Pyrrolidine Dithiocarbamate Prevents Neuroinflammation and Cognitive Dysfunction after Endotoxemia in Rats

Abstract

Systemic inflammation, for example as a result of infection, often contributes to long-term complications. Neuroinflammation and cognitive decline are key hallmarks of several neurological conditions, including advance age. The contribution of systemic inflammation to the central nervous system (CNS) remains not fully understood. Using a model of peripheral endotoxemia with lipopolysaccharide (LPS) we investigated the role of nuclear factor-κB (NF-κB) activity in mediating long-term neuroinflammation and cognitive dysfunction in aged rats. Herein we describe the anti-inflammatory effects of pyrrolidine dithiocarbamate (PDTC), a selective NF-κB inhibitor, in modulating systemic cytokines including tumor necrosis factor (TNF)-α and interleukin-1β (IL-1β) and CNS markers after LPS exposure in aged rats. In the hippocampus, PDTC not only reduced neuroinflammation by modulating canonical NF-κB activity but also affected IL-1β expression in astrocytes. Parallel effects were observed on behavior and postsynaptic density-95 (PSD95), a marker of synaptic function. Taken together these changes improved acute and long-term cognitive function in aged rats after LPS exposure.

Baicalin Ameliorates Cognitive Impairment and Protects Microglia from LPS-Induced Neuroinflammation via the SIRT1/HMGB1 Pathway

“…Previous studies have demonstrated that intraperitoneal administration of LPS leads to spatial learning and memory deficits [ 7 , 31 ]. Therefore, the protective effects of BAI on LPS-induced cognitive deficits were examined in this well-established mouse model.…”

“…), (iii) LPS+BAI (2 mg/kg LPS i.p.+103 mg/kg BAI, intragastric gavage i.g., daily), (iv) BAI alone (103 mg/kg), (v) BAI+LPS+EX-527 (a selective SIRT1 inhibitor, 5 mg/kg/day, every 2 days for a total of 7 days before LPS and 5 mg/kg/day after LPS), and (vi) LPS+EX-527. We chose this LPS dose based on previous studies in which LPS at 2 mg/kg reliably induced sickness behavior and learning deficits in C57BL/6 J mice [ 31 , 32 ]. The chemical structure of BAI is shown in Figure 1(a) .…”

Inhibition of NF-κB by Pyrrolidine Dithiocarbamate Prevents the Inflammatory Response in a Ligature-Induced Peri-Implantitis Model: A Canine Study

“…Additionally, PDTC has effective anti-inflammatory and anti-tumor properties [14]. Previously, several studies have shown that PDTC can affect inflammation, such as by inhibiting ultraviolet B-induced skin inflammation and by preventing neuroinflammation and cognitive dysfunction after endotoxemia [15,16]. However, few studies have clarified the relationships among PDTC, TLR4, NF-κB and peri-implantitis.…”

Influence of three different anesthesia protocols on aged rat brain: a resting-state functional magnetic resonance imaging study

“…The training process was performed as described in our previous study with some modifications. [ 25 ] Briefly, the MWM test was divided into two parts: spatial acquisition trials (days 1–5) and probe trial (day 7). The rats were rested on day 6.…”

“…[ 8 , 21 ] Because neuroinflammation has been proved to be a major cause for AD [ 22 ] and PD [ 23 ] in aged patients, aged rats are an ideal choice for mechanism studies. [ 24 , 25 ] However, doses of inhalational anesthetics in aged rats differ from those used in adults. [ 26 ] Meanwhile, the levels of important neural receptors in CNS, including γ-amino butyric acid A (GABA A ) receptors [ 27 ] and N-methyl-D-aspartate receptors [ 28 ] also modulate with aging, indicating that the effect of anesthesia on aged brain requires further study.…”