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Chemico-biological Interactions Feb 2021Oxidopamine (6-hydroxydopamine, 6-OHDA) is a toxin commonly used for the creation of experimental animal models of Parkinson's disease, attention-deficit hyperactivity... (Review)
Review
Oxidopamine (6-hydroxydopamine, 6-OHDA) is a toxin commonly used for the creation of experimental animal models of Parkinson's disease, attention-deficit hyperactivity disorder, and Lesch-Nyhan syndrome. Its exact mechanism of action is not completely understood, although there are many indications that it is related to the generation of reactive oxygen species (ROS), primarily in dopaminergic neurons. In certain experimental conditions, oxidopamine may also cause programmed cell death via various signaling pathways. Oxidopamine may also have a significant impact on chromatin structure and nuclear structural organization in some cells. Today, many researchers use oxidopamine-associated oxidative damage to evaluate different antioxidant-based pharmacologically active compounds as drug candidates for various neurological and non-neurological diseases. Additional research is needed to clarify the exact biochemical pathways associated with oxidopamine toxicity, related ROS generation and apoptosis. In this short review, we focus on the recent research in experimental physiology and pharmacology, related to the cellular and animal experimental models of oxidopamine - mediated toxicity.
Topics: Animals; Humans; Oxidative Stress; Oxidopamine; Reactive Oxygen Species
PubMed: 33450287
DOI: 10.1016/j.cbi.2021.109380 -
Molecular Therapy : the Journal of the... Oct 2022Parkinson's disease is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra with no effective cure available....
Parkinson's disease is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra with no effective cure available. MicroRNA-124 has been regarded as a promising therapeutic entity for Parkinson's disease due to its pro-neurogenic and neuroprotective roles. However, its efficient delivery to the brain remains challenging. Here, we used umbilical cord blood mononuclear cell-derived extracellular vesicles as a biological vehicle to deliver microRNA (miR)-124-3p and evaluate its therapeutic effects in a mouse model of Parkinson's disease. In vitro, miR-124-3p-loaded small extracellular vesicles induced neuronal differentiation in subventricular zone neural stem cell cultures and protected N27 dopaminergic cells against 6-hydroxydopamine-induced toxicity. In vivo, intracerebroventricularly administered small extracellular vesicles were detected in the subventricular zone lining the lateral ventricles and in the striatum and substantia nigra, the brain regions most affected by the disease. Most importantly, although miR-124-3p-loaded small extracellular vesicles did not increase the number of new neurons in the 6-hydroxydopamine-lesioned striatum, the formulation protected dopaminergic neurons in the substantia nigra and striatal fibers, which fully counteracted motor behavior symptoms. Our findings reveal a novel promising therapeutic application of small extracellular vesicles as delivery agents for miR-124-3p in the context of Parkinson's disease.
Topics: Animals; Disease Models, Animal; Dopaminergic Neurons; Extracellular Vesicles; Mice; MicroRNAs; Neurodegenerative Diseases; Oxidopamine; Parkinson Disease; Substantia Nigra
PubMed: 35689381
DOI: 10.1016/j.ymthe.2022.06.003 -
ELife May 2022Lineage reprogramming of resident glial cells to dopaminergic neurons (DAns) is an attractive prospect of the cell-replacement therapy for Parkinson's disease (PD)....
