Degeneration Of Nigrostriatal Dopaminergic Neurons Research Articles

The progression of artificial intelligence technology and Parkinson’s disease

Parkinson’s disease is a neurodegenerative disease that seriously endangers the health of middle-aged and old people and is characterized by the degeneration of nigrostriatal dopaminergic neurons as its main pathologic feature. Due to its numerous influencing factors, unclear pathogenic mechanisms, and complex clinical manifestations, the diagnosis and treatment of Parkinson’s disease still face huge challenges. In recent years, artificial intelligence technology has developed rapidly and its application in the medical field has become increasingly widespread. This article reviews the achievements of artificial intelligence in the diagnosis and treatment of Parkinson’s disease, with a view to benefiting patients with Parkinson’s disease in the future.

Sericin alleviates motor dysfunction by modulating inflammation and TrkB/BDNF signaling pathway in the rotenone-induced Parkinson’s disease model

BackgroundParkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the degeneration of nigrostriatal dopaminergic neurons and movement impairment. Based on theories, neuroinflammatory processes may be vital in the etiology of PD and other neurodegenerative diseases. Reports show that rotenone has neurotoxic, inflammatory, and motor impairment effects in PD. Sericin is a natural polymer with effective properties, such as neuroprotective and anti-inflammatory. Therefore, this study aimed to examine the effects of sericin administration on motor dysfunction by modulating inflammation and tyrosine kinase B/brain-derived neurotrophic factor (TrkB/BDNF) pathway in the rotenone-induced PD model.MethodsWistar male rats (3-months-old) were treated with rotenone (2 mg/kg every 48 h for 30 days) to induce a rotenone-induced PD model. Also, sericin was administered orally at dose of 200 mg/kg every 48 h for 30 days. Rotarod and bar tests were performed for motor dysfunction. The protein levels of BDNF, c-fos, TrkB, tumor necrosis factor- α (TNF-α), interleukin-6 (IL-6) and catalase activity were evaluated in the striatum area.ResultsResults showed that sericin increased latent time in the rotarod test and decreased the time staying on the pole in the bar test compared to the PD group (P < 0.001 for both tests). Moreover, sericin treatments decreased TNF-α (P < 0.001) and IL-6 (P < 0.001) concentration levels and enhanced the levels of BDNF (P < 0.001), c-fos (P < 0.001), TrkB (P < 0.001) proteins and catalase activity (P < 0.05) in the striatum area compared to the PD group.ConclusionThese results support a protective benefit of sericin therapy in a rotenone-induced PD paradigm by reducing motor impairment, inflammatory response, and disruption of the TrkB/BDNF signaling pathway.

Low-dose inhalation exposure to trichloroethylene induces dopaminergic neurodegeneration in rodents.

Trichloroethylene (TCE) is one of the most pervasive environmental contaminants in the world and is associated with Parkinson disease (PD) risk. Experimental models in rodents show that TCE is selectively toxic to dopaminergic neurons at high doses of ingestion, however, TCE is a highly volatile toxicant, and the primary pathway of human exposure is inhalation. As TCE is a highly lipophilic, volatile organic compound (VOC), inhalation exposure results in rapid diffusion throughout the brain, avoiding first-pass hepatic metabolism that necessitated high doses to recapitulate exposure conditions observed in human populations. We hypothesized that inhalation of TCE would induce significantly more potent neurodegeneration than ingestion and better recapitulate environmental conditions of vapor intrusion or off gassing from liquid TCE. To this end, we developed a novel, whole-body passive exposure inhalation chamber in which we exposed 10-month-old male and female Lewis rats to 50 ppm TCE (time weighted average, TWA) or filtered room air (control) over 8 weeks. In addition, we exposed 12-month-old male and female C57Bl/6 mice to 100 ppm TCE (TWA) or control over 12 weeks. Both rats and mice exposed to chronic TCE inhalation showed significant degeneration of nigrostriatal dopaminergic neurons as well as motor and gait impairments. TCE exposure also induced accumulation of pSer129-αSyn in dopaminergic neurons as well as microglial activation within the substantia nigra of rats. Collectively, these data indicate that TCE inhalation causes highly potent dopaminergic neurodegeneration and recapitulates some of the observed neuropathology associated with PD, providing a future platform for insight into the mechanisms and environmental conditions that influence PD risk from TCE exposure.

