Neurosteroid dehydroepiandrosterone sulphate inhibits persistent sodium currents in rat medial prefrontal cortex via activation of sigma-1 receptors

Dehydroepiandrosterone sulphate is one of the most important neurosteroids. In the present paper, we studied the effect of dehydroepiandrosterone sulphate on persistent sodium currents and its mechanism and functional consequence with whole-cell patch clamp recording method combined with a pharmacological approach in the rat medial prefrontal cortex slices. The results showed that dehydroepiandrosterone sulphate inhibited the amplitude of persistent sodium currents and the inhibitory effect was significant at 0.1 microM, reached maximum at 1 microM and decreased with the increase in the concentrations of above 1 microM. The effect of dehydroepiandrosterone sulphate on persistent sodium currents was canceled by the Gi protein inhibitor and the protein kinase C inhibitor, but not by the protein kinase A inhibitor. The effect of dehydroepiandrosterone sulphate on persistent sodium currents was also canceled by the sigma-1 receptor blockers and the sigma-1 receptor agonist could mimic the effect of dehydroepiandrosterone sulphate. Dehydroepiandrosterone sulphate had no significant influence on neuronal excitability but could significantly inhibit chemical inhibition of mitochondria-evoked increase in persistent sodium currents. These results suggest that dehydroepiandrosterone sulphate inhibits persistent sodium currents via the activation of sigma-1 receptors-Gi protein-protein kinase C-coupled signaling pathway, and the main functional consequence of this effect of DHEAS is presumably to protect neurons under ischemia.     

Spinal glial activation contributes to pathological pain states

Chronic pain, a pathological state, affects millions of people worldwide. Despite decades of study on the neuronal processing of pain, mechanisms underlying the creation and maintenance of enhanced pain states after injury or inflammation remain far from clear. In the last decade, however, the discovery that glial activation amplifies pain has challenged classic neuronal views of "pain". This review focuses on recent developments in understanding that spinal cord glia are involved in pathological pain. We overview the action of spinal glia (both microglia and astrocytes) in several persistent pain models, and provide new evidence that spinal glia activation contributes to the development and maintenance of arthritic pain facilitation. We also attempt to discuss some critical questions, such as how signals are conveyed from primary afferents to spinal glia following peripheral nerve injury and inflammation. What causes glia to become activated after peripheral/central injury/inflammation? And how the activated glia alter neuronal sensitivity and pain processing? Answers to these questions might open a new approach for treatment of pathological pain.     

GABA transporter-1 inhibitor NO-711 alters the EEG power spectra and increases non-rapid eye movement sleep in mice

GABA transporter subtype 1(GAT1) constructs high affinity reuptake sites for GABA in the CNS and regulates GABAergic transmission.Compounds that inhibit GAT1 are targets for epilepsy treatment.Sedation has been reported as a side effect of these agents,indicating possible sedative or hypnotic potential.To elucidate the role of GAT1 in sleep-wake regulation,we observed the sleep behaviors of mice treated by NO-711,a selective GAT1 inhibitor.The current data reveal that NO-711(10 mg·kg-1) causes a marked enhancement of EEG power density in theta(4-10 Hz) and the high frequency range EEG activity during the wakefulness and REM sleep,which were quite differed from those induced by zolpidem,a widely used hypnotic that binds preferentially to α1 GABAA receptor.NO-711 administered ip at doses of 1,3 or 10 mg·kg-1 significantly increased the amount of non-rapid eye movement(non-REM,NREM) sleep and shortened the sleep latency to NREM sleep.NO-711 at doses of 3 and 10 mg·kg-1 increased the number of NREM bouts and prolonged the mean duration at 10 mg·kg-1,and increased the number of state transitions from wakefulness to NREM sleep and subsequently from NREM sleep to wakefulness.NO-711 did not affect the architecture of REM sleep.Immunohistochemistry study showed that NO-711 dose-dependently increased c-Fos expression in neurons of the ventrolateral preoptic area(VLPO) and median preoptic nucleus(MnPO),which have been proposed to have a role in sleep-related processes.While the c-Fos expression in wakefulness-related processes nucleus,such as tuberomammillary nucleus(TMN),lateral hypothalamus(LH),and locus ceruleus(LC),were decreased by NO-711 treatment.These results indicated that NO-711 induced NREM sleep by modulating the sleep-wake related nucleus.Suggests GAT1 may be a potential target for hypnotic in treatment of insomnia.     

