Synergistic effects of lipopolysaccharide and rotenone on dopamine neuronal damage in rats.

INTRODUCTION: The etiology of Parkinson's disease (PD) is still unknown. Until now, oxidative stress and neuroinflammation play a crucial role in the pathogenesis of PD. However, the specific synergistic role of oxidative stress and neuroinflammation in the occurrence and development of PD remains unclear. METHODS: The changes in motor behavior, dopamine (DA) neurons quantification and their mitochondrial respiratory chain, glial cells activation and secreted cytokines, Nrf2 signaling pathway, and redox balance in the brain of rats were evaluated. RESULTS: Lipopolysaccharide (LPS)-induced neuroinflammation and rotenone (ROT)-induced oxidative stress synergistically aggravated motor dysfunction, DA neuron damage, activation of glial cells, and release of related mediators, activation of Nrf2 signaling and destruction of oxidative balance. In addition, further studies indicated that after ROT-induced oxidative stress caused direct damage to DA neurons, LPS-induced inflammatory effects had stronger promoting neurotoxic effects on the above aspects. CONCLUSIONS: Neuroinflammation and oxidative stress synergistically aggravated DA neuronal loss. Furtherly, oxidative stress followed by neuroinflammation caused more DA neuronal loss than neuroinflammation followed by oxidative stress.

Effects of intraperitoneal injection of lipopolysaccharide-induced peripheral inflammation on dopamine neuron damage in rat midbrain.

INTRODUCTION: Current studies have documented neuroinflammation is implicated in Parkinson's disease. Recently, growing evidence indicated peripheral inflammation plays an important role in regulation of neuroinflammation and thus conferring protection against dopamine (DA) neuronal damage. However, the underlying mechanisms are not clearly illuminated. METHODS: The effects of intraperitoneal injection of LPS (LPS[i.p.] )-induced peripheral inflammation on substantia nigra (SN) injection of LPS (LPS[SN] )-elicited DA neuronal damage in rat midbrain were investigated. Rats were intraperitoneally injected with LPS (0.5 mg/kg) daily for 4 consecutive days and then given single injection of LPS (8 µg) into SN with an interval of 0 (LPS(i.p.) 0 day ± LPS(SN) ), 30 (LPS(i.p.) 30 days ± LPS(SN) ), and 90 (LPS(i.p.) 90 days ± LPS(SN) ) days after LPS(i.p.) administration. RESULTS: LPS(i.p.) increased the levels of inflammatory factors in peripheral blood in (LPS(i.p.) 0 day ± LPS(SN) ). Importantly, in (LPS(i.p.) 0 day ± LPS(SN) ) and (LPS(i.p.) 30 days ± LPS(SN) ), LPS(i.p.) attenuated LPS(SN) -induced DA neuronal loss in SN. Besides, LPS(i.p.) reduced LPS(SN) -induced microglia and astrocytes activation in SN. Furtherly, LPS(i.p.) reduced pro-inflammatory M1 microglia markers mRNA levels and increased anti-inflammatory M2 microglia markers mRNA levels. In addition, the increased T-cell marker expression and the decreased M1 microglia marker expression and more DA neuronal survival were discerned at the same area of rat midbrain in LPS(SN) -induced DA neuronal damage 30 days after LPS(i.p.) application. CONCLUSION: This study suggested LPS(i.p.) -induced peripheral inflammation might cause T cells to infiltrate the brain to regulate microglia-mediated neuroinflammation, thereby protecting DA neurons.