-
Neuroscience Letters Nov 2020Lenalidomide is a centrally active thalidomide analog that has potent anti-inflammatory and antiangiogenic activities. Currently, it is primarily used in the treatment...
Lenalidomide is a centrally active thalidomide analog that has potent anti-inflammatory and antiangiogenic activities. Currently, it is primarily used in the treatment of multiple myeloma and myelodysplastic syndromes. However, recent studies have revealed in addition to neuroprotection and neuromodulation of lenalidomide. Because of this combination of inflammation and neuro-immunogenic properties, lenalidomide is considered as a high potential compound for the treatment of neurodegenerative diseases. Despite intensive research during the last decade, the role of neurotrophic elements in the effect of lenalidomide is still not well understood. Therefore, in the current study, the effects of lenalidomide on neurodegeneration were investigated in a rotenone model of Parkinson's disease (PD) rat model. The PD rat model was generated by rotenone injection into the substantia nigra pars compacta (SNpc). After validation of the PD model, the rats were treated with lenalidomide (100 mg/kg) for 28 days. Our data shows that lenalidomide alleviated rotenone-induced motor impairments and deficits in dopamine-related behaviors and resulted in increased levels of tumor necrosis factor-α and calcium-binding protein B in the SNpc. Moreover, chronic lenalidomide treatment resulted increase in transforming growth factor immunoreactivity and brain derived neurotrophic factor expression in the SNPc. In addition, chronic treatment mitigated tyrosine hydroxylase expression prevented the rotenone-induced decrease in dopamine levels, and consequently a decrease in caspase-3/9 immunoreactivity. This thus shows that chronic lenalidomide treatment improves neuronal survival. Together with our data demonstrate that lenalidomide, in addition to its anti-inflammatory and immunomodulatory actions, is also capable of increasing neurotrophic factors in the SNpc, thereby preventing rotenone-induced motor impairments.
Topics: Animals; Brain-Derived Neurotrophic Factor; Calcium-Binding Proteins; Caspase 9; Cell Survival; Dopamine; Dopaminergic Neurons; Lenalidomide; Motor Activity; Neuroprotective Agents; Parkinsonian Disorders; Pars Compacta; Rats; Rotenone; Tumor Necrosis Factor-alpha; Tyrosine 3-Monooxygenase
PubMed: 32932183
DOI: 10.1016/j.neulet.2020.135308 -
Neurobiology of Disease Jul 2022In recent years progress in molecular biology and genetics have advanced our understanding of neurological disorders and highlighted synergistic relationships with... (Review)
Review
In recent years progress in molecular biology and genetics have advanced our understanding of neurological disorders and highlighted synergistic relationships with inflammatory and age-related processes. Parkinson's disease (PD) is a common neurodegenerative disorder that is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Increasing extensive evidence supports the contribution of genetic risk variants and inflammation in the pathobiology of this disease. Functional and genetic studies demonstrate an overlap between genes linked to increased risk for PD and autoimmune diseases. Variants identified in loci adjacent to LRRK2, GBA, and HLA establish a crosstalk between the pathobiologies of the two disease spectra. Furthermore, common signalling pathways associated with the pathogenesis of genetic PD are also relevant to inflammatory signaling include MAPK, NF-κB, Wnt and inflammasome signaling. Importantly, post-mortem analyses of brain and cerebrospinal fluid from PD patients show the accumulation of proinflammatory cytokines. In this review we will focus on the principal mechanisms of genetic, inflammatory and age-related risk that intersect in the pathogenesis of PD.
Topics: Dopaminergic Neurons; Humans; Immunity, Innate; Parkinson Disease; Pars Compacta; Signal Transduction
PubMed: 35405260
DOI: 10.1016/j.nbd.2022.105721 -
Neuroscience Letters Sep 2020Parkinson's disease (PD) is the most widespread movement disorder with a prevalence of 1 in 1000 individuals above 60 years of age. Until now, understanding the... (Review)
Review
Parkinson's disease (PD) is the most widespread movement disorder with a prevalence of 1 in 1000 individuals above 60 years of age. Until now, understanding the pathological mechanisms of PD to translate them into therapy has remained a high research priority. In this review, we highlight evidence describing the involvement of microglial dysfunction in PD. Thereafter, we provide current knowledge suggesting that the substantia nigra pars compacta and putamen, compared to other brain regions, show a reduced microglial density, as well as altered morphological and functional properties in homeostatic conditions, while presenting dystrophic features associated with aging. Further, we describe that this defective microglial programing emerges as early as the second postnatal week, persists until adulthood and impacts negatively on their transcriptional pattern and provision of local trophic support. We emphasize the role of α-synuclein oligomers as a major dysfunctional signal underlining microglial-mediated phenotypic switch and adaptive response contributing to neurodegeneration. Moreover, we explore available avenues should microglia be considered as target for neuroprotective or restorative strategies including preventing the aggregation of α-synuclein protofibrils formation. However, we provide a note of caution regarding the success of microglial-targeted PD strategies, using minocycline as an example. In conclusion, we discuss putative neuroprotective agents that were unsuccessful in previous trials but could be reconsidered by focusing on the stage of microglial-dependent pathogenic events during PD in suitable cohorts of patients.
