Age-dependent Effect Imposed by Rotenone Exposure

Background: The increasing awareness that environmental exposure may lead to sporadic neurological disorders has implicated rotenone to the etiology of some neurodegenerative diseases. However, the risk associated with rotenone toxicity remains controversial as a limited amount of research has studied its effects on brain health. Objectives: This work assessed the risk of rotenone exposure to mice of different ages, gender, and duration by examining in vivo effects on brains. Methods: Using a mouse model, the impact of rotenone exposure was determined by analyzing the cellular phenotype in the murine brain. Results: Our results highlight the neurological susceptibility to long-term rotenone exposure in younger ages. For such, younger mice exhibit seizures and convulsions, resulting in shorter lifespan. At the cellular level, rotenone exposure specifically alters the migrating neuroblast populations in the dentate gyrus and causes disorganized pyramidal neurons in the CA3 within the hippocampus. Our findings, albeit the absence of transgenerational inheritance, demonstrated age-related outcomes from rotenone exposure. Discussion: We demonstrated that rotenone exposure specifically influences the population of neuroblasts and pyramidal neurons residing in the hippocampus, a brain region important for learning/memory and associated with convulsive seizure. Our understanding of how exactly rotenone affected region-specific neuronal cells and the molecular mechanism behind exposure risk is still limited. From the perspective of public health, our in vivo study highlights age-related susceptibility to rotenone toxicity. Future investigations in environmental epidemiology should determine whether age and duration of exposure to rotenone in human subjects pertains to the development of seizures or other neurological abnormalities over time.

HSPA9/Mortalin mediates axo-protection and modulates mitochondrial dynamics in neurons

Mortalin is a mitochondrial chaperone protein involved in quality control of proteins imported into the mitochondrial matrix, which was recently described as a sensor of neuronal stress. Mortalin is down-regulated in neurons of patients with neurodegenerative diseases and levels of Mortalin expression are correlated with neuronal fate in animal models of Alzheimer's disease or cerebral ischemia. To date, however, the links between Mortalin levels, its impact on mitochondrial function and morphology and, ultimately, the initiation of neurodegeneration, are still unclear. In the present study, we used lentiviral vectors to over- or under-express Mortalin in primary neuronal cultures. We first analyzed the early events of neurodegeneration in the axonal compartment, using oriented neuronal cultures grown in microfluidic-based devices. We observed that Mortalin down-regulation induced mitochondrial fragmentation and axonal damage, whereas its over-expression conferred protection against axonal degeneration mediated by rotenone exposure. We next demonstrated that Mortalin levels modulated mitochondrial morphology by acting on DRP1 phosphorylation, thereby further illustrating the crucial implication of mitochondrial dynamics on neuronal fate in degenerative diseases.

Reversal effect of Solanum dasyphyllum against rotenone-induced neurotoxicity

We earlier reported the protective effect of Solanum dasyphyllum against cyanide neurotoxicity. In furtherance to this, we investigated the protective effect of S. dasyphyllum against rotenone, a chemical toxin that causes brain-related diseases. Mitochondria fraction obtained from the brain of male Wistar rats was incubated with various solvents (hexane, dichloromethane, ethylacetate, and methanol) extracts of S. dasyphyllum before rotenone exposure. Mitochondria respiratory enzymes (MRE) were evaluated along with markers of oxidative stress. The inhibition of MRE by rotenone was reversed by treatment with various fractions of S. dasyphyllum. The oxidative stress induced by rotenone was also reversed by fractions of S. dasyphyllum. In addition, the ethylacetate fraction of S. dasyphyllum was most potent against rotenone-induced neurotoxicity. In conclusion, S. dasyphyllum is rich in active phytochemicals that can prevent some neurotoxic effects of rotenone exposure. Further study can be done in an in vivo model to substantiate our results.

Acreditation Certificate Acreditation No. 21/E/KPT/2018 Article Tools Print this article Indexing metadata How to cite item Email this article Email the author About The Authors Rodhiyan Rakhmatiar Faculty of Medicine, University of Brawijaya Indonesia Neurology Department Mulyohadi Ali Faculty of Medicine, University of Brawijaya Pharmacology Department M. Dalhar Faculty of Medicine, University of Brawijaya Neurology Department About RJLS Aim and Scope Editorial Board Reviewer Acknowledgement Publication Ethics Visitor Statistic Information for Author Author Guidelines (online version) Online Submission Guideline Online Registration Author Fees Download Template User You are logged in as... riris_rjlsub My Profile Log Out Tools Mendeley User Guide Insert Citation using Mendeley Journal Index Visitor Statistic Notifications View (240 new) Manage Journal Content Search Search Scope Browse By Issue By Author By Title Information For Readers For Authors For Librarians Keywords Acute Coronary Syndrome Antioxidant Avicennia marina Bali Strait Bioremediation CODIS 13 DPPH Eucheuma cottonii ICP11 Litopenaeus vannamei Macrobrachium rosenbergii Morphology Pandanus Physalis minima RFLP SOD Sardinella lemuru WSSV birth weight fermentation rats Effect of Centella asiatica Extract on Locomotor Activity and Hsp60 Expression in Zebrafish models of Parkinsons

