Death Of DAergic Neurons Research Articles

Dopaminergic neuronal death in the substantia nigra associates with change in serum levels of TNF-α and IL-1β; evidence from early experimental model of Parkinson’s disease

ABSTRACT Purpose Studies have shown that inflammation plays a key role in etiology of Parkinson’s disease (PD). However, human studies which have evaluated association between PD and serum levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) have reported conflicting results. In this study, serum and striatum levels of these cytokines were evaluated in 6-hydroxydopamine (6-OHDA) animal model of PD. Method The neurotoxin of 6-OHDA was injected into medial forebrain bundle of right hemisphere and behavioral tests were carried out to eight weeks thereafter to evaluate severity of PD and its progress. Blood was collected before the toxin and in second and eight weeks after that. Survival of dopaminergic (DAergic) neurons in substantia nigra was assessed by immunohistochemistry. TNF-α and IL-1β levels were determined using ELISA kits. Result Severity of behavioral symptoms was gradually increased in 6-OHDA-treated rats. They showed a decrease in serum TNF-α level in the eight week and increase in IL-1β both in the second and eight weeks. They were divided into two subgroups, symptomatic and asymptomatic with severe and moderate degrees in DAergic neuronal death. Significant decrease in serum TNF-α was only observed in the symptomatic subgroup but IL-1β increased in both subgroups. Also, striatal levels of both cytokines were higher in the lesioned hemisphere. Conclusion Increase in serum IL-1β level can reflect moderate degree of lesion in substantia nigra and thereby is used for prognosis of PD before its clinical symptoms are appeared. On the other hand, an increase in serum TNF-α is appeared in advanced stage of PD.

Chronic and progressive dopaminergic neuronal death in substantia nigra associates with a decrease in serum levels of glucose and free fatty acids, the role of interlokin-1 beta.

Human studies indicate that Parkinson's disease (PD) associates with disruption in metabolism of glucose and free fatty acids (FFA). Studies have shown that interlukin-1beta (IL-1β) causes hypoglycemia through insulin- independent mechanisms. Here, we investigated association between dopaminergic neuronal death, as the main pathophysiological mechanism underlying PD, and serum levels of glucose, FFA and IL-1β in 6-hydroxydopamine (6-OHDA) animal model of PD. Neurotoxin of 6-OHDA was injected into medial forebrain bundle and multiple behavioral testes were carried out during eight weeks thereafter. Blood was collected before the toxin and in second and eight weeks thereafter. Then, brain of the animals was perfused to assess survival of dopaminergic (DAergic) neurons in substantia nigra by tyrosine hydroxylase (TH) immunohistochemistry. Glucose, FFA and IL-1β levels were determined using calorimetric method and specific ELISA kits. In compare to control, 6-OHDA- treated rats had less glucose and FFA levels in the eight week and higher IL-1β level in the both second and eight weeks. Based on severity of behavioral symptoms, 6-OHDA- treated rats were divided into two subgroups of severe and mild. Number of TH- positive cells in these subgroups was 83 and 45% less than that in control. Also, both subgroups showed less weight gain, lower glucose and FFA and higher IL-1β in eight week. Our data indicate that moderate to severe progressive DAergic neuronal death in substantia nigra associates with a decrease in serum levels of glucose and FFA. Increase in IL-1β production following neuronal death possibly mediated this decrease.

Actively targeted gold nanoparticle composites improve behavior and cognitive impairment in Parkinson's disease mice

Parkinson's disease (PD) is characterized by motor and non-motor symptoms, primarily affecting dopaminergic neurons (DAergic neurons) in substantia nigra (SN). However, it is still very challenging to identify new drugs that not only inhibit motor dysfunction but also improve non-motor dysfunction. It has been identified as a potential PD treatment that the inhibition of α-syn aggregation could decrease the death of DAergic neurons in SN. In this study, we synthesized gold nanoparticle composites (NPs) that were loaded with plasmid DNA (pDNA) to inhibit α-syn expression. In vivo, our results showed that NPs improved tyrosine hydroxylase (TH) levels and decreased aggregation of α-syn in the SN. Additionally, NPs attenuated motor dysfunction and exploration ability declined. Moreover, NPs reversed the inhibition of long-term potentiation (LTP) and improved non-motor dysfunction in PD mice. These results indicated that NPs had significantly neuroprotective effects not only in motor, but also in non-motor dysfunction to PD mice, providing a new strategy for gene therapy in PD.

Th17 Cells Induce Dopaminergic Neuronal Death via LFA-1/ICAM-1 Interaction in a Mouse Model of Parkinson's Disease.

