Neuroprotective effects of saxagliptin against radiation-induced cognitive impairment: Insights on Akt/CREB/SIRT1/BDNF signaling pathway

Neuroprotective effects of saxagliptin against radiation-induced cognitive impairment: Insights on Akt/CREB/SIRT1/BDNF signaling pathway

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 neuroprotect...

Full description

Saved in:
Bibliographic Details
Published in:Toxicology and applied pharmacology Vol. 489; p. 116994
Main Authors: Abdelhamid, Ashrakt H., Mantawy, Eman M., Said, Riham S., El-Demerdash, Ebtehal
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01-08-2024
Subjects:
Cognitive impairment
GLP-1 signaling
Saxagliptin
ϒ-radiation
Bcl-2
DPP-IV
SAP
GLP-1 signaling
IHC
MDA
SAXA
TBA
CREB
PI3K
ANOVA
ϒ-radiation
Cognitive impairment
Saxagliptin
WBI
PBS
AD
GLP-1
BDNF
Akt
SIRT-1
TrkB
ROS
Bax
ELISA
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. [Display omitted] •Saxagliptin (SAXA) effectively alleviated cognitive deterioration caused by 20 Gy Whole Body Irradiation (WBI) in rats.•SAXA prohibited hippocampal oxidative stress and neuronal apoptosis induced by WBI.•SAXA augmented neurogenesis through Akt/CREB/BDNF/SIRT-1 signaling axes.•SAXA offers a new neuroprotective approach for cancer patients exposed to WBI.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0041-008X
1096-0333
1096-0333
DOI:10.1016/j.taap.2024.116994