Lineage reprogramming of resident glial cells to dopaminergic neurons (DAns) is an attractive prospect of the cell-replacement therapy for Parkinson's disease (PD). However, it is unclear whether repressing polypyrimidine tract binding protein 1 (PTBP1) could efficiently convert astrocyte to DAns in the substantia nigra and striatum. Although reporter-positive DAns were observed in both groups after delivering the adeno-associated virus (AAV) expressing a reporter with shRNA or CRISPR-CasRx to repress astroglial PTBP1, the possibility of AAV leaking into endogenous DAns could not be excluded without using a reliable lineage-tracing method. By adopting stringent lineage-tracing strategy, two other studies show that either knockdown or genetic deletion of quiescent astroglial PTBP1 fails to obtain induced DAns under physiological condition. However, the role of reactive astrocytes might be underestimated because upon brain injury, reactive astrocyte can acquire certain stem cell hallmarks that may facilitate the lineage conversion process. Therefore, whether reactive astrocytes could be genuinely converted to DAns after PTBP1 repression in a PD model needs further validation. In this study, we used -mediated specific astrocyte-lineage-tracing method to investigate whether reactive astrocytes could be converted to DAns in a 6-hydroxydopamine (6-OHDA) mouse model of PD. However, we found that no astrocyte-originated DAn was generated after effective and persistent knockdown of astroglial PTBP1 either in the substantia nigra or in striatum, while AAV 'leakage' to nearby neurons was easily observed. Our results confirm that repressing PTBP1 does not convert astrocytes to DAns, regardless of physiological or PD-related pathological conditions.
Topics: Animals; Astrocytes; Dependovirus; Disease Models, Animal; Dopaminergic Neurons; Heterogeneous-Nuclear Ribonucleoproteins; Mice; Oxidopamine; Parkinson Disease; Polypyrimidine Tract-Binding Protein; Substantia Nigra
PubMed: 35535997
DOI: 10.7554/eLife.75636 -
Journal of Neural Transmission (Vienna,... Feb 20206-Hydroxydopamine (6-OHDA), which is a neurotoxin that selectively destroys catecholaminergic nerves in sympathetically innervated tissues, has been used to provide a... (Review)
Review
6-Hydroxydopamine (6-OHDA), which is a neurotoxin that selectively destroys catecholaminergic nerves in sympathetically innervated tissues, has been used to provide a model of Parkinson's disease in experimental animals. It is rapidly autoxidised to yield potentially toxic products and reactive oxygen species. Its ability to release Fe(II) from protein storage sites also results in the formation of hROS. This account will consider how this family of toxic products may contribute to the observed effects of 6-OHDA.
Topics: Animals; Disease Models, Animal; Humans; Neurotoxins; Oxidopamine; Parkinson Disease
PubMed: 31894418
DOI: 10.1007/s00702-019-02133-6 -
Current Topics in Behavioral... 2022To describe animals that express abnormal behaviors as a model of Attention-Deficit Hyperactivity Disorder (ADHD) implies that the abnormalities are analogous to those...
To describe animals that express abnormal behaviors as a model of Attention-Deficit Hyperactivity Disorder (ADHD) implies that the abnormalities are analogous to those expressed by ADHD patients. The diagnostic features of ADHD comprise inattentiveness, impulsivity, and hyperactivity and so these behaviors are fundamental for validation of any animal model of this disorder. Several experimental interventions such as neurotoxic lesion of neonatal rats with 6-hydroxydopamine (6-OHDA), genetic alterations, or selective inbreeding of rodents have produced animals that express each of these impairments to some extent. This article appraises the validity of claims that these procedures have produced a model of ADHD, which is essential if they are to be used to investigate the underlying cause(s) of ADHD and its abnormal neurobiology.
Topics: Animals; Attention Deficit Disorder with Hyperactivity; Behavior, Animal; Disease Models, Animal; Impulsive Behavior; Oxidopamine; Rats
PubMed: 35604570
DOI: 10.1007/7854_2022_342 -
Journal of Theoretical Biology Oct 2016We demonstrate that a proapoptotic chemical agent, oxidopamine, induces dose dependent changes in chromatin textural patterns which can be quantified using the Gray...
