Protective effects of naloxone in two‐hit seizure model

Yang, Lu; Li, Fuhai; Ge, Wei; Mi, Changrui; Wang, Rong; Sun, Ryan

doi:10.1111/j.1528-1167.2009.02250.x

Cited by 22 publications

(14 citation statements)

References 35 publications

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“…However, ouabain did not inhibit the TLR4 Ca 2ϩ -evoked responses in our astrocytes. Furthermore, naloxone is known to reduce IL-1␤ synthesis in rats (27), which we were unable to reproduce in our astrocytes.…”

Section: Discussionmentioning

confidence: 81%

“…We opted to use them instead of more traditional anti-inflammatory agents because naloxone in ultralow concentrations has been suggested to have anti-inflammatory properties (27) in addition to its powerful effect as a -opioid receptor antagonist. Also, ultralow dose naloxone is effective in restoration of the antinociceptive effect of morphine in rats and in addition increases anti-inflammatory cytokine IL-10 expression (26).…”

Section: Discussionmentioning

confidence: 99%

“…We hypothesized that the astrocytes are influenced by the inflammation inducer LPS and that it is possible to restore some aspects of the cells to a homeostatic state using exposure to a substance that may have anti-inflammatory properties. We aimed to test this using naloxone, particularly in very low concentrations (26,27). We further aimed to test ouabain in low and high concentrations and its effects of Na ϩ /K ϩ -ATPase activity (28) and evoked Ca 2ϩ transients in astrocytes (28 -30).…”

Section: Interleukin-1␤ (Il-1␤) Release Was Increased After 24 H In Lpsmentioning

confidence: 99%

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Naloxone and Ouabain in Ultralow Concentrations Restore Na+/K+-ATPase and Cytoskeleton in Lipopolysaccharide-treated Astrocytes

Forshammar

Block

Lundborg

et al. 2011

Journal of Biological Chemistry

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Infection, tissue damage, or other conditions can lead to a neuroinflammatory state. Lipopolysaccharide (LPS) exposure can be used experimentally as a model to generate an inflammatory response both in vitro and in vivo. Endotoxin, or LPS, is a potent inflammatory activator (1) in astrocytes and microglia, with stimulation of Toll-like receptor 4 (TLR4) (2). The expression of TLR4 is up-regulated in astrocytes under neuroinflammatory conditions (3). Activation of TLR4 leads to activation of nuclear factor-B, a factor that regulates expression of genes involved in immune responses, including release of the proinflammatory cytokines tumor necrosis factor-␣ (TNF-␣) and interleukin-1␤ (IL-1␤) (2).Astrocytes in networks, positioned between the vasculature and synapses, monitor neuronal signaling, including rebuilding of synapses (4, 5). Astrocytes express almost the same repertoire of receptors and ion channels as neurons. They regulate synaptic transmission via a bidirectional communication with neurons, and they release gliotransmitters as well as factors, including cytokines, fatty acid metabolites, and free radicals (6 -8).The Ca 2ϩ signaling in astrocytes over long distances is analogous to, but much slower than, the propagation of action potentials in neurons (9). These astrocytic Ca 2ϩ waves (10, 11) can be evoked by transmitters released from neurons and glial cells, followed by activation of especially G protein-coupled receptors. Cytosolic Ca 2ϩ plays a key role as a second messenger, and the control of Ca 2ϩ signals is therefore critical. This involves coordination of Ca 2ϩ entry across the plasma membrane (PM), 2 Ca 2ϩ release from the endoplasmatic reticulum (ER), refilling of the ER stores, and extrusion across the PM (12). The Na ϩ -Ca 2ϩ exchanger, a Ca 2ϩ transporter that controls the intracellular Ca 2ϩ concentrations, is driven by the Na ϩ electrochemical gradient across the PM. This Na ϩ pump, Na ϩ /K ϩ -ATPase, indirectly modulates Ca 2ϩ signaling (13), and inflammatory stimuli influence Ca 2ϩ homeostasis in the astrocyte networks (5, 14 -16).The cytoskeleton seems to be important in this system for controlling of PM microdomains and the ER complex. The adaptor protein ankyrin B is associated with the Na ϩ pump and also with ER proteins, such as the inositol 1,4,5-trisphosphate (IP 3 ) receptor. The main cytoplasmic matrix of proteins, spectrin and actin, are attached to ankyrin B. An intact cytoskeleton is required for the propagation of astrocytic Ca 2ϩ waves (17)

