Gender Differences in the Association of Neutrophil Gelatinase-Associated Lipocalin with Cognitive Impairment and Depression in Heart Failure

Introduction Heart failure increases the risk to develop depression, which worsens prognosis. Depression is more common in women than in men. Neutrophil Gelatinase‐Associated Lipocalin (NGAL), a regulator of inflammation and indicator of prognosis in heart failure patients, is also associated with depression. The aim of this study was to investigate the association of NGAL with behavior in both male and female rats with heart failure. Methods Male and female Wistar rats were subjected to coronary artery ligation (MI) or sham surgery. Three weeks later, depressive symptoms were obtained from the open field test (OF) and cognitive functioning from the novel object and novel location test. Plasma levels of NGAL were measured with Elisa, and NGAL expression in the brain was obtained using immunohistochemistry. Results In males, but not in females, plasma NGAL appeared correlated to infarct size. We found both a gender (F=6.53, p=0.005) and an MI (F=6.63, p=0.013) effect in plasma NGAL levels, with higher levels in male compared to female rats and MI compared to sham rats. An MI effect (F=4.19, p=0.049) and interaction effect (F=7.87, p=0.09) were found in the number of NGAL positive cells in the paraventricular nucleus of the hypothalamus (PVN), post‐hoc analysis showed that NGAL was elevated only in male rats upon MI. Spatial object recognition was impaired in male MI compared to sham rats (discrimination index 54.3% vs 78.3%, p<0.01). No significant effect of MI was seen in the OF. In male rats, plasma NGAL showed a negative correlation with distance in the OF (r=−0.384, p=0.044) and discrimination index of the moved object in the novel location test (r=−0.570, p=0.033). Additionally, PVN NGAL negatively correlated to distance spent in the OF in male rats (r=0.464, p=0.039). In female rats no behavioral changes were seen after MI and NGAL did not correlate with behavioral outcomes. Discussion Data indicate gender specific effects of MI on the expression of NGAL and on behavior. This suggests that post‐MI inflammatory processes and their potential effects on depressive‐like behavior and cognition, may be differently regulated in male and female rats.