T helper (Th)17 cells, a subset of CD4+ T lymphocytes, have strong pro-inflammatory property and appear to be essential in the pathogenesis of many inflammatory diseases. However, the involvement of Th17 cells in Parkinson's disease (PD) that is characterized by a progressive degeneration of dopaminergic (DAergic) neurons in the nigrostriatal system is unclear. Here, we aimed to demonstrate that Th17 cells infiltrate into the brain parenchyma and induce neuroinflammation and DAergic neuronal death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- or 1-methyl-4-phenylpyridinium (MPP+)-induced PD models. Blood-brain barrier (BBB) disruption in the substantia nigra (SN) was assessed by the signal of FITC-labeled albumin that was injected into blood circulation via the ascending aorta. Live cell imaging system was used to observe a direct contact of Th17 cells with neurons by staining these cells using the two adhesion molecules, leukocyte function-associated antigen (LFA)-1 and intercellular adhesion molecule (ICAM)-1, respectively. Th17 cells invaded into the SN where BBB was disrupted in MPTP-induced PD mice. Th17 cells exacerbated DAergic neuronal loss and pro-inflammatory/neurotrophic factor disorders in MPP+-treated ventral mesencephalic (VM) cell cultures. A direct contact of LFA-1-stained Th17 cells with ICAM-1-stained VM neurons was dynamically captured. Either blocking LFA-1 in Th17 cells or blocking ICAM-1 in VM neurons with neutralizing antibodies abolished Th17-induced DAergic neuronal death. These results establish that Th17 cells infiltrate into the brain parenchyma of PD mice through lesioned BBB and exert neurotoxic property by promoting glial activation and importantly by a direct damage to neurons depending on LFA-1/ICAM-1 interaction.

Brain Iron Metabolism Dysfunction in Parkinson's Disease.

Dysfunction of iron metabolism, which includes its uptake, storage, and release, plays a key role in neurodegenerative disorders, including Parkinson's disease (PD), Alzheimer's disease, and Huntington's disease. Understanding how iron accumulates in the substantia nigra (SN) and why it specifically targets dopaminergic (DAergic) neurons is particularly warranted for PD, as this knowledge may provide new therapeutic avenues for a more targeted neurotherapeutic strategy for this disease. In this review, we begin with a brief introduction describing brain iron metabolism and its regulation. We then provide a detailed description of how iron accumulates specifically in the SN and why DAergic neurons are especially vulnerable to iron in PD. Furthermore, we focus on the possible mechanisms involved in iron-induced cell death of DAergic neurons in the SN. Finally, we present evidence in support that iron chelation represents a plausable therapeutic strategy for PD.

PGC-1α/ERRα-Sirt3 Pathway Regulates DAergic Neuronal Death by Directly Deacetylating SOD2 and ATP Synthase β

Parkinson's disease (PD) heavily affects humans and little is known about its cause and pathogenesis. Sirtuin 3 (Sirt3) plays a key role in regulating mitochondrial dysfunction, which is the main cause of DAergic neuronal loss in PD. We investigated the mechanisms of neuroprotective role of Sirt3 in DAergic neuronal survival. Sirt3 was reduced in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-treated neurons with its overexpression being neuroprotective. We identified that Sirt3 interacted with manganese superoxide dismutase (SOD2) and adenosine triphosphate (ATP) synthase β and modulated their activities by deacetylating SOD2 (K130) and ATP synthase β (K485) to prevent reactive oxygen species accumulation and ATP depletion, and to alleviate DAergic neuronal death upon MPTP treatment. Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) interacted with estrogen-related receptor alpha (ERRα) that bound to the Sirt3 promoter as its transcription factor to regulate Sirt3 expression and DAergic neuronal death. In the mouse midbrain, MPTP administration led to the loss of PGC-1α and Sirt3, high acetylation level of SOD2 and ATP synthase β, and the specific loss of DAergic neurons, while Sirt3 overexpression could protect against DAergic neuronal loss. Sirt3 knockout mice exhibited more sensitive and more DAergic neuronal loss to MPTP treatment. The study provides new insights into a critical PGC-1α/ERRα-Sirt3 pathway, linking regulation of mitochondrial protein acetylation and DAergic neuronal death in PD pathogenesis, which provide a potential therapeutic strategy and target in PD treatment. These results provide a vital PGC-1α/ERRα-Sirt3 pathway that protects against DAergic neuronal death by directly deacetylating SOD2 (K130) and ATP synthase β (K485) in PD.