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Interleukin-1␤ (Il-1␤) Release Was Increased After 24 H In Lpsmentioning

confidence: 99%

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Naloxone and Ouabain in Ultralow Concentrations Restore Na+/K+-ATPase and Cytoskeleton in Lipopolysaccharide-treated Astrocytes

Forshammar

Block

Lundborg

et al. 2011

Journal of Biological Chemistry

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“…In a drug addiction study, Wang et al demonstrated that the acute Gs coupling induced by morphine is completely prevented by co-treatment with both (-) and (+)-naloxone [10]. Similarly, it has been reported that naloxone displays neuroprotective effects in a two-hit seizure model by reducing both cytokine production and microglial activation [11]. Both (-) and (+)-naloxone have also been found to be capable of reducing the severity of aortic atherosclerosis in apolipoprotein-E (apo-E)-deficient mice through inhibition of macrophage activation and superoxide release [12].…”

Section: Introductionmentioning

confidence: 99%

Naloxone inhibits immune cell function by suppressing superoxide production through a direct interaction with gp91 phox subunit of NADPH oxidase

Wang

Zhou

Gao

et al. 2012

J Neuroinflammation

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BackgroundBoth (-) and (+)-naloxone attenuate inflammation-mediated neurodegeneration by inhibition of microglial activation through superoxide reduction in an opioid receptor-independent manner. Multiple lines of evidence have documented a pivotal role of overactivated NADPH oxidase (NOX2) in inflammation-mediated neurodegeneration. We hypothesized that NOX2 might be a novel action site of naloxone to mediate its anti-inflammatory actions.MethodsInhibition of NOX-2-derived superoxide by (-) and (+)-naloxone was measured in lipopolysaccharide (LPS)-treated midbrain neuron-glia cultures and phorbol myristate acetate (PMA)-stimulated neutrophil membranes by measuring the superoxide dismutase (SOD)-inhibitable reduction of tetrazolium salt (WST-1) or ferricytochrome c. Further, various ligand (3H-naloxone) binding assays were performed in wild type and gp91phox-/- neutrophils and transfected COS-7 and HEK293 cells. The translocation of cytosolic subunit p47phox to plasma membrane was assessed by western blot.ResultsBoth (-) and (+)-naloxone equally inhibited LPS- and PMA-induced superoxide production with an IC50 of 1.96 and 2.52 μM, respectively. Competitive binding of 3H-naloxone with cold (-) and (+)-naloxone in microglia showed equal potency with an IC50 of 2.73 and 1.57 μM, respectively. 3H-Naloxone binding was elevated in COS-7 and HEK293 cells transfected with gp91phox; in contrast, reduced 3H-naloxone binding was found in neutrophils deficient in gp91phox or in the presence of a NOX2 inhibitor. The specificity and an increase in binding capacity of 3H-naloxone were further demonstrated by 1) an immunoprecipitation study using gp91phox antibody, and 2) activation of NOX2 by PMA. Finally, western blot studies showed that naloxone suppressed translocation of the cytosolic subunit p47phox to the membrane, leading to NOX2 inactivation.ConclusionsStrong evidence is provided indicating that NOX2 is a non-opioid novel binding site for naloxone, which is critical in mediating its inhibitory effect on microglia overactivation and superoxide production.

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“…Similarly, naloxone is also anti-inflammatory, reducing IL-1beta synthesis and microglial activation following early life seizure induction. It also lowered the vulnerability of immature brains to a second seizure episode in adulthood (Yang et al, 2010b). In terms of cytokines and inflammatory mediators, IL-1 beta has been shown to be proconvulsant, and IL-1 receptor antagonism (via IL-1Ra) has proven to be a powerful inhibitor of seizures (Vezzani et al, 1999, Vezzani et al, 2000.…”

Section: Microglia As a Therapeutic Target For Epilepsymentioning

confidence: 99%