Neuroprotective effects of GSK-343 in an in vivo model of MPTP-induced nigrostriatal degeneration

Parkinson’s disease (PD) is characterized by the degeneration of dopaminergic nigrostriatal neurons, which causes disabling motor disorders. Scientific findings support the role of epigenetics mechanism in the development and progression of many neurodegenerative diseases, including PD. In this field, some studies highlighted an upregulation of Enhancer of zeste homolog 2 (EZH2) in the brains of PD patients, indicating the possible pathogenic role of this methyltransferase in PD. The aim of this study was to evaluate the neuroprotective effects of GSK-343, an EZH2 inhibitor, in an in vivo model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic degeneration. Specifically, nigrostriatal degeneration was induced by MPTP intraperitoneal injection. GSK-343 was administered intraperitoneally daily at doses of 1 mg/kg, 5 mg/kg and 10 mg/kg, mice were killed 7 days after MPTP injection. Our results demonstrated that GSK-343 treatment significantly improved behavioral deficits and reduced the alteration of PD hallmarks. Furthermore, GSK-343 administration significantly attenuated the neuroinflammatory state through the modulation of canonical and non-canonical NF-κB/IκBα pathway as well as the cytokines expression and glia activation, also reducing the apoptosis process. In conclusion, the obtained results provide further evidence that epigenetic mechanisms play a pathogenic role in PD demonstrating that the inhibition of EZH2, mediated by GSK-343, could be considered a valuable pharmacological strategy for PD.

Cntnap4 partial deficiency exacerbates α-synuclein pathology through astrocyte–microglia C3-C3aR pathway

Parkinson’s disease (PD) is the most common progressive neurodegenerative movement disorder, which is characterized by dopaminergic (DA) neuron death and the aggregation of neurotoxic α-synuclein. Cntnap4, a risk gene of autism, has been implicated to participate in PD pathogenesis. Here we showed Cntnap4 lacking exacerbates α-synuclein pathology, nigrostriatal DA neuron degeneration and motor impairment, induced by injection of adeno-associated viral vector (AAV)-mediated human α-synuclein overexpression (AAV-hα-Syn). This scenario was further validated in A53T α-synuclein transgenic mice injected with AAV-Cntnap4 shRNA. Mechanistically, α-synuclein derived from damaged DA neuron stimulates astrocytes to release complement C3, activating microglial C3a receptor (C3aR), which in turn triggers microglia to secrete complement C1q and pro-inflammatory cytokines. Thus, the astrocyte–microglia crosstalk further drives DA neuron death and motor dysfunction in PD. Furthermore, we showed that in vivo depletion of microglia and microglial targeted delivery of a novel C3aR antagonist (SB290157) rescue the aggravated α-synuclein pathology resulting from Cntnap4 lacking. Together, our results indicate that Cntnap4 plays a key role in α-synuclein pathogenesis by regulating glial crosstalk and may be a potential target for PD treatment.

Oxidative Stress and Neuroinflammation in Parkinson's Disease: The Role of Dopamine Oxidation Products.

Parkinson's disease (PD) is a chronic neurodegenerative condition affecting more than 1% of people over 65 years old. It is characterized by the preferential degeneration of nigrostriatal dopaminergic neurons, which is responsible for the motor symptoms of PD patients. The pathogenesis of this multifactorial disorder is still elusive, hampering the discovery of therapeutic strategies able to suppress the disease's progression. While redox alterations, mitochondrial dysfunctions, and neuroinflammation are clearly involved in PD pathology, how these processes lead to the preferential degeneration of dopaminergic neurons is still an unanswered question. In this context, the presence of dopamine itself within this neuronal population could represent a crucial determinant. In the present review, an attempt is made to link the aforementioned pathways to the oxidation chemistry of dopamine, leading to the formation of free radical species, reactive quinones and toxic metabolites, and sustaining a pathological vicious cycle.

