Minocycline Alleviates Cluster Formation of Activated Microglia and Age-dependent Dopaminergic Cell Death in the Substantia Nigra of Zitter Mutant Rat

AbstractParkinson’s disease dementia is neuropathologically characterized by aggregates of α-synuclein (Lewy bodies) in limbic and neocortical areas of the brain with additional involvement of Alzheimer’s disease-type pathology. Whilst immune activation is well-described in Parkinson’s disease (PD), how it links to protein aggregation and its role in PD dementia has not been explored. We hypothesized that neuroinflammatory processes are a critical contributor to the pathology of PDD. To address this hypothesis, we examined 7 brain regions at postmortem from 17 PD patients with no dementia (PDND), 11 patients with PD dementia (PDD), and 14 age and sex-matched neurologically healthy controls. Digital quantification after immunohistochemical staining showed a significant increase in the severity of α-synuclein pathology in the hippocampus, entorhinal and occipitotemporal cortex of PDD compared to PDND cases. In contrast, there was no difference in either tau or amyloid-β pathology between the groups in any of the examined regions. Importantly, we found an increase in activated microglia in the amygdala of demented PD brains compared to controls which correlated significantly with the extent of α-synuclein pathology in this region. Significant infiltration of CD4+ T lymphocytes into the brain parenchyma was commonly observed in PDND and PDD cases compared to controls, in both the substantia nigra and the amygdala. Amongst PDND/PDD cases, CD4+ T cell counts in the amygdala correlated with activated microglia, α-synuclein and tau pathology. Upregulation of the pro-inflammatory cytokine interleukin 1β was also evident in the substantia nigra as well as the frontal cortex in PDND/PDD versus controls with a concomitant upregulation in Toll-like receptor 4 (TLR4) in these regions, as well as the amygdala. The evidence presented in this study show an increased immune response in limbic and cortical brain regions, including increased microglial activation, infiltration of T lymphocytes, upregulation of pro-inflammatory cytokines and TLR gene expression, which has not been previously reported in the postmortem PDD brain.

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Evaluation of the cellular protection by novel spiropyrazole compounds in dopaminergic cell death

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2020.113140 ◽

2021 ◽

pp. 113140

Author(s):

Jamila Zaiter ◽

Achraf Hibot ◽

Abderrafia Hafid ◽

Mostafa Khouili ◽

Claudia M.B. Neves ◽

...

Keyword(s):

Cell Death ◽

Dopaminergic Cell ◽

Cellular Protection

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Three-Dimensional Electron Microscopy Reconstruction of Degenerative Dopaminergic Neurons Surrounded by Activated Microglia in Substantia Nigra

Ultrastructural Pathology ◽

10.3109/01913123.2015.1042609 ◽

2015 ◽

Vol 39 (6) ◽

pp. 369-377

Author(s):

Kazuhiko Nakadate ◽

Sawako Tanaka-Nakadate

Keyword(s):

Electron Microscopy ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Three Dimensional ◽

Dimensional Electron ◽

Activated Microglia

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Neuroprotective Effect of Nortriptyline in Overt Hepatic Encephalopathy Through Attenuation of Mitochondrial Dysfunction

ASN NEURO ◽

10.1177/1759091418810583 ◽

2018 ◽

Vol 10 ◽

pp. 175909141881058 ◽

Cited By ~ 3

Author(s):

Ji Heun Jeong ◽

Do Kyung Kim ◽

Nam-Seob Lee ◽

Young-Gil Jeong ◽

Ho Won Kim ◽

...

Keyword(s):

Cell Death ◽

Hepatic Encephalopathy ◽

Substantia Nigra ◽

Mitochondrial Dysfunction ◽

Mitochondrial Permeability Transition ◽

Neuroprotective Effect ◽

Motor Deficits ◽

Apoptotic Pathway ◽

Duct Ligation ◽

Overt Hepatic Encephalopathy

Hyperammonemia associated with overt hepatic encephalopathy (OHE) causes excitotoxic neuronal death through activation of the cytochrome C (CytC)-mediated mitochondria-dependent apoptotic pathway. We tested the therapeutic effect of nortriptyline (NT), a mitochondrial permeability transition pore (mPTP) blocker that can possibly inhibit mitochondrial CytC efflux to the cytosol on in vivo and in vitro OHE models. After ensuring the generation of OHE rats, established by bile duct ligation (BDL), they were intraperitoneally administered either 20 mg/kg NT (i.e., BDL+NT) or another vehicle (i.e., BDL+VEH) for 14 days. Compared with the control, BDL+VEH showed an increment of motor deficits, cell death, synaptic loss, apoptosis, and mitochondria with aberrant morphology in substantia nigra compacta dopaminergic (DA-ergic) neurons. However, the extent was significantly reversed in BDL+NT. Subsequently, we studied the neuroprotective mechanism of NT using PC-12 cells, a DA-ergic cell line, which exposed glutamate used as an excitotoxin. Compared with the control, the cells exposed to 15 mM glutamate (i.e., GLU) showed incremental cell death, apoptosis, and demise in mitochondrial respiration. Importantly, efflux of CytC from mitochondria to cytosol and the dissipation of mitochondrial membrane potential (△Ψm), an indicator of mPTP opening, were prominent in GLU. However, compared with the GLU, the cells cotreated with 10 μM NT (i.e., GLU+NT) showed a significant reduction in the aforementioned phenomenon. Together, we concluded that NT can be used for OHE therapeutics, mitigating the excitotoxic death of substantia nigra compacta DA-ergic neurons via mPTP-associated mitochondrial dysfunction inhibition.

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