We demonstrate that a proapoptotic chemical agent, oxidopamine, induces dose dependent changes in chromatin textural patterns which can be quantified using the Gray level co-occurrence matrix (GLCM) method. Peripheral blood (heparin-pretreated) samples were treated with oxidopamine (6-OHDA, 6-hydroxydopamine) to achieve effective concentrations of 100, 200 and 300µM. The samples were smeared on microscope slides and fixated in methanol. The smears were stained using a modification of Feulgen method for DNA visualization. For each stained smear, a sample of 30 lymphocyte chromatin structures were visualized and analyzed. This way, textural parameters for a total of 120 nuclei micrographs were calculated. For each chromatin structure, five different GLCM features were calculated: angular second moment, GLCM entropy, inverse difference moment, GLCM correlation, and GLCM variance. Oxidopamine induced the rise of the values of GLCM entropy and variance, and the reduction of angular second moment, correlation, and inverse difference moment. The trends for GLCM parameter changes were found to be highly significant (p<0.001). These results indicate that GLCM mathematical algorithm might be successfully used in detection and evaluation of discrete early apoptotic structural changes in Feulgen-stained chromatin of peripheral blood lymphocytes that are not detectable using conventional microscopy/cell biology techniques.
Topics: Algorithms; Biosensing Techniques; Chromatin; Entropy; Humans; Lymphocytes; Oxidopamine; Pattern Recognition, Automated; ROC Curve
PubMed: 27424557
DOI: 10.1016/j.jtbi.2016.07.018 -
Journal of Extracellular Vesicles Nov 2023Extracellular vesicles (EVs) play a crucial role in intercellular communication, participating in the paracrine trophic support or in the propagation of toxic molecules,...
Extracellular vesicles (EVs) play a crucial role in intercellular communication, participating in the paracrine trophic support or in the propagation of toxic molecules, including proteins. RTP801 is a stress-regulated protein, whose levels are elevated during neurodegeneration and induce neuron death. However, whether RTP801 toxicity is transferred trans-neuronally via EVs remains unknown. Hence, we overexpressed or silenced RTP801 protein in cultured cortical neurons, isolated their derived EVs (RTP801-EVs or shRTP801-EVs, respectively), and characterized EVs protein content by mass spectrometry (MS). RTP801-EVs toxicity was assessed by treating cultured neurons with these EVs and quantifying apoptotic neuron death and branching. We also tested shRTP801-EVs functionality in the pathologic in vitro model of 6-Hydroxydopamine (6-OHDA). Expression of RTP801 increased the number of EVs released by neurons. Moreover, RTP801 led to a distinct proteomic signature of neuron-derived EVs, containing more pro-apoptotic markers. Hence, we observed that RTP801-induced toxicity was transferred to neurons via EVs, activating apoptosis and impairing neuron morphology complexity. In contrast, shRTP801-EVs were able to increase the arborization in recipient neurons. The 6-OHDA neurotoxin elevated levels of RTP801 in EVs, and 6-OHDA-derived EVs lost the mTOR/Akt signalling activation via Akt and RPS6 downstream effectors. Interestingly, EVs derived from neurons where RTP801 was silenced prior to exposing them to 6-OHDA maintained Akt and RPS6 transactivation in recipient neurons. Taken together, these results suggest that RTP801-induced toxicity is transferred via EVs, and therefore, it could contribute to the progression of neurodegenerative diseases, in which RTP801 is involved.
Topics: Transcription Factors; Oxidopamine; Proteomics; Proto-Oncogene Proteins c-akt; Extracellular Vesicles
PubMed: 37932242
DOI: 10.1002/jev2.12378 -
Journal of Neural Transmission.... 1997The catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) has recently been found to be formed endogenously in patients suffering from Parkinson's disease. In this... (Review)
Review
The catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) has recently been found to be formed endogenously in patients suffering from Parkinson's disease. In this article, we highlight the latest findings on the biochemical mechanism of 6-OHDA toxicity. 6-OHDA has two ways of action: it easily forms free radicals and it is a potent inhibitor of the mitochondrial respiratory chain complexes I and IV. The inhibition of respiratory enzymes by 6-OHDA is reversible and insensitive towards radical scavengers and iron chelators with the exception of desferrioxamine. We conclude that free radicals are not involved in the interaction between 6-OHDA and the respiratory chain and that the two mechanisms are biochemically independent, although they may act synergistically in vivo.
