Acute Neuroinflammatory Response in the Substantia Nigra Pars Compacta of Rats after a Local Injection of Lipopolysaccharide

Abstract

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-α, IL-1β, 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.

Lipopolysaccharide-based endotoxemia produce toxicity in peripheral organs and microglia migration in a dose-dependent manner in rat substantia nigra

“…Also, Sun et al [29] determined that the intraperitoneal injection of LPS induced an increase in Iba-1 positive cells, also a microglia marker, observing changes in hippocampal microglia morphology such as enlargement of the cytoplasm and cell bodies, which is the characteristic feature of reactive microglia. Our data of microglial morphological changes are in accordance with a previous report of Flores-Martinez et al [13]. For this, the accumulation of microglia (active) around of SNpc could exacerbate the damage to dopaminergic neurons, as has been observed in this study (loss of 40% of dopamine neurons) and that is in line at 47% referred by Qin et al [26].…”

Does lipopolysaccharide-based neuroinflammation induce microglia polarization?

“…With regard to main LPS effects, the intracranial injection of this immunogen produces dose-dependent microglial activation and increases neurodegeneration in susceptible brain nuclei (e.g. SN) in mice and rats [4,8,30,44,55,56,93]. Furthermore, depending on the LPS that is injected in SN [24,78], globus pallidus [102], neostriatum [19] or lateral ventricles [43], the microglial activation is indistinctly characterized by morphological changes, cellular stress and antiand pro-inflammatory cytokine production.…”

“…The level of activation of microglial cells depends on the intensity, duration and type of the stimulus and can generate a neuroprotective or neurotoxic response [30,31]. At the level of the CNS and PNS, two phenotypes of microglia, M1 and M2, have been distinguished.…”

“…These morphological changes have been associated with the expression of the genes Ccr2, Nox2, TNF, Ly6c, IL12a, IL12b and Icam1 [17]. To assess microglial activation, markers such as ionized calcium binding adapter molecule-1 (Iba-1) [44], cluster of differentiation 68 (CD68) [67], CD11b or CD11b/c [8], CD206 [2] and complement receptor type 3 (CR3) [109], which is commonly named as OX42 [30], have been used. Among these markers, the most common ones are CD16/32 and CD86 for the M1 subtype, and CD206 and CD11b for M2 microglia [108] (Fig.…”

The Causative and Curative Roles of Brain-Derived Neurotrophic Factor in Parkinson’s Disease

“…Parkinson's disease is the second most common neurodegenerative disease worldwide, with high annual costs of treatment. The death of dopaminergic neurons and inflammation are the main cellular processes associated with motor and cognitive dysfunctions in PD [1][2][3][4]; these events can be potentiated by the loss of the brain-derived neurotrophic factor (BDNF), a key neurotropic factor in degeneration and regeneration processes.…”