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Neuroprotective effects of saxagliptin against radiation-induced cognitive impairment: Insights on Akt/CREB/SIRT1/BDNF signaling pathway.
Abdelhamid, Ashrakt H; Mantawy, Eman M; Said, Riham S; El-Demerdash, Ebtehal.
Afiliación
  • Abdelhamid AH; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
  • Mantawy EM; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
  • Said RS; Department of Drug Radiation Research, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo, Egypt.
  • El-Demerdash E; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt. Electronic address: Ebtehal_dm@pharma.asu.edu.eg.
Toxicol Appl Pharmacol ; 489: 116994, 2024 Aug.
Article en En | MEDLINE | ID: mdl-38857790
ABSTRACT
Radiation-induced cognitive impairment has recently fueled scientific interest with an increasing prevalence of cancer patients requiring whole brain irradiation (WBI) in their treatment algorithm. Saxagliptin (SAXA), a dipeptidyl peptidase-IV (DPP-IV) inhibitor, has exhibited competent neuroprotective effects against varied neurodegenerative disorders. Hence, this study aimed at examining the efficacy of SAXA in alleviating WBI-induced cognitive deficits. Male Sprague Dawley rats were distributed into control group, WBI group exposed to 20 Gy ϒ-radiation, SAXA group treated for three weeks with SAXA (10 mg/kg. orally, once daily), and WBI/SAXA group exposed to 20 Gy ϒ-radiation then treated with SAXA (10 mg/kg. orally, once daily). SAXA effectively reversed memory deterioration and motor dysfunction induced by 20 Gy WBI during behavioural tests and preserved normal histological architecture of the hippocampal tissues of irradiated rats. Mechanistically, SAXA inhibited WBI-induced hippocampal oxidative stress via decreasing lipid peroxidation while restoring catalase antioxidant activity. Moreover, SAXA abrogated radiation-induced hippocampal neuronal apoptosis through downregulating proapoptotic Bcl-2 Associated X-protein (Bax) and upregulating antiapoptotic B-cell lymphoma 2 (Bcl-2) expressions and eventually diminishing expression of cleaved caspase 3. Furthermore, SAXA boosted hippocampal neurogenesis by upregulating brain-derived neurotrophic factor (BDNF) expression. These valuable neuroprotective capabilities of SAXA were linked to activating protein kinase B (Akt), and cAMP-response element-binding protein (CREB) along with elevating the expression of sirtuin 1 (SIRT-1). SAXA successfully mitigated cognitive dysfunction triggered by WBI, attenuated oxidative injury, and neuronal apoptosis, and enhanced neurogenesis through switching on Akt/CREB/BDNF/SIRT-1 signaling axes. Such fruitful neurorestorative effects of SAXA provide an innovative therapeutic strategy for improving the cognitive capacity of cancer patients exposed to radiotherapy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Adamantano / Transducción de Señal / Ratas Sprague-Dawley / Proteína de Unión a Elemento de Respuesta al AMP Cíclico / Fármacos Neuroprotectores / Factor Neurotrófico Derivado del Encéfalo / Dipéptidos / Proteínas Proto-Oncogénicas c-akt / Sirtuina 1 / Disfunción Cognitiva Límite: Animals Idioma: En Revista: Toxicol Appl Pharmacol Año: 2024 Tipo del documento: Article País de afiliación: Egipto Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Adamantano / Transducción de Señal / Ratas Sprague-Dawley / Proteína de Unión a Elemento de Respuesta al AMP Cíclico / Fármacos Neuroprotectores / Factor Neurotrófico Derivado del Encéfalo / Dipéptidos / Proteínas Proto-Oncogénicas c-akt / Sirtuina 1 / Disfunción Cognitiva Límite: Animals Idioma: En Revista: Toxicol Appl Pharmacol Año: 2024 Tipo del documento: Article País de afiliación: Egipto Pais de publicación: Estados Unidos