Topics: Animals; Brain; Chelating Agents; Free Radical Scavengers; Free Radicals; Humans; Mitochondria; Models, Neurological; Nerve Degeneration; Neurons; Neurotoxins; Oxidative Stress; Oxidopamine; Oxygen Consumption; Parkinson Disease
PubMed: 9120425
DOI: 10.1007/978-3-7091-6842-4_7 -
Behavioural Pharmacology Mar 2005Caffeine is the most widely consumed psychostimulant substance, being self-administered throughout a wide range of conditions and present in numerous dietary products.... (Review)
Review
Caffeine is the most widely consumed psychostimulant substance, being self-administered throughout a wide range of conditions and present in numerous dietary products. Due to its widespread use and low abuse potential, caffeine is considered an atypical drug of abuse. The main mechanism of action of caffeine occurs via the blockade of adenosine A1 and A2A receptors. Adenosine is a modulator of CNS neurotransmission and its modulation of dopamine transmission through A2A receptors has been implicated in the effects of caffeine. This review provides an updated summary of the results reported in the literature concerning the behavioural pharmacology of caffeine and the neurochemical mechanisms underlying the psychostimulant effects elicited by caffeine. The review focuses on the effects of caffeine mediated by adenosine A2A receptors and on the influence that pre-exposure to caffeine may exert on the effects of classical drugs of abuse.
Topics: Adrenergic Agents; Animals; Behavior; Caffeine; Central Nervous System Stimulants; Drug Interactions; Humans; Motor Activity; Oxidopamine; Rats; Receptor, Adenosine A2A; Receptors, Dopamine; Reinforcement, Psychology
PubMed: 15767841
DOI: 10.1097/00008877-200503000-00001 -
BMC Biology Nov 2023Diets high in saturated fat and sugar, termed "Western diets," have been associated with several negative health outcomes, including increased risk for neurodegenerative...
BACKGROUND
Diets high in saturated fat and sugar, termed "Western diets," have been associated with several negative health outcomes, including increased risk for neurodegenerative disease. Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and is characterized by the progressive death of dopaminergic neurons in the brain. We build upon previous work characterizing the impact of high-sugar diets in Caenorhabditis elegans to mechanistically evaluate the relationship between high-sugar diets and dopaminergic neurodegeneration.
RESULTS
Adult high-glucose and high-fructose diets, or exposure from day 1 to 5 of adulthood, led to increased lipid content, shorter lifespan, and decreased reproduction. However, in contrast to previous reports, we found that adult chronic high-glucose and high-fructose diets did not induce dopaminergic neurodegeneration alone and were protective from 6-hydroxydopamine (6-OHDA) induced degeneration. Neither sugar altered baseline electron transport chain function and both increased vulnerability to organism-wide ATP depletion when the electron transport chain was inhibited, arguing against energetic rescue as a basis for neuroprotection. The induction of oxidative stress by 6-OHDA is hypothesized to contribute to its pathology, and high-sugar diets prevented this increase in the soma of the dopaminergic neurons. However, we did not find increased expression of antioxidant enzymes or glutathione levels. Instead, we found evidence suggesting downregulation of the dopamine reuptake transporter dat-1 that could result in decreased 6-OHDA uptake.
CONCLUSIONS
Our work uncovers a neuroprotective role for high-sugar diets, despite concomitant decreases in lifespan and reproduction. Our results support the broader finding that ATP depletion alone is insufficient to induce dopaminergic neurodegeneration, whereas increased neuronal oxidative stress may drive degeneration. Finally, our work highlights the importance of evaluating lifestyle by toxicant interactions.
Topics: Animals; Humans; Caenorhabditis elegans; Oxidopamine; Dopamine; Neurodegenerative Diseases; Nerve Degeneration; Dopaminergic Neurons; Adenosine Triphosphate; Sugars; Fructose; Glucose; Disease Models, Animal
PubMed: 37950228
DOI: 10.1186/s12915-023-01733-9