The effect of NADPH-oxidase inhibitor apocynin on cognitive impairment induced by moderate lateral fluid percussion injury: Role of inflammatory and oxidative brain damage

Ferreira, Ana Paula Oliveira; Rodrigues, Fernanda Silva; Della-Pace, Iuri Domingues; Mota, Bibiana Castagna; Oliveira, Sara Marchesan; Gewehr, Camila de Campos Velho; Bobinski, Franciane; Oliveira, Clarissa Vasconcelos de; Brum, Juliana Sperotto; Oliveira, Mauro Schneider; Furian, Ana Flávia; Barros, Claudio S.L.; Ferreira, Juliano; Santos, Adair R.S.; Fighera, Michele Rechia; Royes, Luiz Fernando Freire

doi:10.1016/j.neuint.2013.09.012

Cited by 64 publications

(52 citation statements)

References 56 publications

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“…37,38 NOX2 activation contributes to oxidative stress and neuroinflammation after ischemic brain injury 39,40 and TBI ,9,23,41,42 and inhibition of this enzyme, either directly or indirectly, is highly neuroprotective in TBI models. 23,[41][42][43][44][45] Redox signaling is an essential component of M1-like polarization of macrophages, 16 and reports also have confirmed ROS regulation of microglial M2-like activation. 46 Notably, attenuation of microglial ROS through genetic or pharmacological inhibition of NOX2 increases microglial M2-like phenotype markers in response to LPS.…”

Section: Fig 7 (Continued)mentioning

confidence: 81%

Microglial/Macrophage Polarization Dynamics following Traumatic Brain Injury

Kumar

Álvarez‐Croda

Stoica

et al. 2016

Journal of Neurotrauma

255

256

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Activated microglia and macrophages exert dual beneficial and detrimental roles after central nervous system injury, which are thought to be due to their polarization along a continuum from a classical pro-inflammatory M1-like state to an alternative anti-inflammatory M2-like state. The goal of the present study was to analyze the temporal dynamics of microglia/macrophage polarization within the lesion micro-environment following traumatic brain injury (TBI) using a moderate-level controlled cortical impact (CCI) model in mice. We performed a detailed phenotypic analysis of M1-and M2-like polarized microglia/macrophages, as well as nicotinamide adenine dinucleotide phosphate oxidase (NOX2) expression, through 7 days post-injury using real-time polymerase chain reaction (qPCR), flow cytometry and image analyses. We demonstrated that microglia/macrophages express both M1-and M2-like phenotypic markers early after TBI, but the transient up-regulation of the M2-like phenotype was replaced by a predominant M1-or mixed transitional (Mtran) phenotype that expressed high levels of NOX2 at 7 days post-injury. The shift towards the M1-like and Mtran phenotype was associated with increased cortical and hippocampal neurodegeneration. In a follow up study, we administered a selective NOX2 inhibitor, gp91ds-tat, to CCI mice starting at 24 h post-injury to investigate the relationship between NOX2 and M1-like/Mtran phenotypes. Delayed gp91ds-tat treatment altered M1-/M2-like balance in favor of the anti-inflammatory M2-like phenotype, and significantly reduced oxidative damage in neurons at 7 days post-injury. Therefore, our data suggest that despite M1-like and M2-like polarized microglia/macrophages being activated after TBI, the early M2-like response becomes dysfunctional over time, resulting in development of pathological M1-like and Mtran phenotypes driven by increased NOX2 activity.

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Section: Fig 7 (Continued)mentioning

confidence: 81%

Microglial/Macrophage Polarization Dynamics following Traumatic Brain Injury

Kumar

Álvarez‐Croda

Stoica

et al. 2016

Journal of Neurotrauma

255

256

View full text Add to dashboard Cite

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“…C-G, Shamϩvehicle: n ϭ 7 slices/6 animals; ShamϩA33: n ϭ 6 slices/5 animals; TBIϩvehicle: n ϭ 6 slices/6 animals; TBIϩA33: n ϭ 7 slices/6 animals. (Taupin et al, 1993;Yakovlev and Faden, 1994;Fan et al, 1996;Knoblach et al, 1999;Vitarbo et al, 2004;Lotocki et al, 2006;Shojo et al, 2010;Ferreira et al, 2013;Su et al, 2014;Tsai et al, 2015). At 30 min postinjury, as well as 1 h before kill, animals received 0.3 mg/kg A33 (i.p.)…”

