A Noradrenergic Lesion Attenuates Surgery-Induced Cognitive Impairment in Rats by Suppressing Neuroinflammation

Abstract

Postoperative cognitive dysfunction (POCD) is a common postoperative neurocognitive complication in elderly patients. However, the specific pathogenesis is unknown, and it has been demonstrated that neuroinflammation plays a key role in POCD. Recently, increasing evidence has proven that the locus coeruleus noradrenergic (LCNE) system participates in regulating neuroinflammation in some neurodegenerative disorders. We hypothesize that LCNE plays an important role in the neuroinflammation of POCD. In this study, 400 μg of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) was injected intracerebroventricularly into each rat 7 days before anesthesia/surgery to deplete the locus coeruleus (LC) noradrenaline (NE). We applied a simple laparotomy and brief upper mesenteric artery clamping surgery as the rat POCD model. The open field test, novel objection and novel location (NL) recognition, and Morris water maze (MWM) were performed to assess postoperative cognition. High-performance liquid chromatography (HPLC) was used to measure the level of NE in plasma and brain tissues, and immunofluorescence staining was applied to evaluate the activation of microglia and astrocytes. We also used enzyme-linked immune-sorbent assay (ELISA) to assess the levels of inflammatory cytokines and brain-derived neurotrophic factor (BDNF). Pretreatment with DSP-4 decreased the levels of systemic and central NE, increased the level of interleukin-6 (IL-6) in the plasma at 6 h after the surgery, decreased the concentration of IL-6 in the prefrontal cortex and hippocampus, and decreased the level of interleukin-1β (IL-1β) in the plasma, prefrontal cortex, and hippocampus at 1 week postoperatively. In addition, DSP-4 treatment attenuated hippocampal-dependent learning and memory impairment in rats with POCD, with a downregulation of the activation of microglia and astrocytes in the prefrontal cortex and hippocampus. In conclusion, these findings provide evidence of the effects of LCNE in modulating neuroinflammation in rats with POCD and provide a new perspective in the prevention and treatment of POCD.

Dexmedetomidine Ameliorated Cognitive Dysfunction Induced by Intestinal Ischemia Reperfusion in Mice with Possible Relation to the Anti-inflammatory Effect Through the Locus Coeruleus Norepinephrine System

“…These findings were consistent with those reported by Wang et al, who showed that DSP-4 suppressed neuroinflammation caused by intestinal ischemia and attenuated cognitive impairment [ 49 ]. When dexmedetomidine was administered after DSP-4 administration, we found that DSP-4 could not attenuate the protective effect of dexmedetomidine on hippocampal inflammatory injury, and dexmedetomidine did not further enhance or weaken the effects of DSP-4.…”

“…Accumulating research findings show that the LCNE system is involved in neuroinflammation. Nonetheless, the role of LCNE in regulation of inflammation remains controversial[ 23 , 48 , 49 ]. To evaluate whether dexmedetomidine improved neuroinflammation and cognitive function through the LCNE system after intestinal ischemia/reperfusion injury in mice, we used the neurotoxic drug DSP-4 to selectively degrade LC norepinephrine neurons at 2 weeks and 1 week before operation, which was confirmed by immunofluorescence staining showing a significant decrease in TH-positive neurons in the LC.…”

“…We postulated that the reasons may be as follows: first, some studies have proven that when the DSP-4 was used, NE of the relevant brain regions decreased by 60–80%. This may be attributed to the fact that the residual TH-positive neurons release NE to the hippocampus during intestinal ischemia/reperfusion injury [ 49 , 50 ]. However, it remains unclear whether there is a release of NE from the brain region of the non-locus coeruleus to the hippocampus during intestinal ischemia/reperfusion [ 51 ].…”

Noradrenaline in Alzheimer’s Disease: A New Potential Therapeutic Target

“…Indeed, it has recently been shown that intracerebroventricular administration of DSP4 increases microglial and astrocyte activation, reducing the learning abilities of the animals as well as their memory. However, DSP4 treatment resulted in protective effects against hippocampal dependent learning and memory impairment due to surgery in a model of post operative cognitive dysfunction [ 76 ]. For this reason, the development of alternative ways to simulate the depletion of LC neurons could yield more reliable results.…”

Opposing effects of β-2 and β-1 adrenergic receptor signaling on neuroinflammation and dopaminergic neuron survival in α-synuclein-mediated neurotoxicity

“…For instance, in neurotoxin-based models of PD, reduction of brain NE is shown to increase neuroin ammation and dopaminergic neuron degeneration in the SNpc [4][5][6], while other studies nd no effect on dopamine levels or dopaminergic neuron survival after brain NE depletion [7][8][9][10]. Outside of PD pathologies, depletion of brain NE has been reported to be neuroprotective by reducing microglia activation [11]. These diverse responses re ect the many and complex physiological functions regulated by NE in the brain [12,13].…”