Topics: Animals; Humans; Microglia; Parkinson Disease; Pars Compacta; Phenotype; Putamen
PubMed: 32561452
DOI: 10.1016/j.neulet.2020.135164 -
Neuroscience Apr 1984In an attempt to evaluate the cellular organization and efferent projections of the nucleus tegmenti pedunculopontinus pars compacta, several experiments were performed...
In an attempt to evaluate the cellular organization and efferent projections of the nucleus tegmenti pedunculopontinus pars compacta, several experiments were performed in the rat. From measurements of neurons in the nucleus tegmenti pedunculopontinus pars compacta in Nissl-stained sections, the nucleus was observed to contain many large neurons which made it possible to demarcate this nucleus from surrounding pontomesencephalic reticular formation. Two other neuronal populations, medium and small neurons, were also seen in the nucleus tegmenti pedunculopontinus pars compacta. Detailed measurements showed that 90% by volume of all neurons in the nucleus tegmenti pedunculopontinus pars compacta were large and medium-sized neurons. After injections of [3]leucine into the nucleus tegmenti pedunculopontinus pars compacta, transported label was observed in dorsally and ventrally coursing ascending fibers. The dorsally coursing fibers entered the centrolateral nucleus and centre median-parafascicular complex of the thalamus. The ventrally coursing fibers produced accumulation of silver grains in the ventral tegmental area, substantia nigra pars compacta, subthalamic nucleus, zona incerta and lateral hypothalamus. Crossed fibers of the nucleus tegmenti pedunculopontinus pars compacta were observed sparsely at the levels of the thalamus and posterior commissure, and to a greater degree through the supraoptic commissure of Meynert. Much less anterograde labeling was seen in the equivalent terminal sites on the contralateral side of the brain. By electron microscopic autoradiography major terminal sites of axons of the nucleus tegmenti pedunculopontinus pars compacta were examined in rats injected with [3H]leucine in the nucleus tegmenti pedunculopontinus pars compacta and later injected with horseradish peroxidase in the striatum and pallidum. Statistical data showed preferential radiolabeling of terminals forming asymmetrical synaptic contact with dendrites in the centrolateral nucleus, centre median-parafascicular complex and subthalamic nucleus. Apparent terminations in the substantia nigra pars compacta proposed in earlier studies and shown in the present light microscopic autoradiograms were not supported by this ultrastructural analysis. Several radiolabeled terminals of the asymmetrical type contacting horseradish peroxidase labeled dendrites in the thalamus confirmed direct input from the nucleus tegmenti pedunculopontinus pars compacta to the thalamostriate projection neurons. [3H]choline injections into the thalamus and subthalamic nucleus produced retrograde perikaryal labeling of large neurons in the nucleus tegmenti pedunculopontinus pars compacta.
Topics: Animals; Brain Mapping; Cholinergic Fibers; Diencephalon; Efferent Pathways; Male; Microscopy, Electron; Pons; Rats; Rats, Inbred Strains; Substantia Nigra; Tegmentum Mesencephali
PubMed: 6738860
DOI: 10.1016/0306-4522(84)90204-5 -
Journal of Biomedical Science Mar 2018Parkinson's disease is described as resulting from dopaminergic cells progressive degeneration, specifically in the substantia nigra pars compacta that influence the... (Review)
Review
BACKGROUND
Parkinson's disease is described as resulting from dopaminergic cells progressive degeneration, specifically in the substantia nigra pars compacta that influence the voluntary movements control, decision making and time perception.
AIM
This review had a goal to update the relation between time perception and Parkinson's Disease.
METHODOLOGY
We used the PRISMA methodology for this investigation built guided for subjects dopaminergic dysfunction in the time judgment, pharmacological models with levodopa and new studies on the time perception in Parkinson's Disease. We researched on databases Scielo, Pubmed / Medline and ISI Web of Knowledge on August 2017 and repeated in September 2017 and February 2018 using terms and associations relevant for obtaining articles in English about the aspects neurobiology incorporated in time perception. No publication status or restriction of publication date was imposed, but we used as exclusion criteria: dissertations, book reviews, conferences or editorial work.
RESULTS/DISCUSSION
We have demonstrated that the time cognitive processes are underlying to performance in cognitive tasks and that many are the brain areas and functions involved and the modulators in the time perception performance.
