Pre-extinction activation of hippocampal AMPK prevents fear renewal in mice.

As a type of fear relapse, fear renewal compromises the efficacy of fear extinction, which serves as the laboratory analog of exposure therapy (a therapeutic strategy for anxiety disorders). Interventions aiming to prevent fear renewal would thus benefit exposure therapy. To date, it remains unknown whether central adenosine monophosphate (AMP)-activated protein kinase (AMPK) activation could produce inhibitory effects on fear renewal. Here, using pharmacological approach and virus-mediated gene overexpression technique, we demonstrated that activation of AMPK in dorsal hippocampus shortly before fear extinction training completely abolished subsequent fear renewal in male mice without affecting other types of fear relapse, including spontaneous recovery of fear and fear reinstatement. Furthermore, we also found that metformin, a first-line antidiabetic drug, was capable of preventing fear renewal in male mice by stimulating AMPK in dorsal hippocampus. Collectively, our study provides insight into the role of hippocampal AMPK in regulation of fear renewal and indicates that increasing activity of hippocampal AMPK can prevent fear renewal, thus enhancing the potency of exposure therapy.

Anemoside A3 rapidly reverses depression-like behaviors and weakening of excitatory synaptic transmission in mouse models of depression.

BACKGROUND AND AIM: Developing fast-acting antidepressants attracts considerable attention. Anemoside A3, a natural triterpenoid glycoside isolated from Pulsatillae Radix, has been reported to produce antidepressant-like action in the forced swim test. We herein explore the fast-onset antidepressant-like potentials and antidepressant mechanisms of anemoside A3. METHODS: The forced swim test and tail suspension test were used to determine the acute antidepressant-like action of anemoside A3. This action of anemoside A3 was confirmed in chronic mild stress and chronic social defeat stress models. In vitro extracellular field potential recordings were conducted to investigate the impact of anemoside A3 on chronic stress-induced alterations at temporoammonic-CA1 synapses. Western blot, whole-cell patch-clamp recordings, and microinjections of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor antagonists into the stratum lacunosum-moleculare were performed to unravel the contribution of stratum lacunosum-moleculare α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors to anemoside A3's antidepressant-like activity. In vivo microdialysis and pharmacological depletion of serotonin were implemented to examine the role of the serotonin system in the antidepressant-like effect of anemoside A3. RESULTS: Anemoside A3 administered intraperitoneally displayed acute antidepressant-like effects in the mouse forced swim test and tail suspension test and anemoside A3 treatment (intraperitoneally) for five days was sufficient to reverse depression-related behaviors of mice subjected to chronic stress. Accordingly, chronic social defeat stress-induced weakening of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor-mediated neurotransmission in the temporoammonic-CA1 pathway and downregulation of synaptic GluA2-lacking α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor expression in the stratum lacunosum-moleculare could both be normalized by five days of anemoside A3 treatment (intraperitoneally). Moreover, intra-stratum lacunosum-moleculare infusion of GluA2-lacking α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor antagonist abolished anemoside A3's antidepressant-like effect. Lastly, serotonin system was not implicated in anemoside A3's antidepressant-like effect. CONCLUSIONS: Our results suggest that anemoside A3 induces a rapid antidepressant-like response by a stratum lacunosum-moleculare GluA2-lacking α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor-dependent mechanism. In view of this, anemoside A3 represents a promising agent for depression treatment.

Peroxidase-like activity of nanocrystalline cobalt selenide and its application for uric acid detection.

Dendrite-like cobalt selenide nanostructures were synthesized from cobalt and selenium powder precursors by a solvothermal method in anhydrous ethylenediamine. The as-prepared nanocrystalline cobalt selenide was found to possess peroxidase-like activity that could catalyze the reaction of peroxidase substrates in the presence of H2O2. A spectrophotometric method for uric acid (UA) determination was developed based on the nanocrystalline cobalt selenide-catalyzed coupling reaction between N-ethyl-N-(3-sulfopropyl)-3-methylaniline sodium salt and 4-aminoantipyrine (4-AAP) in the presence of H2O2. Under optimum conditions, the absorbance was proportional to the concentration of UA over the range of 2.0-40 µM with a detection limit of 0.5 µM. The applicability of the proposed method has been validated by determination of UA in human serum samples with satisfactory results.

Methylene Blue Mitigates Acute Neuroinflammation after Spinal Cord Injury through Inhibiting NLRP3 Inflammasome Activation in Microglia.

The spinal cord injury (SCI) is a detrimental neurological disease involving the primary mechanical injury and secondary inflammatory damage. Curtailing the detrimental neuroinflammation would be beneficial for spinal cord function recovery. Microglia reside in the spinal cord and actively participate in the onset, progression and perhaps resolution of post-SCI neuroinflammation. In the current study, we tested the effects of methylene blue on microglia both in vitro and in a rat SCI model. We found that methylene blue inhibited the protein levels of IL-1ß and IL-18 rather than their mRNA levels in activated microglia. Further investigation indicated that methylene blue deceased the activation of NLRP3 inflammasome and NLRC4 inflammasome in microglia in vitro. Moreover, in the rat SCI model, the similar effect of methylene blue on post-SCI microglia was also observed, except that the activation of NLRC4 inflammasome was not seen. The inhibition of microglia NLRP3 inflammasome was associated with down-regulation of intracellular reactive oxygen species (ROS). The administration of methylene blue mitigated the overall post-SCI neuroinflammation, demonstrated by decreased pro-inflammatory cytokine production and leukocyte infiltrates. Consequently, the neuronal apoptosis was partially inhibited and the hind limb locomotor function was ameliorated by methylene blue treatment. Our research highlights the role of methylene blue in inhibiting post-SCI neuroinflammation, and suggests that methylene blue might be used for SCI therapy.