Oxidative stress-dependent changes in immune responses and cell death in the substantia nigra after ozone exposure in rat

Abstract

Parkinson's disease has been associated with the selective loss of neurons in the substantia nigra pars compacta. Increasing evidence suggests that oxidative stress plays a major role. The resulting increase in reactive oxygen species triggers a sequence of events that leads to cell damage, activation of microglia cells and neuroinflammatory responses. Our objective was to study whether chronic exposure to low doses of ozone, which produces oxidative stress itself, induces progressive cell death in conjunction with glial alterations in the substantia nigra. Animals were exposed to an ozone-free air stream (control) or to low doses of ozone for 7, 15, 30, 60, or 90 days. Each group underwent (1) spectrophotometric analysis for protein oxidation; (2) western blot testing for microglia reactivity and nuclear factor kappa B expression levels; and (3) immunohistochemistry for cytochrome c, GFAP, Iba-1, NFkB, and COX-2. Our results indicate that ozone induces an increase in protein oxidation levels, changes in activated astrocytes and microglia, and cell death. NFkB and cytochrome c showed an increase until 30 days of exposure, while cyclooxygenase 2 in the substantia nigra increased from 7 days up to 90 days of repetitive ozone exposure. These results suggest that oxidative stress caused by ozone exposure induces changes in inflammatory responses and progressive cell death in the substantia nigra in rats, which could also be occurring in Parkinson's disease.

Emerging Role of Sirtuin 2 in Parkinson’s Disease

“…Similar results were obtained in experiments in which mice were treated with MPTP, substantiating the role of SIRT2 in aggravating oxidative damage (Guan et al, 2016). DA neurons are sensitive to oxidative stress based on the high content of iron and polyunsaturated fatty acids, leading to a greater generation of ROS and an increased rate of DA neuron death due to mitochondrial dysfunction and neuroinflammation (Sanders and Timothy Greenamyre, 2013;Mackeh et al, 2014;Navarro-Yepes et al, 2014;Rivas-Arancibia et al, 2015;Guo et al, 2018).…”

Serum amyloid A: an ozone‐induced circulating factor with potentially important functions in the lung‐brain axis

“…Among the most prevalent toxicants in polluted air, O 3 has been associated with respiratory and cardiovascularrelated health issues and, more recently, has been implicated in CNS dysfunction. Such dysfunctions include cognitive decline and dementia (2)(3)(4), increased stroke risk (5)(6)(7), neuroinflammation and oxidative stress (8)(9)(10)(11)(12), and accumulation of amyloid-b and a-synuclein that are pathologic proteins in Alzheimer's disease and Parkinson's disease, respectively (11)(12)(13)(14)(15); however, the mechanisms by which O 3 exposure could adversely affect CNS function remain unknown. We posit that O 3 inhalation elevates circulating proinflammatory mediators that can access the CNS by crossing the blood-brain barrier (BBB).…”

Oleuropein protects against lipopolysaccharide‐induced sepsis and alleviates inflammatory responses in mice

“…The activation of these classical pathways can lead to the secretion of inflammatory mediators, regulation of oxidative stress response, as well as the acceleration of inflammation. 40 After activation of NF-κB, it translocates to the nucleus in order to control the target genes. 41 Furthermore, the MAPK pathway has a crucial role in controlling cellular processes including the production of inflammation mediators.…”