CONCLUSIONS
The influence of dopaminergic on Parkinson's Disease is an important research tool in Neuroscience while allowing for the search for clarifications regarding behavioral phenotypes of Parkinson's disease patients and to study the areas of the brain that are involved in the dopaminergic circuit and their integration with the time perception mechanisms.
Topics: Basal Ganglia; Parkinson Disease; Pars Compacta; Synaptic Transmission; Time Perception
PubMed: 29554962
DOI: 10.1186/s12929-018-0428-2 -
Neurochemistry International Oct 2019Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide and is characterized for being an idiopathic and multifactorial disease. Extensive... (Review)
Review
Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide and is characterized for being an idiopathic and multifactorial disease. Extensive research has been conducted to explain the origin of the disease, but it still remains elusive. It is well known that dopamine oxidation, through the endogenous formation of toxic metabolites, is a key process in the activation of a cascade of molecular events that leads to cellular death in the hallmark of PD. Thio-catecholamines, such as 5-S-cysteinyl-dopamine, 5-S-glutathionyl-dopamine and derived benzothiazines, are endogenous metabolites formed in the dopamine oxidative degradation pathway. Those metabolites have been shown to be highly toxic to neurons in the substantia nigra pars compacta, activating molecular mechanisms that ultimately lead to neuronal death. In this review we describe the origin, formation and the toxic effects of 5-S-cysteinyl-dopamine and its oxidative derivatives that cause death to dopaminergic neurons. Furthermore, we correlate the formation of those metabolites with the neurodegeneration progress in PD. In addition, we present the reported neuroprotective strategies of products that protect against the cellular damage of those thio-catecholamines. Finally, we discuss the advantages in the use of 5-S-cysteinyl-dopamine as a potential biomarker for PD.
Topics: Biomarkers; Dopamine; Dopaminergic Neurons; Endoplasmic Reticulum Stress; Humans; Metabolic Networks and Pathways; Mitochondria; Nerve Tissue Proteins; Neuroprotective Agents; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Pars Compacta; Sulfur; alpha-Synuclein
PubMed: 31369776
DOI: 10.1016/j.neuint.2019.104514 -
Current Drug Research Reviews 2021Evidence has emerged over the last 2 decades to ascertain the proof of concepts viz. mitochondrial dysfunction, inflammation-derived oxidative damage and... (Review)
Review
Evidence has emerged over the last 2 decades to ascertain the proof of concepts viz. mitochondrial dysfunction, inflammation-derived oxidative damage and cytokine-induced toxicity that play a significant role in Parkinson's disease (PD). The available pharmacotherapies for PD are mainly symptomatic and typically indicate L-DOPA to restrain dopamine deficiency and its consequences. In the 21st century, the role of antibiotics has emerged at the forefront of medicines in health and human illness. There are several experimental and pre-clinical evidences that support the potential use of antibiotics as a neuroprotective agent. The astonishing effects of antibiotics and their neuroprotective properties against neurodegeneration and neuro-inflammation would be phenomenal for the development of effective therapy against PD. Antibiotics are also testified as useful in not only preventing the formation of alpha-synuclein but also acting on mitochondrial dysfunction and neuro-inflammation. Thus, the possible therapy with antibiotics in PD would impact both pathways leading to neuronal cell death in substantia nigra and pars compacta in the midbrain. Moreover, the antibiotic-based pharmacotherapy will open a scientific research avenue to add more to the evidence-based and rational use of antibiotics for the treatment and management of PD and other neurodegenerative disorders.
Topics: Anti-Bacterial Agents; Humans; Levodopa; Parkinson Disease; Pars Compacta; Substantia Nigra
PubMed: 33719951
DOI: 10.2174/2589977513666210315095133 -
Neuroscience Sep 1994Turning in circles is among the behaviors elicited by unilateral cholinergic stimulation of the substantia nigra. Recent studies have shown that microinjection of...
Cholinergic stimulation of rostral and caudal substantia nigra pars compacta produces opposite effects on circling behavior and striatal dopamine release measured by brain microdialysis.
Turning in circles is among the behaviors elicited by unilateral cholinergic stimulation of the substantia nigra. Recent studies have shown that microinjection of cholinergic agonists into the substantia nigra pars compacta increases dopamine release and turnover in the striatum of anesthetized rats [Hernández-López et al. (1992) Brain. Res. 598, 114-120; Blaha and Winn (1993) J. Neurosci, 13, 1035-1044]. In this study, the relationship between circling behavior and striatal dopamine release following cholinergic stimulation of the substantia nigra pars compacta neurons was assessed by brain microdialysis in awake rats. The results indicate that cholinergic stimulation of the substantia nigra pars compacta with the mixed nicotinic-muscarinic cholinergic agonist carbachol modulates striatal dopamine release, and this effect is accompanied by circling behavior and stereotypies. Microinjection of carbachol (109 nmol) in the caudal portions of the substantia nigra pars compacta induced contralateral circling associated with an increase of dopamine release in neostriatum. On the contrary, ipsilateral circling and reduction of striatal dopamine release was elicited when the same dose of the drug was applied in the rostral portions of the substantia nigra pars compacta. The above findings are in accordance with recent electrophysiological studies suggesting the existence of sub-populations of nigrostriatal dopaminergic neurons, and indicate that the substantia nigra pars compacta is functionally compartmentalized. We conclude that the cholinergic input to the substantia nigra pars compacta could modulate the motor behavior through regulating the firing rate of nigrostriatal dopaminergic neurons and dopamine release in the neostriatum.
