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The third isoform of the Na + –Ca 2+  exchanger (NCX3) is crucial for a physiological fine-tuning of the Ca 2+  fluxes in excitable tissues. In this view, the NCX3 accounts for the aberrant Ca 2+  influx seen during neuronal excitotoxicity, such as in Alzheimer’s disease (AD). However, little is known about NCX3 regulation and functional properties.  Withania somnifera  (L.) Dunal ( W. somnifera ), a traditional indigenous plant widely recognized for having numerous medicinal values, was undertaken to determine its potential therapeutic benefit against aggregated Aβ 1–42 -induced NCX3 dysregulation and the thereof cognition impairment in 5xFAD mice. The undertaken sourced dried roots of authenticated  W. somnifera  physicochemical compositional tests satisfied standards of pharmacognostic quality, and further phytochemical analysis of the roots methanol extract revealed the roots constitute several antioxidants. Following an intra-gastric gavage administration of synthesized  W. somnifera  roots methanolic extract from postnatal day 30 (P30) to P75, in vivo cognitional studies and then neurochemical examinations of the NCX3 expression level, Aβ plaque deposition, and antioxidant activities in the AD-associated brain regions of 4-month-old 5xFAD mice suggests that the oxidative stress normalizing effects of  W. somnifera  constituents, operating on the NCX3, may have a therapeutic role in the improvement of cognition in AD.

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Sodium–calcium exchanger isoform-3 targeted Withania somnifera (L.) Dunal therapeutic intervention ameliorates cognition in the 5xFAD mouse model of Alzheimer’s disease