Parkinson's disease characterized by a decrease in motor activity is a progressive neurodegenerative disorder caused by the degeneration of dopaminergic neurons. Centella asiatica is suspected of having a neuroprotectant effect and is not yet known how Centella asiatica role in the prevention of Parkinson's disease. The study was conducted to prove the effect of Centella asiatica extract on the expression of Hsp60 and locomotor activity zebrafish models of Parkinson's with rotenone exposure. The study was conducted using 25 zebrafish divided into various groups. Centella asiatica extract and rotenone exposure have given for 28 days, observed locomotor activity on days 0, 7, 14, 21 and 28. The expression of Hsp60 measured using immunohistochemical techniques. There is a significant difference between locomotor activity at various doses of Centella asiatica (p<0.05) with a very strong correlation (r=0.929; p<0.01) where the higher doses of Centella asiatica, the higher locomotor activity. Found a significant difference between the reduced expression of Hsp60 to various Centella asiatica dose group (p<0.05) but no correlation between the expression of Hsp60 with Centella asiatica dose groups and locomotor activity. Centella asiatica extract is able to increase locomotor activity and decrease the expression of Hsp60 in zebrafish models of Parkinson's.

Coordinated Action of miR-146a and Parkin Gene Regulate Rotenone-induced Neurodegeneration

Mitochondrial dysfunction is a common cause in pathophysiology of different neurodegenerative diseases. Elimination of dysfunctional and damaged mitochondria is a key requirement for maintaining homeostasis and bioenergetics of degenerating neurons. Using global microRNA (miRNA) profiling in a systemic rotenone model of Parkinson’s disease, we have identified miR-146a as upmost-regulated miRNA, which is known as inflammation regulatory miRNA. Here, we report the role of activated nuclear factor kappa beta (NF-kβ) in miR-146a-mediated downregulation of Parkin protein, which inhibits clearance of damaged mitochondria and induces neurodegeneration. Our studies have shown that 4-week rotenone exposure (2.5 mg/kg b.wt) induced oxidative imbalance-mediated NF-kβ activation in 1-year-old rat’s brain. Activated NF-kβ binds in promoter region of miR-146a gene and induces its transcription, which downregulates levels of Parkin protein. Decreased amount of Parkin protein results in accumulation of damaged and dysfunctional mitochondria, which further promotes the generation of reactive oxygen species in degenerating neurons. In conclusion, our studies have identified direct role of NF-kβ-mediated upregulation of miR-146a in regulating mitophagy through inhibition of the Parkin gene.

Healthspan Maintenance and Prevention of Parkinson’s-like Phenotypes with Hydroxytyrosol and Oleuropein Aglycone in C. elegans

Numerous studies highlighted the beneficial effects of the Mediterranean diet (MD) in maintaining health, especially during ageing. Even neurodegeneration, which is part of the natural ageing process, as well as the foundation of ageing-related neurodegenerative disorders like Alzheimer’s and Parkinson’s disease (PD), was successfully targeted by MD. In this regard, olive oil and its polyphenolic constituents have received increasing attention in the last years. Thus, this study focuses on two main olive oil polyphenols, hydroxytyrosol (HT) and oleuropein aglycone (OLE), and their effects on ageing symptoms with special attention to PD. In order to avoid long-lasting, expensive, and ethically controversial experiments, the established invertebrate model organism Caenorhabditis elegans was used to test HT and OLE treatments. Interestingly, both polyphenols were able to increase the survival after heat stress, but only HT could prolong the lifespan in unstressed conditions. Furthermore, in aged worms, HT and OLE caused improvements of locomotive behavior and the attenuation of autofluorescence as a marker for ageing. In addition, by using three different C. elegans PD models, HT and OLE were shown i) to enhance locomotion in worms suffering from α-synuclein-expression in muscles or rotenone exposure, ii) to reduce α-synuclein accumulation in muscles cells, and iii) to prevent neurodegeneration in α-synuclein-containing dopaminergic neurons. Hormesis, antioxidative capacities and an activity-boost of the proteasome & phase II detoxifying enzymes are discussed as potential underlying causes for these beneficial effects. Further biological and medical trials are indicated to assess the full potential of HT and OLE and to uncover their mode of action.

Effects of Enteric Environmental Modification by Coffee Components on Neurodegeneration in Rotenone-Treated Mice

Epidemiological studies have shown that coffee consumption decreases the risk of Parkinson’s disease (PD). Caffeic acid (CA) and chlorogenic acid (CGA) are coffee components that have antioxidative properties. Rotenone, a mitochondrial complex I inhibitor, has been used to develop parkinsonian models, because the toxin induces PD-like pathology. Here, we examined the neuroprotective effects of CA and CGA against the rotenone-induced degeneration of central dopaminergic and peripheral enteric neurons. Male C57BL/6J mice were chronically administered rotenone (2.5 mg/kg/day), subcutaneously for four weeks. The animals were orally administered CA or CGA daily for 1 week before rotenone exposure and during the four weeks of rotenone treatment. Administrations of CA or CGA prevented rotenone-induced neurodegeneration of both nigral dopaminergic and intestinal enteric neurons. CA and CGA upregulated the antioxidative molecules, metallothionein (MT)-1,2, in striatal astrocytes of rotenone-injected mice. Primary cultured mesencephalic or enteric cells were pretreated with CA or CGA for 24 h, and then further co-treated with a low dose of rotenone (1–5 nM) for 48 h. The neuroprotective effects and MT upregulation induced by CA and CGA in vivo were reproduced in cultured cells. Our data indicated that intake of coffee components, CA and CGA, enhanced the antioxidative properties of glial cells and prevents rotenone-induced neurodegeneration in both the brain and myenteric plexus.