piplartine and Cognitive-Dysfunction

Advances in the early diagnosis and treatment have led to increases in breast cancer survivorship. Survivors report cognitive impairment symptoms such as loss of concentration and learning and memory deficits which significantly reduce the patient's quality of life. Additional therapies are needed to prevent these side effects and, the precise mechanisms of action responsible are not fully elucidated. However, increasing evidence points toward the use of neuroprotective compounds with antioxidants and anti-inflammatory properties as tools for conserving learning and memory. Here, we examine the ability of piperlongumine (PL), an alkaloid known to have anti-inflammatory and antioxidant effects, to play a neuroprotective role in 16-week-old female C57BL/6J mice treated with a common breast cancer regimen of doxorubicin, cyclophosphamide, and docetaxel (TAC). During social memory testing, TAC-treated mice exhibited impairment, while TAC/PL co-treated mice did not exhibit measurable social memory deficits. Proteomics analysis showed ERK1/2 signaling is involved in TAC and TAC/PL co-treatment. Reduced Nrf2 mRNA expression was also observed. mRNA levels of Gria2 were increased in TAC treated mice and reduced in TAC/PL co-treated mice. In this study, PL protects against social memory impairment when co-administered with TAC via multifactorial mechanisms involving oxidative stress and synaptic plasticity.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Breast Neoplasms; Chemotherapy-Related Cognitive Impairment; Cognitive Dysfunction; Dioxolanes; Female; Inflammation; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Quality of Life; RNA, Messenger; Signal Transduction

Piperlongumine (PL), a biologically active compound from the Piper species, has been shown to exert various pharmacological effects in a number of conditions, including tumours, diabetes, pain, psychiatric disorders and neurodegenerative disease. In this study, we evaluated the therapeutic effects of PL on hippocampal function and cognition decline in aged mice. PL (50 mg/kg/day) was intragastrically administrated to 23‑month‑old female C57BL/6J mice for 8 weeks. Novel object recognition and nest building behaviour tests were used to assess cognitive and social functions. Additionally, immunohistochemistry and western blot analysis were performed to examine the effects of PL on the hippocampus. We found that the oral administration of PL significantly improved novel object recognition and nest building behaviour in aged mice. Although neither the percentage area occupied by astrocytes and microglia nor the level of 4‑hydroxynonenal protein, a specific marker of lipid peroxidation, were altered by PL treatment, the phosphorylation levels of N‑methyl‑D‑aspartate receptor subtype 2B (NR2B), calmodulin‑dependent protein kinase II alpha (CaMKIIα) and extracellular signal‑regulated kinase 1/2 (ERK1/2) were markedly increased in the hippocampus of aged mice following the administration of PL. We also found that PL treatment resulted in a CA3‑specific increase in the phosphorylation level of cyclic AMP response element binding protein, which is recognized as a potent marker of neuronal plasticity, learning and memory. Moreover, the number of doublecortin‑positive cells, a specific marker of neurogenesis, was significantly increased following PL treatment in the dentate gyrus of the hippocampus. On the whole, these data demonstrate that PL treatment may be a potential novel approach in the treatment of age‑related cognitive impairment and hippocampal changes.

Topics: Aging; Animals; Astrocytes; CA3 Region, Hippocampal; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cognitive Dysfunction; Dioxolanes; Female; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase 3