Degeneration of nigrostriatal dopaminergic neurons in the early to intermediate stage of dementia with Lewy bodies and Parkinson's disease

ObjectiveTo investigate differences in nigrostriatal dopaminergic neuron degeneration between dementia with Lewy bodies (DLB) and Parkinson's disease (PD) in the early to intermediate stage of these diseases. MethodsAn integrative neuroimaging analysis was developed using 3-Tesla neuromelanin-sensitive MRI and 123I-FP-CIT dopamine transporter SPECT, and the relationship and laterality of three variables, including neuromelanin-related contrast in the substantia nigra (NRCSN) and locus coeruleus (NRCLC) and the specific binding ratio (SBR) in the striatum, were examined in detail. Patients with DLB and PD and control subjects (n = 29, 52, and 18, respectively) were enrolled. ResultsA significantly greater decrease in the SBR in the bilateral hemispheres was observed in DLB than in PD. After adjusting for the interhemispheric asymmetry in neuromelanin-related MRI contrast by using the Z-score, linear regression between the NRCSN and SBR was performed for the most-affected/least-affected sides of the hemispheres as defined by the interhemispheric differences in each variable (SBR, NRCSN, standardized [SBR + NRCSN]). In DLB, the highest, albeit statistically non-significant, correlation was observed in the SBR-based, most-affected side. In PD, the highest correlation was observed in the (SBR + NRCSN)-based, most-affected side, which approximated the value of the clinically-defined, most-affected side. A non-significant correlation was observed only in the (SBR + NRCSN)-based or clinically-defined, least-affected side. ConclusionLoss of the soma and presynaptic terminals may occur independently in DLB with a large decrease in the presynaptic terminals. The close relationship observed between the degeneration of the soma and presynaptic terminals suggested that axon degeneration may dominate in PD.

Endonuclease VIII-like 1 deficiency potentiates nigrostriatal dopaminergic neuron degeneration in a male mouse model of Parkinson's disease.

Parkinson's disease (PD) is a common movement disorder caused by a characteristic loss of dopaminergic neurons in the substantia nigra and degeneration of dopamine terminals in the dorsal striatum. Previous studies have suggested that oxidative stress-induced DNA damage may be involved in PD pathogenesis, as steady-state levels of several types of oxidized nucleobases were shown to be elevated in PD brain tissues. These DNA lesions are normally removed from the genome by base excision repair, which is initiated by DNA glycosylase enzymes such as endonuclease VIII-like 1 (Neil1). In this study, we show that Neil1 plays an important role in limiting oxidative stress-induced degeneration of dopaminergic neurons. In particular, Neil1-deficient male mice exhibited enhanced sensitivity to nigrostriatal degeneration after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, and Neil1-deficient animals had higher levels of γH2AX-marked DNA damage than wild-type (WT) controls, regardless of treatment status. Moreover, MPTP-treated Neil1-/- male mice had slightly elevated expression of genes related to the nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant pathway. Treatment with the Nrf2 activator, monomethyl fumarate, reduced PD-like behaviors and pathology in Neil1-/- male mice, suggesting that Neil1 is an important defense molecule in an oxidative cellular environment. Taken together, these results suggest that Neil1 DNA glycosylase may play an important role in limiting oxidative stress-mediated PD pathogenesis.

A review of the current research on in vivo and in vitro detection for alpha-synuclein: a biomarker of Parkinson's disease.

Parkinson's disease is a health-threatening neurodegenerative disease of the elderly with clinical manifestations of motor and non-motor deficits such as tremor palsy and loss of smell. Alpha-synuclein (α-Syn) is the pathological basis of PD, it can abnormally aggregate into insoluble forms such as oligomers, fibrils, and plaques, causing degeneration of nigrostriatal dopaminergic neurons in the substantia nigra in the patient's brain and the formation of Lewy bodies (LBs) and Lewy neuritis (LN) inclusions. As a result, achieving α-Syn aggregate detection in the early stages of PD can effectively stop or delay the progression of the disease. In this paper, we provide a brief overview and analysis of the molecular structures and α-Syn in vivo and in vitro detection methods, such as mass spectrometry, antigen-antibody recognition, electrochemical sensors, and imaging techniques, intending to provide more technological support for detecting α-Syn early in the disease and intervening in the progression of Parkinson's disease.

