Wan-Yu Huang1, Ko-Hung Liu2, Shankung Lin2, Ting-Yu Chen2, Chien-Yu Tseng2, Hsuan-Ying Chen2, Hung-Ming Wu3, Kuei-Sen Hsu4. 1. Institute of Basic Medicine, College of Medicine, National Cheng-Kung University, Tainan, Taiwan; Pediatrics of Kung-Ten General Hospital, Taichung City, Taiwan. 2. Inflammation Research & Drug Development Center, Changhua Christian Hospital, Changhua, Taiwan. 3. Inflammation Research & Drug Development Center, Changhua Christian Hospital, Changhua, Taiwan; Department of Neurology, Changhua Christian Hospital, Changhua City, Taiwan; Institute of Acupuncture, School of Chinese Medicine, China Medical University, Taichung City, Taiwan. Electronic address: 18288@cch.org.tw. 4. Institute of Basic Medicine, College of Medicine, National Cheng-Kung University, Tainan, Taiwan. Electronic address: richard@mail.ncku.edu.tw.
Abstract
BACKGROUND: Research indicates that sepsis increases the risk of developing cognitive impairment. After systemic inflammation, a corresponding activation of microglia is rapidly induced in the brain, and multiple neurotoxic factors, including inflammatory mediators (e.g., cytokines) and reactive oxygen species (e.g., superoxide), are also released that contribute to neuronal injury. NADPH oxidase (NOX) enzymes play a vital role in microglial activation through the generation of superoxide anions. We hypothesized that NOX isoforms, particularly NOX2, could exhibit remarkable abilities in developing cognitive deficits induced by systemic inflammation. METHODS: Mice with deficits of NOX2 organizer p47phox (p47phox-/-) and wild-type (WT) mice treated with the NOX inhibitor diphenyleneiodonium (DPI) were used in this study. Intraperitoneal lipopolysaccharide (LPS) injection was used to induce systemic inflammation. Spatial learning and memory were compared among treatment groups using the radial arm maze task. Brain tissues were collected for evaluating the transcript levels of proinflammatory cytokines, whereas immunofluorescence staining and immunoblotting were conducted to determine the percentage of activated glia (microglia and astroglia) and damaged neurons and the expression of synaptic proteins and BDNF. RESULTS: Cognitive impairment induced by systemic inflammation was significantly attenuated in the p47phox-/- mice compared to that in the WT mice. The p47phox-/- mice exhibited reduced microglial and astroglial activation and neuronal damage and attenuated the induction of multiple proinflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and CCL2. Similar to that observed in the p47phox-/- mice, the administration of DPI significantly attenuated the cognitive impairment, reduced the glial activation and brain cytokine concentrations, and restored the expression of postsynaptic proteins (PSD-95) and BDNF in neurons and astrocytes, compared to those in the vehicle-treated controls within 10 days after LPS injection. CONCLUSIONS: This study clearly demonstrates that NOX2 contributes to glial activation with subsequent reduction in the expression of BDNF, synaptic dysfunction, and cognitive deficits after systemic inflammation in an LPS-injected mouse model. Our results provide evidence that NOX2 might be a promising pharmacological target that could be used to protect against synaptic dysregulation and cognitive impairment following systemic inflammation.
BACKGROUND: Research indicates that sepsis increases the risk of developing cognitive impairment. After systemic inflammation, a corresponding activation of microglia is rapidly induced in the brain, and multiple neurotoxic factors, including inflammatory mediators (e.g., cytokines) and reactive oxygen species (e.g., superoxide), are also released that contribute to neuronal injury. NADPH oxidase (NOX) enzymes play a vital role in microglial activation through the generation of superoxide anions. We hypothesized that NOX isoforms, particularly NOX2, could exhibit remarkable abilities in developing cognitive deficits induced by systemic inflammation. METHODS:Mice with deficits of NOX2 organizer p47phox (p47phox-/-) and wild-type (WT) mice treated with the NOX inhibitor diphenyleneiodonium (DPI) were used in this study. Intraperitoneal lipopolysaccharide (LPS) injection was used to induce systemic inflammation. Spatial learning and memory were compared among treatment groups using the radial arm maze task. Brain tissues were collected for evaluating the transcript levels of proinflammatory cytokines, whereas immunofluorescence staining and immunoblotting were conducted to determine the percentage of activated glia (microglia and astroglia) and damaged neurons and the expression of synaptic proteins and BDNF. RESULTS:Cognitive impairment induced by systemic inflammation was significantly attenuated in the p47phox-/-mice compared to that in the WT mice. The p47phox-/-mice exhibited reduced microglial and astroglial activation and neuronal damage and attenuated the induction of multiple proinflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and CCL2. Similar to that observed in the p47phox-/-mice, the administration of DPI significantly attenuated the cognitive impairment, reduced the glial activation and brain cytokine concentrations, and restored the expression of postsynaptic proteins (PSD-95) and BDNF in neurons and astrocytes, compared to those in the vehicle-treated controls within 10 days after LPS injection. CONCLUSIONS: This study clearly demonstrates that NOX2 contributes to glial activation with subsequent reduction in the expression of BDNF, synaptic dysfunction, and cognitive deficits after systemic inflammation in an LPS-injected mouse model. Our results provide evidence that NOX2 might be a promising pharmacological target that could be used to protect against synaptic dysregulation and cognitive impairment following systemic inflammation.
Authors: Ping Gong; Yan-Qing Chen; Ai-Hua Lin; Hai-Bo Zhang; Yan Zhang; Richard D Ye; Yang Yu Journal: Alzheimers Res Ther Date: 2020-11-12 Impact factor: 6.982
Authors: Marcelo Gomes Granja; Letícia Pires Alves; Marina Leardini-Tristão; Michelle Edelman Saul; Letícia Coelho Bortoni; Flávia Maciel de Moraes; Erica Camila Ferreira; Bianca Portugal Tavares de Moraes; Victória Zerboni da Silva; Adrielle Ferreira Ribeiro Dos Santos; Adriana Ribeiro Silva; Cassiano Felippe Gonçalves-de-Albuquerque; Victorio Bambini-Junior; Andrew S Weyrich; Matthew T Rondina; Guy A Zimmerman; Hugo Caire de Castro-Faria-Neto Journal: J Neuroinflammation Date: 2021-02-25 Impact factor: 8.322