The Aqueous Fraction of Areca catechu Nut Ameliorates Demyelination in Prefrontal Cortex-Induced Depressive Symptoms and Cognitive Decline through Brain-Derived Neurotrophic Factor-Cyclic Adenosine Monophosphate Response Element-Binding Activation.

OBJECTIVE: To investigate if Areca catechu L. treatment could ameliorate depressive symptoms and cognitive decline by facilitating myelination processes in prefrontal cortex. METHODS: A mouse model of cuprizoneinduced demyelination was used to mimic demyelinating disease. Two concentrations of A. catechu nut extract (ANE; 1% and 2%) were administered orally in the diet for 8 weeks. Depressive symptoms and cognition-associated behaviors were evaluated in tests of locomotor activity, tail suspension, and forced swimming; spatial memory was tested with the Y-maze. Expression of myelin basic protein (MBP), 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase), glutathione S-transferases pi (GSTpi), brain-derived neurotrophic factor (BDNF), and the transcription factor cyclic adenosine monophosphate (cAMP) response element-binding (CREB) were evaluated by western blot. RESULTS: Animals subjected to demyelination showed hyperactivity (P<0.01), impaired spatial memory (P<0.01), and depressive behaviors (P<0.05). Internally, they displayed signifificant myelin damage in the cortex, lower expression of CNPase and GSTpi, slightly decreased BDNF (P>0.05), and signifificantly reduced p-CREB (P<0.05). Nevertheless, ANE treatment demonstrated signifificant anti-depressant activity and enhancement of working memory (P<0.05 or 0.01). In addition, ANE treatment increased MBP, CNPase and GSTpi protein expression in prefrontal cortex (P<0.05). Concomitant with increased BDNF production (P<0.05), ANE treatment up-regulated phosphorylated CREB, but without statistical signifificance (P>0.05). CONCLUSION: ANE treatment might ameliorate depressive symptoms and cognitive decline by facilitating myelination processes in prefrontal cortex via induction of BDNF-CREB activation.

Astrocyte-dependent protective effect of quetiapine on GABAergic neuron is associated with the prevention of anxiety-like behaviors in aging mice after long-term treatment.

Previous studies have demonstrated that quetiapine (QTP) may have neuroprotective properties; however, the underlying mechanisms have not been fully elucidated. In this study, we identified a novel mechanism by which QTP increased the synthesis of ATP in astrocytes and protected GABAergic neurons from aging-induced death. In 12-month-old mice, QTP significantly improved cell number of GABAegic neurons in the cortex and ameliorated anxiety-like behaviors compared to control group. Complimentary in vitro studies showed that QTP had no direct effect on the survival of aging GABAergic neurons in culture. Astrocyte-conditioned medium (ACM) pretreated with QTP (ACMQTP) for 24 h effectively protected GABAergic neurons against aging-induced spontaneous cell death. It was also found that QTP boosted the synthesis of ATP from cultured astrocytes after 24 h of treatment, which might be responsible for the protective effects on neurons. Consistent with the above findings, a Rhodamine 123 test showed that ACMQTP, not QTP itself, was able to prevent the decrease in mitochondrial membrane potential in the aging neurons. For the first time, our study has provided evidence that astrocytes may be the conduit through which QTP is able to exert its neuroprotective effects on GABAergic neurons. The neuroprotective properties of quetiapine (QTP) have not been fully understood. Here, we identify a novel mechanism by which QTP increases the synthesis of ATP in astrocytes and protects GABAergic neurons from aging-induced death in a primary cell culture model. In 12-month-old mice, QTP significantly improves cell number of GABAegic neurons and ameliorates anxiety-like behaviors. Our study indicates that astrocytes may be the conduit through which QTP exerts its neuroprotective effects on GABAergic neurons.