Inhibition of phosphodiesterase 10A mitigates neuronal injury by modulating apoptotic pathways in cold-induced traumatic brain injury

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dc.contributor.authorBeker, Mustafa Çağlar
dc.contributor.authorAltıntaş, Mehmet Özgen
dc.contributor.authorDoğan, Enes
dc.contributor.authorBayraktaroğlu, Çiğdem
dc.contributor.authorBalaban, Buse
dc.contributor.authorÖzpınar, Ayşenur
dc.contributor.authorŞengün, Nursena
dc.contributor.authorAltunay, Serdar
dc.contributor.authorKılıç, Ertuğrul
dc.date.accessioned2025-10-13T13:23:49Z
dc.date.available2025-10-13T13:23:49Z
dc.date.issued2024
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Rejeneratif ve Restoratif Tıp Araştırmaları Merkezi (REMER)
dc.departmentİstanbul Medipol Üniversitesi, Rektörlük, Sağlık Bilim ve Teknolojileri Araştırma Enstitüsü
dc.description.abstractBrain injury develops from a complex series of pathophysiological phases, resulting in acute necrotic or delayed apoptotic cell death after traumatic brain injury (TBI). Inhibition of apoptotic cell death is critical for the treatment of acute neurodegenerative disorders, such as TBI. Here, we investigated the role of phosphodiesterase 10A (PDE10A) in the development of neuronal injury, particularly in apoptotic cell death. Using the PDE10A inhibitor TAK-063, we found that PDE10A inhibition is associated with decreased brain injury, brain swelling, and blood brain barrier disruption 48 h after cold-induced TBI. Furthermore, a particularly notable result was observed with 3 mg/kg TAK-063, which reduced disseminated neuronal injury. Protein abundance analysis revealed that PDE10A inhibition activates survival kinases AKT and ERK-1/-2, which were associated with the decreased activation of MMP-9 and PTEN. Additionally, iNOS and nNOS levels significantly reduced in the TAK-063 group, playing roles in inflammation and apoptosis. A planar surface immunoassay was performed for in-depth analyses of the apoptotic signaling pathways. We observed that inhibition of PDE10A resulted in the decreased expression of TNFRSF1A, TNFRSF10B, and TNFRSF6 receptors, particularly inducing apoptotic cell death. Moreover, these findings correlated with reduced levels of pro-apoptotic proteins, including PTEN, p27, Cytochrome-c, cleaved Caspase-3, Bad, and p53. Interestingly, TAK-063 treatment reduced levels of anti-apoptotic proteins or enzymes, including XIAP, Claspin, and HIF1α, without affecting Bcl-x, MCL-1, SMAC, HO-1, HO-2, HSP27, HSP60, and HSP70. The findings suggest that PDE10A regulates cellular signaling predominantly pro-apoptotic pathways, and inhibition of this protein is a promising approach for the treatment of acute brain injury.
dc.identifier.citationBeker, M. Ç., Altıntaş, M. Ö., Doğan, E., Bayraktaroğlu, Ç., Balaban, B., Özpınar, A. ... Kılıç, E. (2024). Inhibition of phosphodiesterase 10A mitigates neuronal injury by modulating apoptotic pathways in cold-induced traumatic brain injury. Molecular and Cellular Neuroscience, 131. http://dx.doi.org/10.1016/j.mcn.2024.103977
dc.identifier.doi10.1016/j.mcn.2024.103977
dc.identifier.issn1044-7431
dc.identifier.issn1095-9327
dc.identifier.pmid39437931
dc.identifier.scopus2-s2.0-85207144393
dc.identifier.scopusqualityQ2
dc.identifier.urihttp://dx.doi.org/10.1016/j.mcn.2024.103977
dc.identifier.urihttps://hdl.handle.net/20.500.12511/13096
dc.identifier.volume131
dc.identifier.wosWOS:001344684300001
dc.identifier.wosqualityQ3
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorBeker, Mustafa Çağlar
dc.institutionauthorDoğan, Enes
dc.institutionauthorBayraktaroğlu, Çiğdem
dc.institutionauthorBalaban, Buse
dc.institutionauthorÖzpınar, Ayşenur
dc.institutionauthorAltunay, Serdar
dc.institutionauthorKılıç, Ertuğrul
dc.institutionauthorid0000-0002-9476-8488
dc.institutionauthorid0009-0009-3039-8826
dc.institutionauthorid0000-0002-7318-4053
dc.institutionauthorid0009-0006-4237-8580
dc.institutionauthorid0000-0002-4051-2559
dc.institutionauthorid0000-0001-6494-8923
dc.language.isoen
dc.relation.ispartofMolecular and Cellular Neuroscience
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/embargoedAccess
dc.subjectCamp
dc.subjectCold Injury
dc.subjectPDE10A
dc.subjectPhosphodiesterase-10A
dc.subjectTAK-063
dc.subjectTraumatic Brain Injury
dc.titleInhibition of phosphodiesterase 10A mitigates neuronal injury by modulating apoptotic pathways in cold-induced traumatic brain injury
dc.typeArticle

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