Luteolin Enhances Choroid Plexus 5-MTHF Brain Transport to Promote Hippocampal Neurogenesis in LOD Rats

Abstract

Folates, provided by food, are commonly used antidepressant synergists in late-onset depression (LOD). However, increased intake of folic acid in the elderly population might lead to the accumulation of unmetabolized folic acid in the systemic circulation, leading to enhanced deterioration of the central nervous system function. In addition, folates cannot access the brain directly because of the blood–brain barrier. Choroid plexus (CP) 5-methyltetrahydrofolate (5-MTHF) brain transport plays a critical role in regulating the cerebrospinal fluid (CSF) 5-MTHF content. Luteolin is a natural flavonoid that has antidepressant effects and is involved in the anti-folate resistance pathway. It remains unclear whether the antidepressant effects of luteolin are associated with the CP 5-MTHF brain transport. In this study, 20–21-month-old Wistar rats were exposed to the chronic unpredictable mild stress (CUMS) protocol for 6 consecutive weeks to explore the long-term effects of luteolin on behavior, 5-MTHF levels, hippocampal neurogenesis, and folate brain transport of the CP. In vitro primary hippocampal neural stem cells (NSCs) cultured in media containing 10% CSF from each group of rats and choroid plexus epithelial cells (CPECs) cultured in media containing 20 μM luteolin were treated with 100 μM corticosterone and 40 mg/ml D-galactose. We found that aged rats exposed to CUMS showed a significantly reduced sucrose preference, decreased locomotion activity in the open field test and accuracy of the Morris water maze test, increased immobility time in the forced swimming test, accelerated dysfunctional neurogenesis and neuronal loss in the dentate gyrus of LOD rats, as well as decreased CSF and hippocampus 5-MTHF levels, and zona occludens protein 1 (ZO-1), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC) protein levels. In vitro assays showed media containing 10% aged CSF or LOD+ Luteolin-CSF significantly increased the viability of CORT + D-gal-injured NSCs and alleviated dysfunctional neurogenesis and neuronal loss compared with the CORT + D-gal medium. However, media containing 10% LOD-CSF had no such effect. In the meantime, induction of CORT + D-gal significantly decreased the ZO-1, PCFT, RFC, and folate receptor alpha (FR-α) protein levels and transepithelial electrical resistance in rat CPECs. As expected, luteolin treatment was effective in improving these abnormal changes. These findings suggested that luteolin could ameliorate CUMS-induced LOD-like behaviors by enhancing the folate brain transport.

Luteolin alleviates depression‐like behavior by modulating glycerophospholipid metabolism in the hippocampus and prefrontal cortex of LOD rats

“…The LOD and LUT groups were subjected to chronic unpredictable mild stress, and the CUMS protocol was based on our previous study. 5 , 18 Rats were individually housed in Room B during the stress protocol. The stress protocol included fasting (12 h), water deprivation (12 h), continuous illumination at night (20:00–8:00 of the next day, 12 h), plantar shock (1 mA, 2 s/time, 10 times/5 min), white noise (85 dB, 5 h), night strobe illumination (300 times/min, 5 h), hot water swimming (45°C, 5 min), restraint (12 h), wet cage (10 h), and fasting and water deprivation (24 h).…”

“…The LOD and LUT groups were subjected to chronic unpredictable mild stress, and the CUMS protocol was based on our previous study 5,18 . Rats were individually housed in Room B during the stress protocol.…”

“…Studies have demonstrated a reduction in hippocampal volume in LOD patients, with the extent of volume change correlating with the duration and severity of depression 4 . Our previous research has also indicated a loss of mature neurons in the hippocampus with impaired neurogenesis in LOD rats 5 . Additionally, the prefrontal lobe plays a significant modulatory role in negative emotions 6 .…”

“… 4 Our previous research has also indicated a loss of mature neurons in the hippocampus with impaired neurogenesis in LOD rats. 5 Additionally, the prefrontal lobe plays a significant modulatory role in negative emotions. 6 As a key node of cortical and subcortical neural circuits, depressed patients exhibit a deficit in prefrontal cortical metabolism.…”

“… 15 , 16 , 17 Our previous studies have suggested that LUT can enhance the brain's transport of folic acid to promote hippocampal neurogenesis and alter the axonal guidance pathway in cerebrospinal fluid to exert its therapeutic effect on LOD. 5 , 18 …”