Section: Resultsmentioning

confidence: 99%

Chronic Cognitive Dysfunction after Traumatic Brain Injury Is Improved with a Phosphodiesterase 4B Inhibitor

Titus

Wilson

Freund

et al. 2016

Journal of Neuroscience

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Learning and memory impairments are common in traumatic brain injury (TBI) survivors. However, there are no effective treatments to improve TBI-induced learning and memory impairments. TBI results in decreased cAMP signaling and reduced cAMP-response-element binding protein (CREB) activation, a critical pathway involved in learning and memory. TBI also acutely upregulates phosphodiesterase 4B2 (PDE4B2), which terminates cAMP signaling by hydrolyzing cAMP. We hypothesized that a subtype-selective PDE4B inhibitor could reverse the learning deficits induced by TBI. To test this hypothesis, adult male Sprague-Dawley rats received sham surgery or moderate parasagittal fluid-percussion brain injury. At 3 months postsurgery, animals were administered a selective PDE4B inhibitor or vehicle before cue and contextual fear conditioning, water maze training and a spatial working memory task. Treatment with the PDE4B inhibitor significantly reversed the TBI-induced deficits in cue and contextual fear conditioning and water maze retention. To further understand the underlying mechanisms of these memory impairments, we examined hippocampal long-term potentiation (LTP). TBI resulted in a significant reduction in basal synaptic transmission and impaired expression of LTP. Treatment with the PDE4B inhibitor significantly reduced the deficits in basal synaptic transmission and rescued LTP expression. The PDE4B inhibitor reduced tumor necrosis factor-␣ levels and increased phosphorylated CREB levels after TBI, suggesting that this drug inhibited molecular pathways in the brain known to be regulated by PDE4B. These results suggest that a subtype-selective PDE4B inhibitor is a potential therapeutic to reverse chronic learning and memory dysfunction and deficits in hippocampal synaptic plasticity following TBI.

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“…11 12 Indeed, previous studies have shown that superoxide production by NADPH oxidase underlies cognitive impairment after cerebral ischaemia and traumatic brain injury. [13][14][15] However, the role of NADPH oxidase in memory impairment has not been examined in animals exposed to anaesthesia in the neonatal period. Furthermore, it is not known whether targeting NADPH oxidase during anaesthesia protects the neonatal brain from long-term memory deficits.…”

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confidence: 99%

Inhibiting NADPH oxidase protects against long-term memory impairment induced by neonatal sevoflurane exposure in mice

Sun

Satomoto

Adachi

et al. 2016

British Journal of Anaesthesia

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Background: Neonatal exposure to anaesthetics such as sevoflurane has been reported to result in behavioural deficits in rodents. However, while oxidative injury is thought to play an underlying pathological role, the mechanisms of neurotoxicity remain unclear. In the present study, we investigated whether the NADPH oxidase inhibitor apocynin protects against longterm memory impairment produced by neonatal sevoflurane exposure in mice. Methods: Postnatal day six mice were divided into four groups; (1) non-anaesthesia, (2) intraperitoneal apocynin (50 mg kg

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The effect of NADPH-oxidase inhibitor apocynin on cognitive impairment induced by moderate lateral fluid percussion injury: Role of inflammatory and oxidative brain damage

Cited by 64 publications

References 56 publications

Microglial/Macrophage Polarization Dynamics following Traumatic Brain Injury

Microglial/Macrophage Polarization Dynamics following Traumatic Brain Injury

Chronic Cognitive Dysfunction after Traumatic Brain Injury Is Improved with a Phosphodiesterase 4B Inhibitor

Inhibiting NADPH oxidase protects against long-term memory impairment induced by neonatal sevoflurane exposure in mice

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