Rolipram Ameliorates Memory Deficits and Depression-Like Behavior in APP/PS1/tau Triple Transgenic Mice: Involvement of Neuroinflammation and Apoptosis via cAMP Signaling.

BACKGROUND: Alzheimer disease (AD) and depression often cooccur, and inhibition of phosphodiesterase-4 (PDE4) has been shown to ameliorate neurodegenerative illness. Therefore, we explored whether PDE4 inhibitor rolipram might also improve the symptoms of comorbid AD and depression. METHODS: APP/PS1/tau mice (10 months old) were treated with or without daily i.p. injections of rolipram for 10 days. The animal groups were compared in behavioral tests related to learning, memory, anxiety, and depression. Neurochemical measures were conducted to explore the underlying mechanism of rolipram. RESULTS: Rolipram attenuated cognitive decline as well as anxiety- and depression-like behaviors. These benefits were attributed at least partly to the downregulation of amyloid-ß, Amyloid precursor protein (APP), and Presenilin 1 (PS1); lower tau phosphorylation; greater neuronal survival; and normalized glial cell function following rolipram treatment. In addition, rolipram upregulated B-cell lymphoma-2 (Bcl-2) and downregulated Bcl-2-associated X protein (Bax) to reduce apoptosis; it also downregulated interleukin-1ß, interleukin-6, and tumor necrosis factor-α to restrain neuroinflammation. Furthermore, rolipram increased cAMP, PKA, 26S proteasome, EPAC2, and phosphorylation of ERK1/2 while decreasing EPAC1. CONCLUSIONS: Rolipram may mitigate cognitive deficits and depression-like behavior by reducing amyloid-ß pathology, tau phosphorylation, neuroinflammation, and apoptosis. These effects may be mediated by stimulating cAMP/PKA/26S and cAMP/exchange protein directly activated by cAMP (EPAC)/ERK signaling pathways. This study suggests that PDE4 inhibitor rolipram can be an effective target for treatment of comorbid AD and depression.

Effects of Danggui-Shaoyao-San on central neuroendocrine and pharmacokinetics in female ovariectomized rats.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese medicine formula Danggui-Shaoyao-San (DSS) has been reported to have estrogen-like effects and therapeutic effects on the symptoms of Alzheimer's disease (AD). AIM OF THE STUDY: To explore whether the central oxytocin and neuroendocrine system is involved in the modulating effects of DSS on the cognition and neuropsychiatric hebaviors in female AD rats, and to investigate the pharmacokinetics of paeoniflorin and ferulic acid in female AD rats with DSS treatment. MATERIAL AND METHODS: DSS (1.2, 3.2, 8.6 g/kg/day) was orally administered to ovariectomized (OVX) rats, and saline was orally administered to sham operation rats as control group. The Morris water maze test, novel object recognition test, and passive avoidance test were conducted for evaluation of learning and memory abilities, while elevated plus maze test and forced swim test were performed to assess anxiety- and depressive-like behaviors. ELISA kits were used to detect the levels of estrogen (E), estrogen receptor α (ERα), oxytocin (OT), oxytocin receptor (OTR), acetylcholine (Ach), acetylcholin esterase (AchE), and choline acetyl transferase (ChAT) in the cortex. The concentrations of Ach, glutamate (Glu), γ-aminobutyric acid (GABA), 5-hydroxytryptamine (5-HT), norepinephrine (NE) and dopamine (DA) in the hippocampus were assessed by HPLC-MS. The changes of neuronal morphology in the hippocampus were observed by Nissl staining. The pharmacokinetics of paeoniflorin and ferulic acid in OVX rats with DSS treatment were studied by HPLC. RESULTS: In the Morris water maze test, novel object recognition test, and passive avoidance test, OVX rats showed cognitive impairment. In the elevated plus maze test and forced swim test, the anxiety- and depressive-like behaviors of OVX rats were significant as compared to the control group. Treatment of DSS significantly imporved the cognitive deficits, and ameliorated anxiety- and depressive-like behaviors of OVX rats. The expression of E, ERα, OT, OTR, AchE and ChAT in the cortex of model group were significantly decreased, and DSS significantly reversed these changes. The concentrations of Ach, Glu, GABA, 5-HT and NE in the hippocampus of OVX rats were significantly decreased, whereas DSS significantly increased the levels of Ach, Glu, GABA, 5-HT and NE. There was no significant difference in the concentration of DA in the hippocampus among groups. Degenerating neurons in the hippocampal CA3 region were observed in OVX rats, and the number of neurons was decreased. DSS treatment reduced the degenerating neurons, and incresed the number of neurons. The MRT (0 - ∞), AUC (0 - ∞), Cmax and t1/2z values of paeoniflorin, and the AUC 0-∞ and Cmax value of ferulic acid were higher in DSS-treated OVX rats than those in the DSS-treated control rats. CONCLUSIONS: DSS improves the learning and memory ability, and attenuates anxiety- and depressive-like behaviors of OVX rats. The mechanism may be through increasing estrogen, reducing cholinergic damage, and modulating neurotransmitters. The increase in absorption and elimination time of paeoniflorin and ferulic acid in OVX rats may enhance the efficacy of DSS.

Arterial Baroreflex Dysfunction Promotes Neuroinflammation by Activating the Platelet CD40L/Nuclear Factor Kappa B Signaling Pathway in Microglia and Astrocytes.

Arterial baroreflex (ABR) dysfunction has previously been associated with neuroinflammation, the most common pathological feature of neurological disorders. However, the mechanisms mediating ABR dysfunction-induced neuroinflammation are not fully understood. In the present study, we investigated the role of platelet CD40 ligand (CD40L) in neuroinflammation in an in vivo model of ABR dysfunction, and microglia and astrocyte activation in vitro. ABR dysfunction was induced in Sprague‒Dawley rats by sinoaortic denervation (SAD). We used ELSA and immunofluorescence to assess the effect of platelet CD40L on glial cell polarization and the secretion of inflammatory factors. By flow cytometry, we found that rats subjected to SAD showed a high level of platelet microaggregation and upregulation of CD40L on the platelet surface. The promotion of platelet invasion and accumulation was also observed in the brain tissues of rats subjected to SAD. In the animal model and cultured N9 microglia/C6 astrocytoma cells, platelet CD40L overexpression promoted neuroinflammation and activated M1 microglia, A1 astrocytes, and the nuclear factor kappa B (NFκB) signaling pathway. These effects were partially blocked by inhibiting platelet activity with clopidogrel or inhibiting CD40L-mediated signaling. Our results suggest that during ABR dysfunction, CD40L signaling in platelets converts microglia to the M1 phenotype and astrocytes to the A1 phenotype, activating NFκB and resulting in neuroinflammation. Thus, our study provides a novel understanding of the pathogenesis of ABR dysfunction-induced neuroinflammation and indicates that targeting platelet CD40L is beneficial for treating central nervous system (CNS) disorders associated with ABR dysfunction.