Forecasting the global burden of Alzheimer’s disease

BackgroundOur goal was to forecast the global burden of Alzheimer’s disease and evaluate the potential impact of interventions that delay disease onset or progression.MethodsA stochastic, multistate model was used in conjunction with United Nations worldwide population forecasts and data from epidemiological studies of the risks of Alzheimer’s disease.ResultsIn 2006, the worldwide prevalence of Alzheimer’s disease was 26.6 million. By 2050, the prevalence will quadruple, by which time 1 in 85 persons worldwide will be living with the disease. We estimate about 43% of prevalent cases need a high level of care, equivalent to that of a nursing home. If interventions could delay both disease onset and progression by a modest 1 year, there would be nearly 9.2 million fewer cases of the disease in 2050, with nearly the entire decline attributable to decreases in persons needing a high level of care.ConclusionsWe face a looming global epidemic of Alzheimer’s disease as the world’s population ages. Modest advances in therapeutic and preventive strategies that lead to even small delays in the onset and progression of Alzheimer’s disease can significantly reduce the global burden of this disease.     

Cortical basis of communication: Local computation,coordination, attention

Human communication emerges from cortical processing, known to be implemented on a regular repetitive neuronal substratum. The supposed genericity of cortical processing has elicited a series of modeling works in computational neuroscience that underline the information flows driven by the cortical circuitry. In the minimalist framework underlying the current theories for the embodiment of cognition, such a generic cortical processing is exploited for the coordination of poles of representation, as is reported in this paper for the case of visual attention. Interestingly, this case emphasizes how abstract internal referents are built to conform to memory requirements. This paper proposes that these referents are the basis for communication in humans, which is firstly a coordination and an attentional procedure with regard to their congeners.     

Fasudil mediates cell therapy of EAE by immunomodulating encephalomyelitic T cells and macrophages

Although Fasudil has shown therapeutic potential in EAE mice, the mechanism of action are still not fully understood. Here, we examined the immunomodulatory effect of Fasudil on encephalitogenic mononuclear cells (MNCs), and tested the therapeutic potential of Fasudil‐treated MNCs in active EAE. Fasudil inhibited expression of CCL20 on T cells and migration of T cells, decreased CD4⁺IFN‐γ⁺ and CD4⁺IL‐17⁺ T cells, but increased CD4⁺IL‐10⁺ and CD4⁺TGF‐β⁺ T cells. Fasudil reduced expression of CD16/32 and IL‐12, while elevating expression of CD206, CD23, and IL‐10. Fasudil also decreased levels of iNOS/NO, enhanced levels of Arg‐1, and inhibited the TLR‐4/NF‐κB signaling and TNF‐α, shifting M1 macrophage to M2 phenotype. These modulatory effects of Fasudil on T cells and macrophages were not altered by adding autoantigen MOG_35–55 to the culture, i.e., autoantigen‐independent. Further, we observed that, in vitro, Fasudil inhibited the capacity of encephalitogenic MNCs to adoptively transfer EAE and reduced TLR‐4/p‐NF‐κB/p65 and inflammatory cytokines in spinal cords. Importantly, Fasudil‐treated encephalitogenic MNCs exhibited therapeutic potential when injected into actively induced EAE mice. Together, our results not only provide evidence that Fasudil mediates the polarization of macrophages and the regulation of T cells, but also reveal a novel strategy for cell therapy in MS.