Levodopa u terapiji Parkinsonove bolesti

January 2023 marks the 100th anniversary of the birth of Arvid Carlsson, a Swedish scientist, one of the three winners of the Nobel Prize in Medicine in 2000 "for proving that Dopamine is a brain neurotransmitter whose deficiency leads to the symptoms of Parkinson's disease". Levodopa therapy is one of the main achievements of neurology in the twentieth century, and Parkinson' s disease was the first disease in which a specific neurochemical deficiency was confirmed in defined regions of the brain, which forms the basis for rational, chemically supported therapy. The paper briefly reviews the most important achievements in the discovery of Dopamine and levodopa, as well as their functions in the development of Parkinson's disease. Dopamine synthesis, understanding of levodopa synthesis method, possibility of measuring Dopamine concentration in putamen and caudate and its loss in Parkinson' s disease, along with histochemical visualization of nigrostriatal pathway and animal lesion model, enabled understanding of the role of nigrostriatal Dopamine system in the development of Parkinson's disease symptoms. Part of the work is devoted to the metabolism of Dopamine in healthy dopaminergic neurons, and then to its functioning in dopaminergic neurons of Parkinson's disease patients. It is known that in Parkinson's disease, Dopamine deficiency occurs due to selective degeneration of nigrostriatal dopaminergic neurons. Their suffering is triggered by a cascade of events that included the action of potential toxins, the influence of susceptibility genes on the body's response to them, oxidative stress caused by mitochondrial dysfunction, dysfunction of the ubiquitous proteasomal system that leads to the accumulation of incorrectly "packaged" proteins, the exhaustion of the endoplasmic reticulum system and the activation of mycoglia that follows inflammatory process. These changes can lead to programmed cell death of dopaminergic neurons with consequent Dopamine deficiency and the development of PD. Special attention is paid to the consequences of neuron loss on the functioning of the remaining dopaminergic neurons and Dopamine receptors, with reference to the therapeutic motor complications that may arise on that occasion. The basic assumptions about the occurrence of therapeutic complications are still related to the pharmacokinetics of levodopa and the model of its delivery to the brain, which results in non-physiological, pulsatile stimulation of Dopamine receptors. Today's possibilities in achieving a more stable concentration of levodopa with existing strategies are presented, with an answer to the question of whether continuous stimulation can be achieved under the conditions of standard, regular patients' levodopa therapy. In the short final part, the position of levodopa in the guidelines and recommendations for treatment is commented. It is expected that L-dopa will remain the "gold standard" for the treatment of PD at least until the development of more potent and safer Dopamine agonists or the development of neuroprotective or neurorestorative therapies.

AMPK-dependent autophagy activation and alpha-Synuclein clearance: a putative mechanism behind alpha-mangostin's neuroprotection in a rotenone-induced mouse model of Parkinson's disease.

Alpha-Synuclein (α-Syn) accumulation is central to the pathogenesis of Parkinson's disease (PD), hence the quest for finding potential therapeutics that may promote the α-Syn clearance is the need of the hour. To this, activation of the evolutionarily conserved protein and key regulator of the autophagy, 5'AMP-activated protein kinase (AMPK) is well-known to induce autophagy and subsequently the clearance of α-Syn aggregates. Alpha-mangostin (AM) a polyphenolic xanthone obtained from Garcinia Mangostana L. was previously reported to activate AMPK-dependent autophagy in various pre-clinical cancer models. However, no studies evidenced the effect of AM on AMPK-dependent autophagy activation in the PD. Therefore, the present study aimed to investigate the neuroprotective activity of AM in the chronic rotenone mouse model of PD against rotenone-induced α-Syn accumulation and to dissect molecular mechanisms underlying the observed neuroprotection. The findings showed that AM exerts neuroprotection against rotenone-induced α-Syn accumulation in the striatum and cortex by activating AMPK, upregulating autophagy (LC3II/I, Beclin-1), and lysosomal (TFEB) markers. Of note, an in-vitro study utilizing rat pheochromocytoma cells verified that AM conferred the neuroprotection only through AMPK activation, as the presence of inhibitors of AMPK (dorsomorphin) and autophagy (3-methyl adenine) failed to mitigate rotenone-induced α-Syn accumulation. Moreover, AM also counteracted rotenone-induced behavioral deficits, oxidative stress, and degeneration of nigro-striatal dopaminergic neurons. In conclusion, AM provided neuroprotection by ameliorating the rotenone-induced α-Syn accumulation through AMPK-dependent autophagy activation and it can be considered as a therapeutic agent which might be having a higher translational value in the treatment of PD.

