Post-status epilepticus treatment with the Fyn inhibitor, saracatinib, improves cognitive function in mice.

BACKGROUND: Status epilepticus (SE) is a life-threatening neurological disorder. The hippocampus, as an important area of the brain that regulates cognitive function, is usually damaged after SE, and cognitive deficits often result from hippocampal neurons lost after SE. Fyn, a non-receptor Src family of tyrosine kinases, is potentially associated with the onset of seizure. Saracatinib, a Fyn inhibitor, suppresses epileptogenesis and reduces epileptiform spikes. However, whether saracatinib inhibits cognitive deficits after SE is still unknown. METHODS: In the present study, a pilocarpine-induced SE mouse model was used to answer this question by using the Morris water maze and normal object recognition behavioral tests. RESULTS: We found that saracatinib inhibited the loss in cognitive function following SE. Furthermore, we found that the number of hippocampal neurons in the saracatinib treatment group was increased, when compared to the SE group. CONCLUSIONS: These results showed that saracatinib can improve cognitive functions by reducing the loss of hippocampal neurons after SE, suggesting that Fyn dysfunction is involved in cognitive deficits after SE, and that the inhibition of Fyn is a possible treatment to improve cognitive function in SE patients.

Hypobaric hypoxia regulates iron metabolism in rats.

Intermittent hypobaric hypoxia can produce a protective effect on both the nervous system and non-nervous system tissues. Intermittent hypobaric hypoxia preconditioning has been shown to protect rats from cardiac ischemia-reperfusion injury by decreasing cardiac iron levels and reactive oxygen species (ROS) production, thereby decreasing oxidative stress to achieve protection. However, the specific mechanism underlying the protective effect of hypobaric hypoxia is unclear. To shed light on this phenomenon, we subjected Sprague-Dawley rats to hypobaric hypoxic preconditioning (8 hours/day). The treatment was continued for 4 weeks. We then measured the iron content in the heart, liver, spleen, and kidney. The iron levels in all of the assessed tissues decreased significantly after hypobaric hypoxia treatment, corroborating previous results that hypobaric hypoxia may produce its protective effect by decreasing ROS production by limiting the levels of catalytic iron in the tissue. We next assessed the expression levels of several proteins involved in iron metabolism (transferrin receptor, L-ferritin, and ferroportin1 [FPN1]). The increased transferrin receptor and decreased L-ferritin levels after hypobaric hypoxia were indicative of a low-iron phenotype, while FPN1 levels remained unchanged. We also examined hepcidin, transmembrane serine proteases 6 (TMPRSS6), erythroferrone (ERFE), and erythropoietin (EPO) levels, all of which play a role in the regulation of systemic iron metabolism. The expression of hepcidin decreased significantly after hypobaric hypoxia treatment, whereas the expression of TMPRSS6 and ERFE and EPO increased sharply. Finally, we measured serum iron and total iron binding capacity in the serum, as well as red blood cell count, mean corpuscular volume, hematocrit, red blood cell distribution width SD, and red blood cell distribution width CV. As expected, all of these values increased after the hypobaric hypoxia treatment. Taken together, our results show that hypobaric hypoxia can stimulate erythropoiesis, which systemically draws iron away from nonhematopoietic tissue through decreased hepcidin levels.

Mitochondrial Ferritin Is a Hypoxia-Inducible Factor 1α-Inducible Gene That Protects from Hypoxia-Induced Cell Death in Brain.

Aims: Mitochondrial ferritin (protein [FtMt]) is preferentially expressed in cell types of high metabolic activity and oxygen consumption, which is consistent with its role of sequestering iron and preventing oxygen-derived redox damage. As of yet, the mechanisms of FtMt regulation and the protection FtMt affords remain largely unknown. Results: Here, we report that hypoxia-inducible factor 1α (HIF-1α) can upregulate FtMt expression. We verify one functional hypoxia-response element (HRE) in the positive regulatory region and two HREs possessing HIF-1α binding activity in the minimal promoter region of the human FTMT gene. We also demonstrate that FtMt can alleviate hypoxia-induced brain cell death by sequestering uncommitted iron, whose levels increase with hypoxia in these cells. Innovation: In the absence of FtMt, this catalytic metal excess catalyzes the production of cytotoxic reactive oxygen species. Conclusion: Thus, the cell ability to increase expression of FtMt during hypoxia may be a skill to avoid tissue damage derived from oxygen limitation.

Associated and predictive factors of quality of life in patients with temporal lobe epilepsy.

OBJECTIVE: Identifying the factors that are correlated with and predictive of reduced quality of life (QOL) is essential to optimize the treatment of epilepsy and the management of comorbidities. METHODS: We analyzed the independent associations between the Quality of Life in Epilepsy-31 (QOLIE-31) inventory and the demographic, clinical, psychiatric, and cognitive variables of 47 consecutive patients with temporal lobe epilepsy (TLE). Predictors of the correlated variables were analyzed by multiple linear regression analysis. RESULTS: The QOLIE-31 total score was positively correlated with occupational status and Mini-Mental State Examination (MMSE) scores (r = 0.290 and 0.295, respectively; P < 0.05) and negatively correlated with the duration of seizures, adverse effects of antiepileptic drugs (AEDs), and the Pittsburgh Sleep Quality Inventory (PSQI), Self-rating Anxiety Scale (SAS), and Self-rating Depression Scale (SDS) scores (r = -0.357, 0.321, 0.328, -0.672, and -0.565, respectively; P < 0.05; P < 0.01 for the SAS and SDS). In the final multivariate regression model, anxiety, long durations of seizures, adverse effects of AEDs, and depression explained approximately 60.6% (adjusted R2 = 0.606, R coefficient = 0.800) of the QOLIE-31 overall score variance. CONCLUSION: Anxiety, long durations of seizures, adverse effects of AEDs, and depression were significant predictors of QOL, and these variables had relatively high prediction capacities for the overall QOLIE-31 in the regression model. Comorbid anxiety is the most powerful negative determinant of the QOLIE-31.