A comprehensive study on long‐term injury to nigral dopaminergic neurons following intracerebroventricular injection of lipopolysaccharide in rats

Abstract

Parkinson's disease (PD) is characterized by selective and progressive degeneration of dopaminergic neurons in the substantia nigra (SN). Lipopolysaccharide (LPS) can induce chronic inflammation and has been widely used to study the pathogenesis of PD. In this study, a single intracerebroventricular injection of LPS was used to induce neurotoxic effects on dopaminergic neurons in Sprague-Dawley rats. The longterm neurotoxic effects of LPS were evaluated at different time points. Microglia were activated in the hippocampus and striatum at 4 weeks, and in the SN at 24 weeks. Astrocytes were activated in the hippocampus and nigrostriatal system at 2 and 24 weeks. The expression of brain-derived neurotrophic factor in the SN increased at 4 weeks and decreased after 12 weeks, and tyrosine hydroxylase-positive neurons in the SN were shown to have an atrophic appearance, with cell loss evident after 24 weeks. Phospho-a-synuclein expression, a reflection of parkinsonian pathogenesis, increased at 12 weeks, and peaked at 24 weeks. Abnormal motor behavior appeared at 16 weeks and lasted up to 48 weeks. These results indicate that microglia are activated for several months after a single, low dose injection of LPS, which eventually results in progressive and selective damage to dopaminergic neurons in the SN.

A survey from 2012 of evidence for the role of neuroinflammation in neurotoxin animal models of Parkinson's disease and potential molecular targets

“…However, at 24 weeks post LPS treatment, the authors reported a 22% reduction of SNpc DA neurons, which progressed to a 40% reduction by 48 weeks post injection. None of these effects were observed in saline-treated animals (Zhou et al, 2012). Thus, this study suggests that once inflammation is induced in the brain, its neurotoxic effects can be detected long afterwards.…”

Alkaloids from piper longum protect dopaminergic neurons against inflammation-mediated damage induced by intranigral injection of lipopolysaccharide

“…For example, pioglitazone and naloxone have been studied for their potential neuroprotective effects on LPS-induced PD models [24, 25]. It was reported that, the inflammatory reaction induced by injecting LPS into SN had a selective irreversible and long lasting damage on the dopaminergic neurons, which ultimately resulted in neurodegeneration [20, 22, 26]. Many studies also showed that a single intranigral injection of LPS led to depletion of DA and loss of dopaminergic neurons in animals [21, 27, 28].…”

Parkinson’s disease and enhanced inflammatory response

“…41 The authors also show that activated microglia persist in LPS-injected mice at 48 weeks postinjection. This suggests that a single neuroinflammatory event in a region distant to the SN can transmit insult likely through cerebrospinal fluid and have long-lasting effects.…”