Characterization of Nasco grape pomace-loaded nutriosomes and their neuroprotective effects in the MPTP mouse model of Parkinson's disease.

Grape pomaces have recently received great attention for their richness in polyphenols, compounds known to exert anti-inflammatory and antioxidant effects. These pomaces, however, have low brain bioavailability when administered orally due to their extensive degradation in the gastrointestinal tract. To overcome this problem, Nasco pomace extract was incorporated into a novel nanovesicle system called nutriosomes, composed of phospholipids (S75) and water-soluble maltodextrin (Nutriose® FM06). Nutriosomes were small, homogeneously dispersed, had negative zeta potential, and were biocompatible with intestinal epithelial cells (Caco-2). Nasco pomace extract resulted rich in antioxidant polyphenols (gallic acid, catechin, epicatechin, procyanidin B2, and quercetin). To investigate the neuroprotective effect of Nasco pomace in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease (PD), Nasco nutriosomes or Nasco suspension was administered intragastrically and their neuroprotective effects were evaluated. Degeneration of nigro-striatal dopaminergic neurons induced by subacute MPTP treatment, the pathological hallmark of PD, was assessed through immunohistochemical evaluation of tyrosine hydroxylase (TH) in the caudate-putamen (CPu) and substantia nigra pars compacta (SNc), and the dopamine transporter (DAT) in CPu. Immunohistochemical analysis revealed that Nasco nutriosomes significantly prevented the reduction in TH- and DAT-positive fibres in CPu, and the number of TH-positive cells in SNc following subacute MPTP treatment, while Nasco suspension counteracted MPTP toxicity exclusively in SNc. Overall, these results highlight the therapeutic effects of Nasco pomace extract when administered in a nutriosome formulation in the subacute MPTP mouse model of PD and validate the effectiveness of the nutriosome preparation over suspension as an innovative nano-drug delivery system for in vivo administration.

Removal of proteinase K resistant αSyn species does not correlate with cell survival in a virus vector-based Parkinson's disease mouse model

Parkinson's disease (PD) is characterized by degeneration of nigrostriatal dopaminergic neurons and accumulation of α-synuclein (αSyn) as Lewy bodies. Currently, there is no disease-modifying therapy available for PD. We have shown that a small molecular inhibitor for prolyl oligopeptidase (PREP), KYP-2047, relieves αSyn-induced toxicity in various PD models by inducing autophagy and preventing αSyn aggregation. In this study, we wanted to study the effects of PREP inhibition on different αSyn species by using cell culture and in vivo models.We used Neuro2A cells with transient αSyn overexpression and oxidative stress or proteasomal inhibition-induced αSyn aggregation to assess the effect of KYP-2047 on soluble αSyn oligomers and on cell viability. Here, the levels of soluble αSyn were measured by using ELISA, and the impact of KYP-2047 was compared to anle138b, nilotinib and deferiprone. To evaluate the effect of KYP-2047 on αSyn fibrillization in vivo, we used unilateral nigral AAV1/2-A53T-αSyn mouse model, where the KYP-2047 treatment was initiated two- or four-weeks post injection.KYP-2047 and anle138b protected cells from αSyn toxicity but interestingly, KYP-2047 did not reduce soluble αSyn oligomers. In AAV-A53T-αSyn mouse model, KYP-2047 reduced significantly proteinase K-resistant αSyn oligomers and oxidative damage related to αSyn aggregation. However, the KYP-2047 treatment that was initiated at the time of symptom onset, failed to protect the nigrostriatal dopaminergic neurons. Our results emphasize the importance of whole αSyn aggregation process in the pathology of PD and raise an important question about the forms of αSyn that are reasonable targets for PD drug therapy.

