In vivo P2X7 inhibition reduces amyloid plaques in Alzheimer's disease through GSK3β and secretases

Díaz‐Hernandéz, Juan Ignacio; Gómez‐Villafuertes, Rosa; León-Otegui, Míriam; Hontecillas-Prieto, Lourdes; Puerto, Ana del; Trejo, José Luís; Lucas, José J.; Garrido, Juan J.; Gualix, Javier; Miras-Portugal, Marı́a Teresa; Dı́az-Hernández, Miguel

doi:10.1016/j.neurobiolaging.2011.09.040

Cited by 172 publications

(156 citation statements)

References 45 publications

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“…First, in an Alzheimer's disease model, injection of amyloid b resulted in an accumulation of IL-1b in WT, but not P2X7 KO mice (Sanz et al, 2009). This correlates with the positive outcomes reported in two different Alzheimer's disease models that used P2X7 antagonists (Ryu and McLarnon, 2008;Diaz-Hernandez et al, 2012). Second, in models of depression, P2X7 KO mice displayed antidepressant-like profiles in comparison with WT controls (Basso et al, 2009;Boucher et al, 2011;Csölle et al, 2013).…”

Section: A P2x7 Antagonists In Rodent Models Of Neurologic Diseasesupporting

confidence: 78%

“…In addition to diseases associated with SNPs, studies of human tissue or mouse models suggest that P2X7 may play important roles in a number of inflammatory, immune, neurologic, or musculoskeletal disorders. Such disorders include multiple sclerosis (Yiangou et al, 2006), amyotrophic lateral sclerosis (Yiangou et al, 2006), Alzheimer's disease (Ryu and McLarnon, 2008;Diaz-Hernandez et al, 2012) (Arbeloa et al, 2012;Chu et al, 2012), neuropathic and inflammatory pain (Chessell et al, 2005), rheumatoid arthritis (Portales-Cervantes et al, 2010;Bhattacharya et al, 2011), glomerulonephritis (Taylor et al, 2009b), pulmonary fibrosis (Riteau et al, 2010), and graft-versus-host disease (Wilhelm et al, 2010). Given the potential importance of P2X7 in health and disease, considerable effort has gone into characterizing the presence and function of mammalian P2X7 receptors, and into the generation of selective P2X7 antagonists and the investigation of the potential therapeutic efficacy of such compounds in rodent models of disease.…”

Section: The P2x7 Receptor In Health and Diseasementioning

confidence: 99%

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The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease

2014

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Section: A P2x7 Antagonists In Rodent Models Of Neurologic Diseasesupporting

confidence: 78%

Section: The P2x7 Receptor In Health and Diseasementioning

confidence: 99%

The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease

2014

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“…There is evidence indicating that the activation of P2X7 receptor is involved in the regulation of COX-2 expression during the inflammatory responses [33,34]. In addition, inhibition of P2X7 receptor has been shown to reduce amyloid plaques in animal model of Alzheimer's disease [35]. In our current study, we found that CoPP activates P2X7 receptor, subsequently induced COX-2 expression in microglial cells.…”

Section: Discussionsupporting

confidence: 61%

Cobalt Protoporphyrin Upregulates Cyclooxygenase-2 Expression Through a Heme Oxygenase-Independent Mechanism

Lin¹,

Tsai

Lin

et al. 2015

Mol Neurobiol

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Cobalt protoporphyrin (CoPP) is a potent HO-1 inducer and generally known to be an antioxidant in various cell types. Little is known about the CoPP-induced cyclooxygenase-2 (COX-2) expression and its downstream signaling in microglial cells. In current study, CoPP caused concentration- and time-dependent increases in COX-2 expression in microglial cells. Furthermore, activation of apoptosis signal-regulating kinase (ASK) 1/MAP kinase involved in CoPP-induced COX-2 expression in microglia. CoPP also induced P2X7 receptor activation, and treatment of P2X7 inhibitors effectively reduced CoPP-induced COX-2 expression. Protein inhibitor of activated STAT (PIAS) 1 is reported to be involved in modulating anti-inflammatory response through negative regulation of transcription factors. Interestingly, treatment with CoPP markedly induced PIAS1 degradation which is regulated by PI3K, Akt, and glycogen synthase kinase 3α/β (GSK3α/β) signaling pathways. These results suggest that CoPP induces COX-2 expression through activating P2X7 receptors and ASK1/MAP kinases as well as PIAS1 degradation signaling pathways. Our study provides a new insight into the regulatory effect of CoPP on neuroinflammation in microglial cells.

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“…P2X7R have been considered an important therapeutic target in many injuries and neurological disorders, including neuropathic pain [24,25], spinal cord injury [26], ischemia [27,28], intracerebral hemorrhage, traumatic brain injury [29], and neurodegenerative diseases such as Alzheimer's disease [30], Huntington's disease [31], Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and depression [18], and also in epilepsy [19,32,33].…”

Section: Introductionmentioning

confidence: 99%

Silencing of P2X7R by RNA interference in the hippocampus can attenuate morphological and behavioral impact of pilocarpine-induced epilepsy

Amorim

Araújo

Valero

et al. 2017

Purinergic Signalling

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Cell signaling mediated by P2X7 receptors (P2X7R) has been suggested to be involved in epileptogenesis, via modulation of intracellular calcium levels, excitotoxicity, activation of inflammatory cascades, and cell death, among other mechanisms. These processes have been described to be involved in pilocarpine-induced status epilepticus (SE) and contribute to hyperexcitability, resulting in spontaneous and recurrent seizures. Here, we aimed to investigate the role of P2X7R in epileptogenesis in vivo using RNA interference (RNAi) to inhibit the expression of this receptor. Small interfering RNA (siRNA) targeting P2X7R mRNA was injected into the lateral ventricles (icv) 6 h after SE. Four groups were studied: SalineVehicle, Saline-siRNA, Pilo-Vehicle, and Pilo-siRNA. P2X7R was quantified by western blotting and neuronal death assessed by Fluoro-Jade B histochemistry. The hippocampal volume (edema) was determined 48 h following RNAi. Behavioral parameters as latency to the appearance of spontaneous seizures and the number of seizures were determined until 60 days after the SE onset. The Saline-siRNA and Pilo-siRNA groups showed a 43 and 37% reduction, respectively, in P2X7R protein levels compared to respective vehicle groups. Neuroprotection was observed in CA1 and CA3 of the PilosiRNA group compared to Pilo-Vehicle. P2X7R silencing in pilocarpine group reversed the increase in the edema detected in the hilus, suprapyramidal dentate gyrus, CA1, and CA3; reduced mortality rate following SE; increased the time to onset of spontaneous seizure; and reduced the number of seizures, when compared to the Pilo-Vehicle group. Therefore, our data highlights the potential of P2X7R as a therapeutic target for the adjunct treatment of epilepsy.

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In vivo P2X7 inhibition reduces amyloid plaques in Alzheimer's disease through GSK3β and secretases

Cited by 172 publications

References 45 publications

The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease

The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease

Cobalt Protoporphyrin Upregulates Cyclooxygenase-2 Expression Through a Heme Oxygenase-Independent Mechanism

Silencing of P2X7R by RNA interference in the hippocampus can attenuate morphological and behavioral impact of pilocarpine-induced epilepsy

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