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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 -
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 -
Neurotoxicity Research Feb 2020Salsolinol (6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline), widely available in many edibles, is considered to alter the function of dopaminergic neurons in the...
Salsolinol (6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline), widely available in many edibles, is considered to alter the function of dopaminergic neurons in the central nervous system and thus, multiple hypotheses on its either physiological and/or pathophysiological role have emerged. The aim of our work was to revisit its potentially neurotoxic and/or neuroprotective role through a series of both in vitro and in vivo experiments. Salsolinol in the concentration range 10-250 μM did not show any significant release of lactate dehydrogenase from necrotic SH-SY5Y cells and was able in the concentration of 50 and 100 μM to rescue SH-SY5Y cells from death induced by HO. Its neuroprotective effect against neurotoxin 6-hydroxydopamine was also determined. Salsolinol was found to decrease significantly the reactive oxygen species level in SH-SY5Y cells treated by 500 μM HO and the caspase activity induced by 300 μM of HO or 100 μM of 6-hydroxydopamine. Serum levels of TNFα and CRP of salsolinol-treated rats were not significantly different from control animals. Both TNFα and CRP served as indirect markers of neurotoxicity and/or neuroprotection. Although the neurotoxic properties of salsolinol have numerously been emphasized, its neuroprotective properties should not be neglected and need greater consideration.
Topics: Animals; Apoptosis; Cell Death; Cell Line, Tumor; Cells, Cultured; Dose-Response Relationship, Drug; Humans; Inflammation Mediators; Isoquinolines; Male; Neuroprotective Agents; Oxidopamine; Rats; Rats, Wistar
PubMed: 31732870
DOI: 10.1007/s12640-019-00118-7 -
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 -
Proceedings of the National Academy of... Jul 2022Clinical evidence suggests that pain hypersensitivity develops in patients with attention-deficit/hyperactivity disorder (ADHD). However, the mechanisms and neural...
Clinical evidence suggests that pain hypersensitivity develops in patients with attention-deficit/hyperactivity disorder (ADHD). However, the mechanisms and neural circuits involved in these interactions remain unknown because of the paucity of studies in animal models. We previously validated a mouse model of ADHD obtained by neonatal 6-hydroxydopamine (6-OHDA) injection. Here, we have demonstrated that 6-OHDA mice exhibit a marked sensitization to thermal and mechanical stimuli, suggesting that phenotypes associated with ADHD include increased nociception. Moreover, sensitization to pathological inflammatory stimulus is amplified in 6-OHDA mice as compared to shams. In this ADHD model, spinal dorsal horn neuron hyperexcitability was observed. Furthermore, ADHD-related hyperactivity and anxiety, but not inattention and impulsivity, are worsened in persistent inflammatory conditions. By combining in vivo electrophysiology, optogenetics, and behavioral analyses, we demonstrated that anterior cingulate cortex (ACC) hyperactivity alters the ACC-posterior insula circuit and triggers changes in spinal networks that underlie nociceptive sensitization. Altogether, our results point to shared mechanisms underlying the comorbidity between ADHD and nociceptive sensitization. This interaction reinforces nociceptive sensitization and hyperactivity, suggesting that overlapping ACC circuits may be targeted to develop better treatments.
Topics: Animals; Attention Deficit Disorder with Hyperactivity; Disease Models, Animal; Gyrus Cinguli; Hyperalgesia; Impulsive Behavior; Mice; Optogenetics; Oxidopamine; Pain; Sympatholytics
PubMed: 35858441
DOI: 10.1073/pnas.2114094119 -
Expert Opinion on Therapeutic Targets Oct 2022Parkinsons disease (PD) is the second most common neurodegenerative disease after Alzheimers disease. PD patients exhibit a classic spectrum of motor symptoms, arising... (Review)
Review
INTRODUCTION
Parkinsons disease (PD) is the second most common neurodegenerative disease after Alzheimers disease. PD patients exhibit a classic spectrum of motor symptoms, arising when dopamine neurons in the substantia nigra pars compacta are reduced by 60%. The dopamine precursor L-DOPA represents the most effective therapy for improving PD motor dysfunctions, thus far available. Unfortunately, long-term treatment with L-DOPA is associated with the development of severe side effects, resulting in abnormal involuntary movements termed levodopa-induced dyskinesia (LID). Amantadine is the only drug currently approved for the treatment of LID indicating that LID management is still an unmet need in PD and encouraging the search for novel anti-dyskinetic drugs or the assessment of combined therapies with different molecular targets.
AREAS COVERED
This review provides an overview of the main preclinical models used to study LID and of the latest preclinical evidence on experimental and clinically available pharmacological approaches targeting non-dopaminergic systems.
EXPERT OPINION
LIDs are supported by complex molecular and neurobiological mechanisms that are still being studied today. This complexity suggests the need of developing personalized pharmacological approach to obtain an effective amelioration of LID condition and improve the quality of life of PD patients.
Topics: Animals; Parkinson Disease; Levodopa; Neurodegenerative Diseases; Quality of Life; Dyskinesia, Drug-Induced; Oxidopamine; Disease Models, Animal; Antiparkinson Agents
PubMed: 36469635
DOI: 10.1080/14728222.2022.2153036 -
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 -
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 -
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 -
Behavioural Pharmacology Jun 2019The quest to better understand the pathophysiology of Parkinson's disease (PD) and to find new therapies to provide greater relief to affected patients continues. The... (Review)
Review
The quest to better understand the pathophysiology of Parkinson's disease (PD) and to find new therapies to provide greater relief to affected patients continues. The use of animal models of PD has been invaluable in the process. Here, we review, through a historical lens, some of the contribution of the 6-hydroxydopamine-lesioned rat and of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned nonhuman primate, in refining our understanding of PD and its treatment-related complications. We examine the mechanisms underlying the toxicity of 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and then explore some of the advances at the molecular, pharmacological, electrophysiological and surgical levels made while experimenting on these animal models. We also discuss behavioural testing that can be performed with these animal models and highlight some of their limitations.
Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Disease Models, Animal; Humans; Oxidopamine; Parkinson Disease; Primates; Rats
PubMed: 30216234
DOI: 10.1097/FBP.0000000000000441