Animal models of Parkinson's disease: a guide to selecting the optimal model for your research.

Parkinson’s disease (PD) is a complex, multisystem disorder characterised by α-synuclein (SNCA) pathology, degeneration of nigrostriatal dopaminergic neurons, multifactorial pathogenetic mechanisms and expression of a plethora of motor and non-motor symptoms. Animal models of PD have already been instructive in helping us unravel some of these aspects. However, much remains to be discovered, requiring continued interrogation by the research community. In contrast with the situation for many neurological disorders, PD benefits from of a wide range of available animal models (pharmacological, toxin, genetic and α-synuclein) but this makes selection of the optimal one for a given study difficult. This is especially so when a study demands a model that displays a specific combination of features. While many excellent reviews of animal models already exist, this review takes a different approach with the intention of more readily informing this decision-making process. We have considered each feature of PD in turn – aetiology, pathology, pathogenesis, motor dysfunctions and non-motor symptoms (NMS) – highlighting those animal models that replicate each. By compiling easily accessible tables and a summary figure, we aim to provide the reader with a simple, go-to resource for selecting the optimal animal model of PD to suit their research needs.

Asparagine endopeptidase deletion ameliorates cognitive impairments by inhibiting proinflammatory microglial activation in MPTP mouse model of Parkinson disease

In addition to motor dysfunction, cognitive impairments have been reported to occur in patients with early-stage Parkinson’s disease (PD). In this study, we examined a PD mouse model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This treatment led to the degeneration of nigrostriatal dopaminergic neurons in mice, a phenomenon that is consistent with previous studies. Besides, spatial memory and object recognition of MPTP-treated mice were impaired, as denoted by the Morris water maze (MWM) and novel object recognition (NOR) tests, respectively. Moreover, hippocampal synaptic plasticity (long-term potentiation and depotentiation) and the levels of synaptic proteins in hippocampus were decreased after MPTP treatment. We also found that MPTP resulted in the microglial activation and an inflammatory response in the striatum and hippocampus. Mammalian asparagine endopeptidase (AEP), a cysteine lysosomal protease, is involved in the cleavage and activation of Toll-like receptors (TLRs). The deletion of AEP can inhibit TLR4 in a mouse model of Alzheimer’s disease, and TLR4 is upregulated in PD, inducing microglial activation and inflammation. We found that AEP deletion provided greater resistance to the toxic effects of MPTP. AEP knockout ameliorated the cognition and the synaptic plasticity defects in the hippocampus. Furthermore, AEP deletion decreased the expression of TLR4 and reduced microglial activation and the levels of several proinflammatory cytokines. Thus, we suggest that AEP plays a role in the inflammation induced by MPTP, and TLR4 might also involve in this process. AEP deletion could be a possible treatment strategy for the cognitive deficits of PD.

Astrocytes and retrograde degeneration of nigrostriatal dopaminergic neurons in Parkinson\u2019s disease: removing axonal debris

