The experimental evidences accumulated during last years point out a relevant role of oxidative stress in neurodegeneration. As anti-cellular oxidative stress agents flavonoids can act either as direct chemical antioxidants, the classic view of flavonoids as antioxidants, or as modulators of enzymes and metabolic and signaling pathways leading to an overshot of reactive oxygen species (ROS) formation, a more recently emerging concept. Flavonoids, a large family of natural antioxidants, undergo a significant hepatic metabolism leading to flavonoid-derived metabolites that are also bioactive as antioxidant agents. The development of more efficient flavonoid's based anti-oxidative stress therapies should also take into account their bioavailability in the brain using alternate administration protocols, and also that the major ROS triggering the cellular oxidative stress are not the same for all neurodegenerative insults and diseases. On these grounds, we have reviewed the reports on neuroprotection by different classes of flavonoids on cellular cultures and model animals. In addition, as they are now becoming valuable pharmacological drugs, due to their low toxicity, the reported adverse effects of flavonoids in model experimental animals and humans are briefly discussed.

STIM1 is an endoplasmic reticulum protein with a role in Ca²⁺mobilization and signaling. As a sensor of intraluminal Ca²⁺levels, STIM1 modulates plasma membrane Ca²⁺channels to regulate Ca²⁺entry. In neuroblastoma SH-SY5Y cells and in familial Alzheimer’s disease patient skin fibroblasts, STIM1 is cleaved at the transmembrane domain by the presenilin-1-associated γ-secretase, leading to dysregulation of Ca²⁺homeostasis. In this report, we investigated expression levels of STIM1 in brain tissues (medium frontal gyrus) of pathologically confirmed Alzheimer’s disease patients, and observed that STIM1 protein expression level decreased with the progression of neurodegeneration. To study the role of STIM1 in neurodegeneration, a strategy was designed to knock-out the expression ofSTIM1gene in the SH-SY5Y neuroblastoma cell line by CRISPR/Cas9-mediated genome editing, as an in vitro model to examine the phenotype of STIM1-deficient neuronal cells. It was proved that, while STIM1 is not required for the differentiation of SH-SY5Y cells, it is absolutely essential for cell survival in differentiating cells. Differentiated STIM1-KO cells showed a significant decrease of mitochondrial respiratory chain complex I activity, mitochondrial inner membrane depolarization, reduced mitochondrial free Ca²⁺concentration, and higher levels of senescence as compared with wild-type cells. In parallel, STIM1-KO cells showed a potentiated Ca²⁺entry in response to depolarization, which was sensitive to nifedipine, pointing to L-type voltage-operated Ca²⁺channels as mediators of the upregulated Ca²⁺entry. The stable knocking-down ofCACNA1Ctranscripts restored mitochondrial function, increased mitochondrial Ca²⁺levels, and dropped senescence to basal levels, demonstrating the essential role of the upregulation of voltage-operated Ca²⁺entry through Ca_v1.2 channels in STIM1-deficient SH-SY5Y cell death.Key messages: STIM1 protein expression decreases with the progression of neurodegeneration in Alzheimer’s disease. STIM1 is essential for cell viability in differentiated SH-SY5Y cells. STIM1 deficiency triggers voltage-regulated Ca²⁺entry-dependent cell death. Mitochondrial dysfunction and senescence are features of STIM1-deficient differentiated cells.