Inflammatory Cells and Cytokines in the Olfactory Bulb of a Rat Model of Neuroinflammation; Insights into Neurodegeneration?
This study examined inflammatory cell and cytokine production in brain tissue from a lipopolysaccharide (LPS)-treated rat model that mimics many of the neuropathologic changes associated with neurodegenerative diseases We also monitored the appearance of a glial cell line-derived neurotrophic factor (GDNF) and circulating nitric oxide (NO) levels, as well as an immune system-associated cells in a selected area of the brain, the olfactory lobe. The studies were based on the hypothesis that LPS treatment stimulates temporal changes within the brain and that these responses include immune cell recruitment, increased tissue levels of immune modulating cytokines and NO, as well as greater glial cell activation resulting in increased production of GDNF. As previously reported by other investigators, our animal model of systemic LPS treatment leads to an increase in the concentrations of circulating cytokines, including TNF-α, IL-Iβ, and IL-6, with a maximum response 6 h post LPS administration. Concomitant with cytokine elevations, circulating NO levels were elevated for several hours post LPS administration. The brain content of the GDNF was also elevated over a similar time frame. Lymphocytes, neutrophils, macrophages, plasma cells, and cytokines were all seen in various areas of LPS-treated brains, often around blood vessels associated with the meninges, with these localizations possibly indicating involvement of both the blood-brain and blood-cerebral spinal fluid barriers in these inflammatory episodes. Our results suggest an involvement of both the peripheral and the central nervous system immune components in response to inflammation and inflammatory episodes. This leads us to propose that inflammation initiates an immune response by activating both microglia and astrocytes and that the presence of continuing and increasing proinflammatory mechanisms results in a situation, where cellular protective mechanisms are overcome and the more susceptible cells enter into cell death pathways, initiating a train of events that is a major part of neurodegeneration.
Available from: PubMed Central
- "Microglial cells function as a source of neurotoxin in many infections, inflammatory brain disease. Ample evidence showed a neuropathological role of microglia had been postulated in most, if not all, neuroinflammatory or neurodegenerative diseases , , , . The activated microglia produce a myriad of inflammatory mediators implicated in neuronal damage. "
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ABSTRACT: Methamphetamine (Meth) abusing represents a major public health problem worldwide. Meth has long been known to induce neurotoxicity. However, the mechanism is still remained poorly understood. Growing evidences indicated that the voltage-gated potassium channels (Kv) were participated in neuronal damage and microglia function. With the whole cell patch clamp, we found that Meth significantly increased the outward K(+) currents, therefore, we explored whether Kv1.3, one of the major K(+) channels expressed in microglia, was involved in Meth-induced microglia damage. Our study showed that Meth significantly increased the cell viability in a dose dependent manner, while the Kv blocker, tetraethylamine (TEA), 4-Aminopyridine (4-AP) and Kv1.3 specific antagonist margatoxin (MgTx), prevented against the damage mediated by Meth. Interestingly, treatment of cells with Meth resulted in increasing expression of Kv1.3 rather than Kv1.5, at both mRNA and protein level, which is partially blocked by MgTx. Furthermore, Meth also stimulated a significant increased expression of IL-6 and TNF-α at protein level, which was significantly inhibited by MgTx. Taken together, these results demonstrated that Kv1.3 was involved in Meth-mediated microglial damage, providing the potential target for the development of therapeutic strategies for Meth abuse.
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Sevoflurane, one of the most commonly used anesthetics in clinic, induced neuroinflammation and caused cognitive impairment. 2-deoxy-d-glucose (2-DG) is a synthetic analogue of glucose and is clinically used in medical imaging safely.
We examined the effect of 2-DG on sevoflurane-induced neuroinflammation in the mouse primary microglia cells. Mouse microglia cells were treated with 4.1% sevoflurane for 6h to examine the expression of interleukin (IL)-6 and tumor necrosis factor (TNF-α) and activation of nuclear factor-kappa B (NF-κB). Pyrrolidine dithiocarbamate (PDTC) or 2-DG was used 1h before sevoflurane treatment.
In the present study, we found that sevoflurane increased level of IL-6 and TNF-α through activating NF-κB signaling, and that 2-DG reduced sevoflurane-induced increase in IL-6 and TNF-α and nuclear NF-κB in microglia cells.
Our data suggests that NF-κB signaling pathway could be a target for sevoflurane-induced neuroinflammation and 2-DG might be a potential therapy to prevent or treat sevoflurane-induced neuroinflammation.
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ABSTRACT: Ca(2+) activity in the CNS is critical for the establishment of developing neuronal circuitry prior to and during early sensory input. In developing olfactory bulb (OB), the neuromodulators that enhance network activity are largely unknown. Here we provide evidence that PACAP-specific PAC1 receptors expressed in P2-P5 mouse OB are functional and enhance network activity as measured by increases in calcium in genetically identified granule cells. We used confocal Ca(2+) imaging of OB slices from Dlx2-tdTomato mice to visualize GABAergic granule cells. To address whether the PACAP-induced Ca(2+) oscillations were direct or indirect effects of PAC1R activation, we used antagonists for the GABA receptors (GABARs) and/or glutamate receptors (GlutRs) in the presence and absence of PACAP. Combined block of GABARs and GlutRs yielded a 68% decrease in the numbers of PACAP responsive cells suggesting that 34% of OB neurons are directly activated by PACAP. Similarly, immunocytochemistry using anti-PAC1 antibody showed that 34% of OB neurons express PAC1R. Blocking either GlutRs or GABARs alone indirectly showed that PACAP stimulates release of both glutamate and GABA which activate GCs. The appearance of PACAP-induced Ca(2+) activity in immature GCs suggests a role for PACAP in GC maturation. To conclude, we find that PACAP has both direct and indirect effects on neonatal OB GABAergic cells and may enhance network activity by promoting glutamate and GABA release. Furthermore, the numbers of PACAP responsive granule cells significantly increased between postnatal day two and five suggesting PACAP-induced Ca(2+) activity contributes to neonatal OB development.
Copyright © 2014, Journal of Neurophysiology.
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