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Grant support

This work was supported by grants from the Instituto de Salud Carlos III (ISCIII) (Programa Miguel Servet II Grants CPII19/00005; PI16/00735; PI19/00082 to JE; and PI18/00357 to DC, partially funded by FEDER - European Union 'Una manera de hacer Europa') and Fundacion Mutua Madrilena to JE; European Union's Horizon 2020 research and innovation programme under the H2020 Marie Skodowska-Curie Actions grant agreement no. 794926 and Stop Fuga de Cerebros Roche Pharma to JMR; and Ministerio de Ciencia e Innovacion RTI2018-094887-B-I00 and RYC-2016-20414 to MN and RYC2019-026870-I to JMR. DC, MCO, VVS and EFL are hired by SESCAM. We also thank Dr. Ju Chen (University of California, San Diego, CA, USA) and Dr. Gertrudis Perea (Cajal Institute, Madrid, Spain) for kindly providing IP3R2-/- animals and Dr. Juan Aguilar (HNP, Toledo, Spain) for technical and scientific support.

Analysis of institutional authors

Ortega, McAuthorEgea, JCorresponding Author

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Article

TLR4 pathway impairs synaptic number and cerebrovascular functions through astrocyte activation following traumatic brain injury

Publicated to:BRITISH JOURNAL OF PHARMACOLOGY. 178 (17): 3395-3413 - 2021-09-01 178(17), DOI: 10.1111/bph.15488

Authors: Rosa, Juliana M.; Farre-Alins, Victor; Ortega, Maria Cristina; Navarrete, Marta; Lopez-Rodriguez, Ana Belen; Palomino-Antolin, Alejandra; Fernandez-Lopez, Elena; Vila-del Sol, Virginia; Decouty, Celine; Narros-Fernandez, Paloma; Clemente, Diego; Egea, Javier;

Affiliations

‎ CSIC, Inst Cajal, Madrid, Spain - Author
‎ Hosp Nacl Paraplejicos, Serv Salud Castilla La Mancha, SESCAM, Expt Neurophysiol & Neuronal Circuits Grp, Toledo, Spain - Author
‎ Hosp Nacl Paraplejicos, Serv Salud Castilla La Mancha, SESCAM, Flow Cytometry Serv, Toledo, Spain - Author
‎ Hosp Nacl Paraplejicos, Serv Salud Castilla La Mancha, SESCAM, Neuroinmune Repair Grp, Toledo, Spain - Author
‎ Hosp Univ Princesa, Inst Invest Sanitaria Princesa IIS IP, Hosp Santa Cristina, Res Unit, Madrid, Spain - Author
‎ Univ Autonoma Madrid, Fac Med, Dept Farmacol & Terapeut, Inst Teofilo Hernando, Madrid, Spain - Author
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Abstract

Background and Purpose Activation of astrocytes contributes to synaptic remodelling, tissue repair and neuronal survival following traumatic brain injury (TBI). The mechanisms by which these cells interact to resident/infiltrated inflammatory cells to rewire neuronal networks and repair brain functions remain poorly understood. Here, we explored how TLR4-induced astrocyte activation modified synapses and cerebrovascular integrity following TBI. Experimental Approach To determine how functional astrocyte alterations induced by activation of TLR4 pathway in inflammatory cells regulate synapses and neurovascular integrity after TBI, we used pharmacology, genetic approaches, live calcium imaging, immunofluorescence, flow cytometry, blood-brain barrier (BBB) integrity assessment and molecular and behavioural methods. Key Results Shortly after a TBI, there is a recruitment of excitable and reactive astrocytes mediated by TLR4 pathway activation with detrimental effects on post-synaptic density-95 (PSD-95)/vesicular glutamate transporter 1 (VGLUT1) synaptic puncta, BBB integrity and neurological outcome. Pharmacological blockage of the TLR4 pathway with resatorvid (TAK-242) partially reversed many of the observed effects. Synapses and BBB recovery after resatorvid administration were not observed in IP(3)R2(-/-) mice, indicating that effects of TLR4 inhibition depend on the subsequent astrocyte activation. In addition, TBI increased the astrocytic-protein thrombospondin-1 necessary to induce a synaptic recovery in a sub-acute phase. Conclusions and Implications Our data demonstrate that TLR4-mediated signalling, most probably through microglia and/or infiltrated monocyte-astrocyte communication, plays a crucial role in the TBI pathophysiology and that its inhibition prevents synaptic loss and BBB damage accelerating tissue recovery/repair, which might represent a therapeutic potential in CNS injuries and disorders.

Keywords

astrocytesbbb breakdownmicroglia/infiltrated monocytessynaptic remodellingtlr4 antagonismAstrocytesBbb breakdownCortexDamageDatabaseInfiltrated monocytesIntegrityMicrogliaMicroglia/infiltrated monocytesNeuronsPhenotypePlasticityRecoverySynaptic remodellingTlr4 antagonismTranscriptomeTraumatic brain injury

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal BRITISH JOURNAL OF PHARMACOLOGY due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2021, it was in position 18/279, thus managing to position itself as a Q1 (Primer Cuartil), in the category Pharmacology & Pharmacy. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 3.53. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 5.2 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 15.92 (source consulted: Dimensions Jun 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-06-29, the following number of citations:

  • WoS: 30
  • Scopus: 53

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-06-29:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 59.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 59 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 40.1.
  • The number of mentions on the social network X (formerly Twitter): 6 (Altmetric).
  • The number of mentions in news outlets: 5 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: Last Author (EGEA MAIQUEZ, FRANCISCO JAVIER).

the author responsible for correspondence tasks has been EGEA MAIQUEZ, FRANCISCO JAVIER.