ObjectiveThe dopaminergic nigrostriatal neurons (DA cells) in healthy people present a slow degeneration with aging, which produces cellular debris throughout life. About 2%–5% of people present rapid cell degeneration of more than 50% of DA cells, which produces Parkinson’s disease (PD). Neuroinflammation accelerates the cell degeneration and may be critical for the transition between the slow physiological and the rapid pathological degeneration of DA cells, particularly when it activates microglial cells of the medial forebrain bundle near dopaminergic axons. As synaptic debris produced by DA cell degeneration may trigger the parkinsonian neuroinflammation, this study investigated the removal of axonal debris produced by retrograde degeneration of DA cells, paying particular attention to the relative roles of astrocytes and microglia.MethodsRats and mice were injected in the lateral ventricles with 6-hydroxydopamine, inducing a degeneration of dopaminergic synapses in the striatum which was not accompanied by non-selective tissue damage, microgliosis or neuroinflammation. The possible retrograde degeneration of dopaminergic axons, and the production and metabolization of DA-cell debris were studied with immunohistochemical methods and analyzed in confocal and electron microscopy images.ResultsThe selective degeneration of dopaminergic synapses in the striatum was followed by a retrograde degeneration of dopaminergic axons whose debris was found within spheroids of the medial forebrain bundle. These spheroids retained mitochondria and most (e.g., tyrosine hydroxylase, the dopamine transporter protein, and amyloid precursor protein) but not all (e.g., α-synuclein) proteins of the degenerating dopaminergic axons. Spheroids showed initial (autophagosomes) but not late (lysosomes) components of autophagy (incomplete autophagy). These spheroids were penetrated by astrocytic processes of the medial forebrain bundle, which provided the lysosomes needed to continue the degradation of dopaminergic debris. Finally, dopaminergic proteins were observed in the cell somata of astrocytes. No microgliosis or microglial phagocytosis of debris was observed in the medial forebrain bundle during the retrograde degeneration of dopaminergic axons.ConclusionsThe present data suggest a physiological role of astrocytic phagocytosis of axonal debris for the medial forebrain bundle astrocytes, which may prevent the activation of microglia and the spread of retrograde axonal degeneration in PD.

Resveratrol in Rodent Models of Parkinson's Disease: A Systematic Review of Experimental Studies.

Parkinson’s disease (PD) is a common neurodegenerative disease featured by progressive degeneration of nigrostriatal dopaminergic neurons (DA) accompanied with motor function impairment. Accumulating evidence has demonstrated that natural compounds from herbs have potent anti-PD efficacy in PD models. Among those compounds, resveratrol, a polyphenol found in many common plants and fruits, is more effective against PD. Resveratrol has displayed a potent neuroprotective efficacy in several PD animal models. However, there is still no systematic analysis of the quality of methodological design of these studies, nor of their results. In this review, we retrieved and analyzed 18 studies describing the therapeutic effect of resveratrol on PD animal models. There are 5 main kinds of PD rodent models involved in the 18 articles, including chemical-induced (MPTP, rotenone, 6-OHDA, paraquat, and maneb) and transgenic PD models. The neuroprotective mechanisms of resveratrol were mainly concentrated on the antioxidation, anti-inflammation, ameliorating mitochondrial dysfunction, and motor function. We discussed the disadvantages of different PD animal models, and we used meta-analysis approach to evaluate the results of the selected studies and used SYRCLE’s risk of bias tool to evaluate the methodological quality. Our analytical approach minimized the bias of different studies. We have also summarized the pharmacological mechanisms of resveratrol on PD models as reported by the researchers. The results of this study support the notion that resveratrol has significant neuroprotective effects on different PD models quantified using qualitative and quantitative methods. The collective information in our review can guide researchers to further plan their future experiments without any hassle regarding preclinical and clinical studies. In addition, this collective assessment of animal studies can provide a qualitative analysis of different PD animal models, either to guide further testing of these models or to avoid unnecessary duplication in their future research.

A Mouse Model of Nigrostriatal Dopaminergic Axonal Degeneration As a Tool for Testing Neuroprotectors.

Degeneration of nigrostriatal dopaminergic neurons in Parkinson’s disease begins from the axonal terminals in the striatum and, then, in retrograde fashion, progresses to the cell bodies in the substantia nigra. Investigation of the dynamics of axonal terminal degeneration may help in the identification of new targets for neuroprotective treatment and be used as a tool for testing potential drugs. We have shown that the degeneration rate of dopaminergic axonal terminals changes over time, and that the striatal dopamine concentration is the most sensitive parameter to the action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This model was validated using neuroprotectors with well-known mechanisms of action: the dopamine transporter inhibitor nomifensine and SEMAX peptide that stimulates the secretion of endogenous neurotrophic factors or acts as an antioxidant. Nomifensine was shown to almost completely protect dopaminergic fibers from the toxic effect of MPTP and maintain the striatal dopamine concentration at the control level. However, SEMAX, slightly but reliably, increased striatal dopamine when administered before MPTP treatment, which indicates that it is more effective as an inductor of endogenous neurotrophic factor secretion rather than as an antioxidant.

