Striatal Neuroinflammation Promotes Parkinsonism in Rats

Abstract

BackgroundSporadic Parkinson's disease (PD) is a progressive neurodegenerative disorder with unknown cause, but it has been suggested that neuroinflammation may play a role in pathogenesis of the disease. Neuroinflammatory component in process of PD neurodegeneration was proposed by postmortem, epidemiological and animal model studies. However, it remains unclear how neuroinflammatory factors contribute to dopaminergic neuronal death in PD.FindingsIn this study, we analyzed the relationship among inducible nitric oxide synthase (iNOS)-derived NO, mitochondrial dysfunction and dopaminergic neurodegeneration to examine the possibility that microglial neuroinflammation may induce dopaminergic neuronal loss in the substantia nigra. Unilateral injection of lipopolysaccharide (LPS) into the striatum of rat was followed by immunocytochemical, histological, neurochemical and biochemical analyses. In addition, behavioral assessments including cylinder test and amphetamine-induced rotational behavior test were employed to validate ipsilateral damage to the dopamine nigrostriatal pathway. LPS injection caused progressive degeneration of the dopamine nigrostriatal system, which was accompanied by motor impairments including asymmetric usage of forelimbs and amphetamine-induced turning behavior in animals. Interestingly, some of the remaining nigral dopaminergic neurons had intracytoplasmic accumulation of α-synuclein and ubiquitin. Furthermore, defect in the mitochondrial respiratory chain, and extensive S-nitrosylation/nitration of mitochondrial complex I were detected prior to the dopaminergic neuronal loss. The mitochondrial injury was prevented by treatment with L-N6-(l-iminoethyl)-lysine, an iNOS inhibitor, suggesting that iNOS-derived NO is associated with the mitochondrial impairment.ConclusionsThese results implicate neuroinflammation-induced S-nitrosylation/nitration of mitochondrial complex I in mitochondrial malfunction and subsequent degeneration of the nigral dopamine neurons.

Intranigral LPS Administration Produces Dopamine, Glutathione but not Behavioral Impairment in Comparison to MPTP and 6-OHDA Neurotoxin Models of Parkinson’s Disease

“…Results were analyzed by two-way ANOVA followed by the Bonferroni's test [9,16]. Although, several others indicated that LPS injections unilaterally [1,28,29] or bilaterally [30,31] in the striatum [32] and intrapallidal [33] produces a decrease in nigral and striatal DA and DOPAC levels and induces locomotor deficits. Most likely, such behavioral differences occurred due to the differential site injections adopted in each study.…”

Parkinson’s disease and enhanced inflammatory response

“…Several groups have injected this region with LPS and observed decreases in SN DA neuron soma, reduced striatal dopamine, and production of proinflammatory cytokines. [38][39][40] Furthermore, this procedure is reported to result in buildup of alpha-synuclein in the soma of DA neurons and deficits in motor performance. [38][39][40] This indicates that inflammatory response in the striatum causes insult that is transmitted to the neuronal soma in the SN or that the inflammatory reaction is not confined to the striatum and encompasses the SN.…”

Serum Uric Acid in Patients with Parkinson’s Disease and Vascular Parkinsonism: A Cross-Sectional Study

“…It has been well documented that inflammation plays an important role in the pathogenesis and severity of PD [2,3]. Several lines of research have shown that serum oxidative stress and proinflammatory cytokines, such as interleukin (IL)-1b, IL-2, IL-6, HLA-DRB1, tumor necrosis factor (TNF)-α, mitochondrial dysfunction and activated microglia, are elevated in the brain and cerebral spinal fluid of PD patients [4,5,6]. …”