Topics: Animals; Carbachol; Corpus Striatum; Dopamine; Functional Laterality; Kinetics; Male; Microdialysis; Microinjections; Rats; Rats, Wistar; Stereotyped Behavior; Substantia Nigra; Time Factors
PubMed: 7830890
DOI: 10.1016/0306-4522(94)90378-6 -
Movement Disorders : Official Journal... Apr 2021Neuromelanin-sensitive magnetic resonance imaging techniques have been developed but currently require relatively long scan times. The aim of this study was to assess...
BACKGROUND
Neuromelanin-sensitive magnetic resonance imaging techniques have been developed but currently require relatively long scan times. The aim of this study was to assess the ability of black-blood delay alternating with nutation for tailored excitation-prepared T1-weighted variable flip angle turbo spin echo (DANTE T1-SPACE), which provides relatively high resolution with a short scan time, to visualize neuromelanin in the substantia nigra pars compacta (SNpc).
METHODS
Participants comprised 49 healthy controls and 25 patients with Parkinson's disease (PD). Contrast ratios of SNpc and hyperintense SNpc areas, which show pixels brighter than thresholds, were assessed between DANTE T1-SPACE and T1-SPACE in healthy controls. To evaluate the diagnostic ability of DANTE T1-SPACE, the contrast ratios and hyperintense areas were compared between healthy and PD groups, and receiver operating characteristic analyses were performed. We also compared areas under the curve (AUCs) between DANTE T1-SPACE and the previously reported gradient echo neuromelanin (GRE-NM) imaging. Each analysis was performed using original images in native space and images transformed into Montreal Neurological Institute space. Values of P < 0.05 were considered significant.
RESULTS
DANTE T1-SPACE showed significantly higher contrast ratios and larger hyperintense areas than T1-SPACE. On DANTE T1-SPACE, healthy controls showed significantly higher contrast ratios and larger hyperintense areas than patients with PD. Hyperintense areas in native space analysis achieved the best AUC (0.94). DANTE T1-SPACE showed AUCs as high as those of GRE-NM.
CONCLUSIONS
DANTE T1-SPACE successfully visualized neuromelanin of the SNpc and showed potential for evaluating PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Magnetic Resonance Imaging; Melanins; Parkinson Disease; Pars Compacta; Substantia Nigra
PubMed: 33314293
DOI: 10.1002/mds.28417 -
Journal of Immunology Research 2018Models of Parkinson's disease with neurotoxins have shown that microglial activation does not evoke a typical inflammatory response in the substantia nigra, questioning...
Models of Parkinson's disease with neurotoxins have shown that microglial activation does not evoke a typical inflammatory response in the substantia nigra, questioning whether neuroinflammation leads to neurodegeneration. To address this issue, the archetypal inflammatory stimulus, lipopolysaccharide (LPS), was injected into the rat substantia nigra. LPS induced fever, sickness behavior, and microglial activation (OX42 immunoreactivity), followed by astrocyte activation and leukocyte infiltration (GFAP and CD45 immunoreactivities). During the acute phase of neuroinflammation, pro- and anti-inflammatory cytokines (TNF-, IL-1, IL-6, IL-4, and IL-10) responded differentially at mRNA and protein level. Increased NO production and lipid peroxidation occurred at 168 h after LPS injection. At this time, evidence of neurodegeneration could be seen, entailing decreased tyrosine hydroxylase (TH) immunoreactivity, irregular body contour, and prolongation discontinuity of TH cells, as well as apparent phagocytosis of TH cells by OX42 cells. Altogether, these results show that LPS evokes a typical inflammatory response in the substantia nigra that is followed by dopaminergic neurodegeneration.
Topics: Acute Disease; Animals; Astrocytes; Cell Differentiation; Cell Movement; Cells, Cultured; Cytokines; Disease Models, Animal; Dopaminergic Neurons; Humans; Leukocytes, Mononuclear; Lipid Peroxidation; Lipopolysaccharides; Male; Microglia; Neurodegenerative Diseases; Neurogenic Inflammation; Parkinson Disease; Pars Compacta; Rats; Rats, Wistar; Tyrosine 3-Monooxygenase
PubMed: 29854828
DOI: 10.1155/2018/1838921