Activation of SIRT-1 Pathway by Nanoceria Sheds Light on Its Ameliorative Effect on Doxorubicin-Induced Cognitive Impairment (Chemobrain): Restraining Its Neuroinflammation, Synaptic Dysplasticity and Apoptosis

Abstract

Chemo fog is one of the most serious health concerns encountered by cancer survivors receiving doxorubicin (DOX)-based chemotherapy. Oxidative stress, neuroinflammation, apoptosis and impairment of synaptic plasticity are regarded as the key factors implicated in DOX-induced cognitive impairment. This research aimed to assess the possible neuroprotective effect of cerium oxide nanoparticles (CeNPs) against DOX-induced neurotoxicity. Forty-eight rats were divided into four groups (12 rats/group): control group, CeNPs group (received oral CeNPs solution (35 mg/kg) daily for 4 weeks), and DOX group (were administered DOX intraperitoneally (2 mg/kg, once/week for 4 weeks)) and DOX+ CeNPs group. The findings revealed that CeNPs mitigated behavioral alterations in DOX-induced cognitive deficit. Additionally, CeNPs alleviated the histopathological abnormalities in hippocampus and ameliorated DOX-induced neuroinflammation by downregulating the expression of NF-κB, TNF-α, IL-1β and IL6. In addition, CeNPs antagonized the apoptosis through reducing the protein expression of cytochrome c and caspase 3. In addition, it stimulated the antioxidant defense, as indicated by upregulating the expression of the Nrf2, HO-1 and PGC-1α genes. CeNPs improved synaptic plasticity via acting on the BDNF. These actions were related through the modification of SIRT-1 expression. Based on the aforementioned results, CeNPs antagonized the doxorubicin-induced neurodegeneration by its antioxidant, anti-inflammatory and antiapoptotic effects, alongside its SIRT-1 mediated mechanisms.

Mangiferin-Mediated Sirtuin Modulation in Chemotherapy-Induced Cognitive Impairment: Insights from Computational Analysis

“…can impact neurotransmitter systems linked to learning and memory. Its regulatory effects on proteins involved in synaptic plasticity, can potentially modulate cognitive outcomes [15]. Additionally, SIRT1 can influence the epigenetic mechanisms (modulation of histone deacetylation) that hold relevance for cognitive function and neuronal vitality [16].…”

Resveratrol and 1,25-dihydroxyvitamin D decrease Lingo-1 levels, and improve behavior in harmaline-induced Essential tremor, suggesting potential therapeutic benefits

“…Recent studies have shown that Sirt1 plays a key role in cognitive performance and regulation of memory function through modulation of BDNF and inhibition of glutamate and the glutamatergic NMDA receptors, which are important factors in the differentiation of hippocampal neuronal cells and synaptic plasticity 90 . Moreover, Sirt1 stimulates the production of antioxidant enzymes and downregulates the expression of proinflammatory markers and apoptotic caspase 3 gene expression, which has been suggested to play a role in positive cognitive effects 91 .…”

Doxorubicin-induced neurotoxicity differently affects the hippocampal formation subregions in adult mice

“…Chemotherapy-induced cognitive impairment or 'chemobrain' has been established as a secondary effect of chemotherapy treatment and it may persist for the following years, with a prevalence between 28% (Schagen, Muller et al 2002) and 75% (Wieneke and Dienst 1995). The cognitive domains reported more often to be impaired in those clinical studies were verbal memory, psychomotor function (Ahles, Saykin et al 2002), visual memory, visuospatial and verbal learning (Castellon, Ganz et al 2004), memory function and attention (Wefel, Lenzi et al 2004), suggesting extensive impairment mainly to the prefrontal cortex (PFC) and hippocampal formation (HF) (Taha, Elazab et al 2022). Doxorubicin (DOX) is one of the most frequently used chemotherapeutic agents in cancer therapy.…”