Acquired dysregulation of dopamine homeostasis reproduces features of Parkinson\u2019s disease

The catecholamine neurotransmitter dopamine has the potential to act as an endogenous neurotoxin when its vesicular sequestration is dysregulated. Despite postmortem analyses from patients with Parkinson’s disease that demonstrate decreased vesicular sequestration of dopamine with a corresponding increase in dopamine metabolism, dopamine’s contribution to nigrostriatal dopaminergic degeneration in Parkinson’s disease has been debated. Here, we present a new in vivo model demonstrating the induction of Parkinson’s disease-associated pathogenic mechanisms of degeneration resulting from acquired dysregulation of dopamine sequestration in nigrostriatal dopaminergic neurons in adult rats. Utilizing adeno-associated virus (serotype 2), viral-mediated small-hairpin RNA interference of endogenous vesicular monoamine transporter 2 (VMAT2) expression resulted in a loss of VMAT2 protein expression in transduced dopaminergic cell bodies in the substantia nigra with a corresponding loss of VMAT2 protein within the striatal terminals. The loss of VMAT2 resulted in an accumulation of cytosolic dopamine and subsequent increased dopamine metabolism, deficits in dopamine-mediated behaviors, and degeneration of nigrostriatal dopaminergic neurons that was rescued through reintroduction of exogenous VMAT2, demonstrating that the toxicity was specific to the loss of VMAT2. Analysis of parkinsonian pathogenic mechanisms of degeneration identified oxidative damage, activation of Parkinson’s disease-associated kinase LRRK2, and the formation of aberrant α-synuclein. This model demonstrates that a progressive acquired loss of VMAT2 expression in adulthood is sufficient to induce Parkinson’s disease-associated pathogenic mechanisms of degeneration and provides a new model to further investigate the consequences of cytosolic dopamine.

Changes in Striatal Medium Spiny Neuron Morphology Resulting from Dopamine Depletion Are Reversible.

The classical motor symptoms of Parkinson’s disease (PD) are caused by degeneration of dopaminergic neurons in the substantia nigra, which is followed by secondary dendritic pruning and spine loss at striatal medium spiny neurons (MSN). We hypothesize that these morphological changes at MSN underlie at least in part long-term motor complications in PD patients. In order to define the potential benefits and limitations of dopamine substitution, we tested in a mouse model whether dendritic pruning and spine loss can be reversible when dopaminergic axon terminals regenerate. In order to induce degeneration of nigrostriatal dopaminergic neurons we used the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57BL/6J mice; 30 mg/kg MPTP was applied i.p. on five consecutive days. In order to assess the consequences of dopamine depletion, mice were analyzed 21 days after the last injection. In order to test reversibility of MSN changes we exploited the property of this model that striatal axon terminals regenerate by sprouting within 90 days and analyzed a second cohort 90 days after MPTP. Degeneration of dopaminergic neurons was confirmed by counting TH-positive neurons in the substantia nigra and by analyzing striatal catecholamines. Striatal catecholamine recovered 90 days after MPTP. MSN morphology was visualized by Golgi staining and quantified as total dendritic length, number of dendritic branch points, and density of dendritic spines. All morphological parameters of striatal MSN were reduced 21 days after MPTP. Statistical analysis indicated that dendritic pruning and the reduction of spine density represent two distinct responses to dopamine depletion. Ninety days after MPTP, all morphological changes recovered. Our findings demonstrate that morphological changes in striatal MSN resulting from dopamine depletion are reversible. They suggest that under optimal conditions, symptomatic dopaminergic therapy might be able to prevent maladaptive plasticity and long-term motor complications in PD patients.