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Pyrrolidine dithiocarbamate attenuates surgery-induced neuroinflammation and cognitive dysfunction possibly via inhibition of nuclear factor ?B.

ABSTRACT: Surgery induces learning and memory impairment. Neuroinflammation may contribute to this impairment. Nuclear factor ?B (NF-?B) is an important transcription factor to regulate the expression of inflammatory cytokines. We hypothesize that inhibition of NF-?B by pyrrolidine dithiocarbamate (PDTC) reduces neuroinflammation and the impairment of learning and memory. To test this hypothesis, four-month-old male Fischer 344 rats were subjected to right carotid exploration under propofol and buprenorphine anesthesia. Some rats received two doses of 50mg/kg PDTC given intraperitoneally 30min before and 6h after the surgery. Rats were tested in the Barnes maze and fear conditioning paradigm begun 6days after the surgery. Expression of various proteins related to inflammation was examined in the hippocampus at 24h or 21days after the surgery. Here, surgery, but not anesthesia alone, had a significant effect on prolonging the time needed to identify the target hole during the training sessions of the Barnes maze. Surgery also increased the time for identifying the target hole in the long-term memory test and decreased context-related learning and memory in fear conditioning test. Also, surgery increased nuclear expression of p65, a NF-?B component, decreased cytoplasmic amount of inhibitor of NF-?B, and increased the expression of interleukin-1?, interleukin-6, ionized calcium binding adaptor molecule 1 and active matrix metalloproteinase 9 (MMP-9). Finally, surgery enhanced IgG extravasation in the hippocampus. These surgical effects were attenuated by PDTC. These results suggest that surgery, but not propofol-based anesthesia, induces neuroinflammation and impairment of learning and memory. PDTC attenuates these effects possibly by inhibiting NF-?B activation and the downstream MMP-9 activity.

SUBMITTER: Zhang J

PROVIDER: S-EPMC3950371 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Pyrrolidine dithiocarbamate attenuates surgery-induced neuroinflammation and cognitive dysfunction possibly via inhibition of nuclear factor κB.

Zhang J J Jiang W W Zuo Z Z

Neuroscience 20131221

Surgery induces learning and memory impairment. Neuroinflammation may contribute to this impairment. Nuclear factor κB (NF-κB) is an important transcription factor to regulate the expression of inflammatory cytokines. We hypothesize that inhibition of NF-κB by pyrrolidine dithiocarbamate (PDTC) reduces neuroinflammation and the impairment of learning and memory. To test this hypothesis, four-month-old male Fischer 344 rats were subjected to right carotid exploration under propofol and buprenorph ...[more]

PMID: 24365462

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Project description:Tyrosine-protein kinase (Syk) plays a potential role in neuroinflammation and adaptive immune responses in several neurodegenerative conditions. Seeing the significant role of Syk in the pathophysiology of neurodegeneration, several pharmacological inhibitors have been developed. One of the known inhibitors of Syk is BAY61-3606, which has shown efficacies in Alzheimer's disease (AD) through regulating amyloid production. However, little is known about its efficacies in neuroinflammation and neurodegeneration. Our finding showed that Syk expression was up-regulated by lipopolysaccharide (LPS)-dependent manner, and BAY61-3606 significantly suppressed the activated microglia (ionized calcium-binding adaptor molecule 1 [Iba-1]) and the inflammatory cytokines (tumor necrosis factor-alpha [TNF-α], interleukin 1-beta [IL-1β], IL-6) and other inflammatory mediators (nuclear factor kappa B [NF-κB], cyclooxygenase-2 [Cox-2], and inducible nitric axide synthase [iNOS]) in the lipopolysaccharide (LPS)-treated in vivo and in vitro models. Moreover, BAY61-3606 significantly reduced microglia-mediated neuronal cell death by regulating the expression of Cytochrome C and Bim (B-cell lymphoma 2 [BCL-2] interacting mediator of cell death) in the LPS-treated mice brain and HT22 cells. Furthermore, the expression of synaptic markers, synaptosomal-associated protein, 25 kDa (SNAP25), synaptophysin (Syp), and postsynaptic density protein-95 (PSD95) in LPS-challenged mice showed that BAY61-3606 significantly recovered the synaptic markers. Finally, we have analyzed the effects of BAY61-3606 against memory and cognitive dysfunctions in the LPS injected mice. The Y-maze test and Passive avoidance test suggested that BAY61-3606 significantly protected against LPS-induced cognitive and memory dysfunctions. The current findings not only highlight the mechanisms of Syk in the pathophysiology of neuro-inflammation, but also support the therapeutic efficacy of BAY61-3606 in the management of neurodegeneration.

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Pyrrolidine dithiocarbamate attenuates surgery-induced neuroinflammation and cognitive dysfunction possibly via inhibition of nuclear factor ?B.

Publications

Pyrrolidine dithiocarbamate attenuates surgery-induced neuroinflammation and cognitive dysfunction possibly via inhibition of nuclear factor κB.

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