LPS Triggers Acute Neuroinflammation and Parkinsonism Involving NLRP3 Inflammasome Pathway and Mitochondrial CI Dysfunction in the Rat

• Published in: International journal of molecular sciences 2023-02, Vol.24 (5), p.4628
• Main Authors: Valenzuela-Arzeta, Irais E, Soto-Rojas, Luis O, Flores-Martinez, Yazmin M, Delgado-Minjares, Karen M, Gatica-Garcia, Bismark, Mascotte-Cruz, Juan U, Nava, Porfirio, Aparicio-Trejo, Omar Emiliano, Reyes-Corona, David, Martínez-Dávila, Irma A, Gutierrez-Castillo, M E, Espadas-Alvarez, Armando J, Orozco-Barrios, Carlos E, Martinez-Fong, Daniel
• Format: Article
• Language: English
• Subjects: Animals; Astrocytes; Basal ganglia; Body temperature; Brain diseases; Calcium-binding protein; Caspase 1 - metabolism; Caspase-1; Central nervous system diseases; Cytokines; Dopamine - metabolism; Dopamine receptors; Dopaminergic Neurons - metabolism; Electron transport chain; Evaluation; Galactosidase; Genotype & phenotype; Glial fibrillary acidic protein; Growth factors; Hypotheses; IL-1β; Inflammasomes - metabolism; Inflammation; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Microglia; Microglia - metabolism; Mitochondria; motor behavior deficits; NADH-ubiquinone oxidoreductase; Neostriatum; Neurodegeneration; neuroinflammation; Neuroinflammatory Diseases; neurotoxic A1 astrocytes; Neurotoxicity; neurotrophic A2 astrocytes; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Parkinson's disease; Parkinsonian Disorders - metabolism; Rats; S100 protein; Saline solutions; Senescence; Sickness behavior; Substantia nigra; Substantia Nigra - metabolism; Tumor necrosis factor-TNF; Tyrosine; Tyrosine 3-monooxygenase
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24054628

Whether neuroinflammation leads to dopaminergic nigrostriatal system neurodegeneration is controversial. We addressed this issue by inducing acute neuroinflammation in the substantia nigra (SN) with a single local administration (5 µg/2 µL saline solution) of lipopolysaccharide (LPS). Neuroinflammatory variables were assessed from 48 h to 30 days after the injury by immunostaining for activated microglia (Iba-1 +), neurotoxic A1 astrocytes (C3 + and GFAP +), and active caspase-1. We also evaluated NLRP3 activation and Il-1β levels by western blot and mitochondrial complex I (CI) activity. Fever and sickness behavior was assessed for 24 h, and motor behavior deficits were followed up until day 30. On this day, we evaluated the cellular senescence marker β-galactosidase (β-Gal) in the SN and tyrosine hydroxylase (TH) in the SN and striatum. After LPS injection, Iba-1 (+), C3 (+), and S100A10 (+) cells were maximally present at 48 h and reached basal levels on day 30. NLRP3 activation occurred at 24 h and was followed by a rise of active caspase-1 (+), Il-1β, and decreased mitochondrial CI activity until 48 h. A significant loss of nigral TH (+) cells and striatal terminals was associated with motor deficits on day 30. The remaining TH (+) cells were β-Gal (+), suggesting senescent dopaminergic neurons. All the histopathological changes also appeared on the contralateral side. Our results show that unilaterally LPS-induced neuroinflammation can cause bilateral neurodegeneration of the nigrostriatal dopaminergic system and are relevant for understanding Parkinson's disease (PD) neuropathology.