Effects of CMF and MET on glutamate and dopamine levels in the brain, and their impact on cognitive function.

OBJECTIVE: Chemotherapy can cause cognitive impairment in cancer survivors. CMF, the combination of cyclophosphamide (CYP), methotrexate (MTX), and 5-fluorouracil (5-FU), is employed for the treatment of several types of cancers, such as metastatic breast cancer. Metformin (MET) is an antidiabetic medication used to treat type 2 diabetes that can reportedly alleviate some toxic effects. In the current study, we investigated the ability of MET to alleviate the effects of CMF in neuronal toxicity. MATERIALS AND METHODS: Rats were treated with two doses of CMF (intraperitoneal injection) and MET (in the daily drinking water). Rats were subjected to fear conditioning memory tests to evaluate memory function following treatment, and brain samples were collected and homogenized using neuronal lysis buffer for assessment of glutamate and dopamine levels by high-performance liquid chromatography (HPLC). RESULTS: Fear conditioning memory tests revealed a significant reduction in memory function in CMF and CMF+MET groups vs. controls, but no significant change in MET groups vs. controls was detected. Similarly, CMF and CMF+MET groups revealed a significant increase in glutamate and dopamine levels in the brain of MET, CMF, and MET+CMF groups vs. controls based on HPLC results. In addition, although glutamate and dopamine levels were increased, levels varied between groups, with highest levels in the CMF+MET group. CONCLUSIONS: Our results demonstrate that cognitive impairment in CMF and CMF+MET groups could result from increased glutamate and dopamine levels in the brain, leading to brain toxicity and failure of MET to alleviate the toxic effects of CMF.

Elucidating the mechanism underlying cognitive dysfunction by investigating the effects of CMF and MET treatment on hippocampal neurons.

OBJECTIVE: Chemotherapy causes long-term cognitive impairment in cancer survivors. A combination of cyclophosphamide (CYP), methotrexate (MTX), and 5-fluorouracil (5-FU) (i.e., CMF) is widely used for cancer treatment. Metformin (MET), an oral antidiabetic drug, confers protection against the adverse effects of chemotherapeutic agents, such as CYP. To elucidate the potential mechanism underlying cognitive dysfunction, we investigated the impact of CMF and MET treatment on the activities of mitochondrial respiratory chain complexes I and IV, as well as lipid peroxidation, in hippocampal neurons. MATERIALS AND METHODS: Hippocampal neurons (H19-7) cells were treated for 24 h with MET (0.5 mM) alone; CYP (1 µM), MTX (0.5 µM), and 5-FU (1 µM); and MET (0.5 mM) + CYP (1 µM), MTX (0.5 mM), and 5-FU (1 µM). A 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide assay was performed to evaluate cell survival. Neurons were collected and homogenized in a neuronal lysis buffer to assess mitochondrial complexes (I and IV) activity and lipid peroxidation. RESULTS: Compared to the control, MET-treated cells showed no significant difference in survival rate; however, CMF- and CMF + MET-treated cells showed a significant reduction in survival rate. In addition, relative to the control, CMF- and CMF + MET-treated cells showed a reduction in mitochondrial complex I activity, whereas no significant changes were observed in mitochondrial complex IV activity. MET-treated cells showed no significant differences in lipid peroxidation, but CMF- and CMF + MET-treated cells showed a slight increase in lipid peroxidation. CONCLUSIONS: The reduction in the activity of mitochondrial complex I and a slight increase in lipid peroxidation levels may explain the cognitive impairment following CMF and MET treatments.

Associations of healthcare providers' awareness, perception, and knowledge of chemotherapy-induced cognitive impairment and their intentions to provide information about it to patients.

OBJECTIVE: Most recent oncology studies support the existence of chemotherapy-induced cognitive impairment. This study's objective was to evaluate the power of healthcare providers' knowledge, awareness, and perception of memory impairment caused by chemotherapeutic agents, as predictors of their intentions to convey information about this side effect to patients. MATERIALS AND METHODS: A cross-sectional online survey with 32 questions and seven domains was distributed. The domains included questions about healthcare providers' behaviors, norms, attitudes, awareness, perceptions, and knowledge about chemotherapeutic agent-induced cognitive impairment and their intentions to inform patients about these side effects. Descriptive and inferential statistics were calculated to analyze associations. RESULTS: A total of 207 healthcare providers completed the survey. Their mean age was 31 (±7.8) years and most of them were physicians (43.5%). Positive relationships were found between healthcare providers' attitudes (ß=0.239, p<0.001), subjective norms (ß=0.219, p<0.001), behavioral control (ß=0.284, p<0.001), and intentions to provide information to patients. Their awareness was positively associated with their age (ß=0.127, p<0.001), and their (or their relatives') receipt of chemotherapeutic agents (ß=1.363, p=0.04); however, a negative relationship was found with physician specialists (ß=-2.659, p<0.001) and Saudi nationality (ß=-2.919, p<0.001). A negative correlation was found between healthcare givers' perceptions and physician specialists (ß=-1.487, p=0.003), and a positive association with participants' total knowledge (ß=0.765, p<0.001). Univariate linear regression analysis of participants' knowledge showed a negative relationship with Saudi nationality (ß= -0.835, p<0.001) and physician specialists (ß= -0.519, p=0.003). CONCLUSIONS: Providers' low scores on awareness, perceptions, and knowledge of these side effects of treatment highlight a need for strategic educational programs that meet patients' needs and improve their quality of life.

