Sirt3-mediated mitochondrial dysfunction is involved in fluoride-induced cognitive deficits.

Excessive fluoride is capable of inducing cognitive deficits, but the mechanisms remain elusive. This study aimed to investigate the effects and underlying mechanisms of fluoride on mitochondrial dysfunction and neurobiological alterations, as well as cognitive impairment. C57BL/6 mice were orally administered 25, 50, and 100 mg/L NaF for 90 days. Cultured human neuroblastoma SH-SY5Y cells were exposed to NaF (110 mg/L) for 24 h in the presence or absence of Sirt3 overexpression. The results demonstrated that chronic exposure to high fluoride induced cognitive deficits and neural/synaptic injury in mice. Fluoride reduced mitochondrial antioxidant enzyme activities and elevated SOD2 acetylation by downregulating Sirt3 expression in the brains of mice and NaF-treated SH-SY5Y cells. Moreover, fluoride lowered mtDNA transcription and induced mitochondrial dysfunction along with increased FoxO3A acetylation in the brains of mice and NaF-treated SH-SY5Y cells. Subsequent experiments revealed that overexpression of Sirt3 significantly attenuated the adverse effects of fluoride on radical scavenging capabilities and mtDNA transcription, as well as mitochondrial function in SH-SY5Y cells. These results suggest that chronic long-term fluoride exposure evokes neural/synaptic injury and cognitive impairment through mitochondrial dysfunction and its associated oxidative stress, which is, at least partly, mediated by Sirt3 inhibition in the mouse brain.

C-phycocyanin Mitigates Cognitive Impairment in Doxorubicin-Induced Chemobrain: Impact on Neuroinflammation, Oxidative Stress, and Brain Mitochondrial and Synaptic Alterations.

Chemotherapy-induced cognitive impairment (CICI) is a common detrimental effect of cancer treatment, occurring in up to 75% of cancer patients. The widely utilized chemotherapeutic agent doxorubicin (DOX) has been implicated in cognitive decline, mostly via cytokine-induced neuroinflammatory and oxidative and mitochondrial damage to brain tissues. C-phycocyanin (CP) has previously been shown to have potent anti-inflammatory, antioxidant, and mitochondrial protective properties. Therefore, this present study was aimed to investigate the neuroprotective effects of CP against DOX-elicited cognitive impairment and explore the underlying mechanisms. CP treatment (50 mg/kg) significantly improved behavioral deficits in DOX-treated mice. Furthermore, CP suppressed DOX-induced neuroinflammation and oxidative stress, mitigated mitochondrial abnormalities, rescued dendritic spine loss, and increased synaptic density in the hippocampus of DOX-treated mice. Our results suggested that CP improves established DOX-induced cognitive deficits, which could be explained at least partly by inhibition of neuroinflammatory and oxidant stress and attenuation of mitochondrial and synaptic dysfunction.