Paraquat Induces Cell Death Through Impairing Mitochondrial Membrane Permeability

Paraquat (PQ) as a Parkinsonian mimetic has been demonstrated to impair dopaminergic (DAergic) neurons and is highly correlated with the etiology of Parkinson's disease (PD) where the death of DAergic neurons has been mainly attributed to impaired mitochondrial functioning. In this study, PQ-induced cytotoxicity focusing on mitochondrial membrane permeability (MMP), which has been implicated to play a part in neurodegeneration, was investigated. Primarily, PQ-induced cytotoxicity and reactive oxygen species (ROS) were inhibited by an inhibitor of NADPH oxidase (NOX), indicating the toxic effect of PQ redox cycling. Further, dibucaine and cyclosporin A which respectively inhibit mitochondrial apoptosis-induced channels (MAC) and mitochondrial permeability transition pores (mPTP) were used and found to prevent PQ-induced mitochondrial dysfunction, such as decreased mitochondrial membrane potential and increased MMP, mitochondrial ROS, and pro-apoptotic factor release. Knockdown of bax and/or bak blocked PQ-induced mitochondrial clusterization of Bax and/or Bak and cytotoxicity, demonstrating the significance of MAC which is composed of Bax and/or Bak. This clusterization coincided with the release of mitochondrial apoptotic factors before there was an increase in inner MMP, indicating that MAC may precede mPTP formation. Besides, NOX inhibitor but not dibucaine attenuated the earlier PQ-induced cytosolic ROS formation or Bax and/or Bak clusterization indicating PQ redox cycling may account for MAC formation. In this model, we have resolved for the first that PQ cytotoxicity through redox cycling may sequentially result in increased outer (MAC) and inner (mPTP) MMP and suggested MMP could be implicated as a therapeutic target in treating neurodegenerative diseases like PD.

Nogo-A and its functions beyond axonal inhibition: the controversial role of Nogo-A in Parkinson's disease.

Nogo-A belongs to the reticulon family (RTN4) and is generally assumed to be one of the most potent myelin associated neurite outgrowth inhibitors in the central nervous system (CNS). Together with other inhibitors such as the myelin associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMgp), several semaphorins and ephrins as well as chondriotin sulphate proteoglycans, Nogo-A contributes to a nonpermissive environment in the brain and spinal cord. Based on their seminal observation that neurons grown in close proximity to CNS derived oligodendrocytes showed a robust decrease in neurite outgrowth and number of processes, Schwab and Caroni (1988) postulated for nonpermissive substrate properties present in the CNS myelin. In further studies, they identified a high molecular weight component from the CNS myelin called NI-250 which was later renamed Nogo-A. In the course it could be demonstrated that Nogo-A is expressed on the surface of oligodendrocytes and is responsible for the inhibition of axonal sprouting. Since the nonpermissive environment plays a very important role in brain injuries and neurodegenerative diseases, Nogo-A and its receptors were extensively studied.

TNF-α regulates miRNA targeting mitochondrial complex-I and induces cell death in dopaminergic cells

Parkinson's disease (PD) is a complex neurological disorder of the elderly population and majorly shows the selective loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) region of the brain. The mechanisms leading to increased cell death of DAergic neurons are not well understood. Tumor necrosis factor-alpha (TNF-α), a pro-inflammatory cytokine is elevated in blood, CSF and striatum region of the brain in PD patients. The increased level of TNF-α and its role in pathogenesis of PD are not well understood. In the current study, we investigated the role of TNF-α in the regulation of cell death and miRNA mediated mitochondrial functions using, DAergic cell line, SH-SY5Y (model of dopaminergic neuron degeneration akin to PD). The cells treated with low dose of TNF-α for prolonged period induce cell death which was rescued in the presence of zVAD.fmk, a caspase inhibitor and N-acetyl-cysteine (NAC), an antioxidant. TNF-α alters mitochondrial complex-I activity, decreases adenosine triphosphate (ATP) levels, increases reactive oxygen species levels and mitochondrial turnover through autophagy. TNF-α differentially regulates miRNA expression involved in pathogenesis of PD. Bioinformatics analysis revealed that the putative targets of altered miRNA included both pro/anti apoptotic genes and subunits of mitochondrial complex. The cells treated with TNF-α showed decreased level of nuclear encoded transcript of mitochondrial complexes, the target of miRNA. To our knowledge, the evidences in the current study demonstrated that TNF-α is a potential regulator of miRNAs which may regulate mitochondrial functions and neuronal cell death, having important implication in pathogenesis of PD.