CMF and MET treatment induce cognitive impairment through upregulation of IL-1α in rat brain.

OBJECTIVE: Cyclophosphamide (CYP), methotrexate (MTX) and 5-fluorouracil (5-FU) (CMF) are chemotherapeutic agents known to cause acute and long-term cognitive impairment in cancer patients. Cognitive function is regulated mainly by neuronal circuitry in the brain, especially the cortex and hippocampus as well as other components of the limbic area. Neuroinflammation mediated by proinflammatory cytokines is a well-known cause of cognitive impairment. Our previous study showed that metformin induced cognitive impairment and neuroinflammation in CMF-treated rats. Understanding the effects and mechanisms of CMF and MET treatment on chemotherapy-related cognitive impairment and the relationship with neuroinflammation may help prevent some of the adverse effects of this type of chemotherapy in cancer patients. MATERIALS AND METHODS: Rats were divided into four groups: control (normal saline), CMF (50 mg/kg CYP, 2 mg/kg MTX, 50 mg/kg 5-FU; two doses administered by intraperitoneal injection over two weeks), MET (2.5 mg/ml - oral administration daily), and CMF+MET group. IL-1α, IRS-1, Akt-a and TNF-α levels in brain tissues were measured by ELISA and data were analyzed by one-way ANOVA test followed by Tukey's test. RESULTS: Compared with the control group, IL-1α levels were significantly increased in the CMF+MET group, whereas there were no significant differences in the MET and CMF groups. On the other hand, IRS-1, TNF-α and Akt-a expression and mitochondrial complex 1 activity indicated that systemic CMF and MET treatment did not change the expression of these proteins in the brain compared to the control group. CONCLUSIONS: Our results indicate that cognitive function is impaired by the administration of two doses of CMF and MET over a period of two weeks as a result of IL-1α overexpression in the brain.

Predictors of smoking among male college students in Saudi Arabia.

Identifying the predictors of smoking in one of the top cigarette-consuming countries in the world is a vital step in smoking prevention. A cross-sectional study assessed the predictors of smoking in a cohort of male students in 3 universities in Saudi Arabia. A pre-tested, validated questionnaire was used to determine sociodemographic characteristics, academic performance, peers' smoking, and presence of a smoker within the family. Of the 337 participants, 30.9% were current smokers (smoked 1 or more cigarettes within the last 30 days). Lower academic performance (OR = 2.29, 95% CI: 1.02-5.17), peer smoking (OR = 4.14, 95% CI: 1.53-11.3) and presence of other smokers in the family (OR = 2.77, 95% CI: 1.37-5.64) were the significant predictors of smoking status identified using multiple logistic regression analysis. These findings highlight the influence of family and peer pressure in initiating cigarette use among the youth of Saudi Arabia.

Predictors of smoking among male college students in Saudi Arabia

Identifying the predictors of smoking in one of the top cigarette-consuming countries in the world is a vital step in smoking prevention. A cross-sectional study assessed the predictors of smoking in a cohort of male students in 3 universities in Saudi Arabia. A pre-tested, validated questionnaire was used to determine sociodemographic characteristics, academic performance, peers' smoking, and presence of a smoker within the family. Of the 337 participants, 30.9% were current smokers [smoked 1 or more cigarettes within the last 30 days]. Lower academic performance [OR = 2.29, 95% CI: 1.02-5.17], peer smoking [OR = 4.14, 95% CI: 1.53-11.3] and presence of other smokers in the family [OR = 2.77, 95% CI: 1.37-5.64] were the significant predictors of smoking status identified using multiple logistic regression analysis. These findings highlight the influence of family and peer pressure in initiating cigarette use among the youth of Saudi Arabia