans en subir de graves conséquences. Il lui a donc fallu développer une façon originale pour assurer surveillance, défense et réparation, qui repose à la fois sur l’architecture complexe des zones d’échange entre la périphérie et le parenchyme nerveux et sur la collaboration très contrôlée de toutes les cellules du SNC. Bien que parfois source de problèmes, comme c’est le cas dans les maladies neurodégénératives, la neuro-inflammation est aussi porteuse de la solution. C’est de cette double nature dont il est ici question

Epigallocatechin-3-gallate, a promising molecule for Parkinson's disease?

Parkinson's disease (PD) is the second most common neurodegenerative disease, and it is characterized by the loss of the neurotransmitter dopamine and neuronal degeneration in the substantia nigra pars compacta. Thus far, current therapeutic strategies have failed to address neuronal degeneration. It has been reported that overproduction of reactive oxygen species, resulting in oxidative stress, and neuroinflammation play an important role in neurodegenerative diseases through the induction of macromolecular oxidative damage and modulation of intracellular signaling pathways concurring to neuronal cell death. Indeed, anti-oxidant and anti-inflammatory drugs have been the subject of recommendation as a complementary therapy alongside an effective symptomatic treatment to hamper the progression of PD. Today, much attention is paid to polyphenols in light of their potent capacity to reduce oxidative stress and inflammation, while having much fewer side effects than most other drugs. Camellia sinensis L. is the most common ancient herbal tea prepared as a beverage worldwide and it possesses numerous beneficial effects on human health. Epigallocatechin-3-gallate is the best-known bioactive component of C. sinensis and is recognized to exert potent neuroprotective effects against oxidative stress, neuroinflammation, protein aggregation, autophagy, and neuronal cell death in vitro as well as in vivo. The present review appraises the available literature on the beneficial role of epigallocatechin-3-gallate pertaining to dopaminergic degeneration characteristic of PD with particular emphasis on its possible mechanisms of action