Glial Activation and Expression of the Serotonin Transporter in Chronic Fatigue Syndrome

Fatigue is commonly reported in a variety of illnesses and has major impact on quality of life. Chronic fatigue syndrome (CFS) is a debilitating syndrome of unknown etiology. The clinical symptoms include problems in neuroendocrine, autonomic, and immune systems. It is becoming clear that the brain is the central regulator of CFS. For example, neuroinflammation, especially induced by activation of microglia and astrocytes, may play a prominent role in the development of CFS, though little is known about molecular mechanisms. Many possible causes of CFS have been proposed. However, in this mini-review, we summarize evidence for a role for microglia and astrocytes in the onset and the maintenance of immunologically induced CFS. In a model using virus mimicking synthetic double-stranded RNA, infection causes sequential signaling such as increased blood brain barrier (BBB) permeability, microglia/macrophage activation through Toll-like receptor 3 (TLR3) signaling, secretion of IL-1β, upregulation of the serotonin transporter (5-HTT) in astrocytes, reducing extracellular serotonin (5-HT) levels and hence reduced activation of 5-HT1A receptor subtype. Hopefully, drug discovery targeting these pathways may be effective for CFS therapy

Bone cancer induces a unique central sensitization through synaptic changes in a wide area of the spinal cord

<p>Abstract</p> <p>Background</p> <p>Chronic bone cancer pain is thought to be partly due to central sensitization. Although murine models of bone cancer pain revealed significant neurochemical changes in the spinal cord, it is not known whether this produces functional alterations in spinal sensory synaptic transmission. In this study, we examined excitatory synaptic responses evoked in substantia gelatinosa (SG, lamina II) neurons in spinal cord slices of adult mice bearing bone cancer, using whole-cell voltage-clamp recording techniques.</p> <p>Results</p> <p>Mice at 14 to 21 days after sarcoma implantation into the femur exhibited hyperalgesia to mechanical stimuli applied to the skin of the ipsilateral hind paw, as well as showing spontaneous and movement evoked pain-related behaviors. SG neurons exhibited spontaneous excitatory postsynaptic currents (EPSCs). The amplitudes of spontaneous EPSCs were significantly larger in cancer-bearing than control mice without any changes in passive membrane properties of SG neurons. In the presence of TTX, the amplitude of miniature EPSCs in SG neurons was increased in cancer-bearing mice and this was observed for cells sampled across a wide range of lumbar segmental levels. Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor- and <it>N</it>-methyl-<it>D</it>-aspartate (NMDA) receptor-mediated EPSCs evoked by focal stimulation were also enhanced in cancer-bearing mice. Dorsal root stimulation elicited mono- and/or polysynaptic EPSCs that were caused by the activation of Aδ and/or C afferent fibers in SG neurons from both groups of animals. The number of cells receiving monosynaptic inputs from Aδ and C fibers was not different between the two groups. However, the amplitude of the monosynaptic C fiber-evoked EPSCs and the number of SG neurons receiving polysynaptic inputs from Aδ and C fibers were increased in cancer-bearing mice.</p> <p>Conclusions</p> <p>These results show that spinal synaptic transmission mediated through Aδ and C fibers is enhanced in the SG across a wide area of lumbar levels following sarcoma implantation in the femur. This widespread spinal sensitization may be one of the underlying mechanisms for the development of chronic bone cancer pain.</p

Selective activation of primary afferent fibers evaluated by sine-wave electrical stimulation

Transcutaneous sine-wave stimuli at frequencies of 2000, 250 and 5 Hz (Neurometer) are thought to selectively activate Aβ, Aδ and C afferent fibers, respectively. However, there are few reports to test the selectivity of these stimuli at the cellular level. In the present study, we analyzed action potentials (APs) generated by sine-wave stimuli applied to the dorsal root in acutely isolated rat dorsal root ganglion (DRG) preparations using intracellular recordings. We also measured excitatory synaptic responses evoked by transcutaneous stimuli in substantia gelatinosa (SG) neurons of the spinal dorsal horn, which receive inputs predominantly from C and Aδ fibers, using in vivo patch-clamp recordings. In behavioral studies, escape or vocalization behavior of rats was observed with both 250 and 5 Hz stimuli at intensity of ~0.8 mA (T5/ T250), whereas with 2000 Hz stimulation, much higher intensity (2.14 mA, T2000) was required. In DRG neurons, APs were generated at T5/T250 by 2000 Hz stimulation in Aβ, by 250 Hz stimulation both in Aβ and Aδ, and by 5 Hz stimulation in all three classes of DRG neurons. However, the AP frequencies elicited in Aβ and Aδ by 5 Hz stimulation were much less than those reported previously in physiological condition. With in vivo experiments large amplitude of EPSCs in SG neurons were elicited by 250 and 5 Hz stimuli at T5/ T250. These results suggest that 2000 Hz stimulation excites selectively Aβ fibers and 5 Hz stimulation activates noxious transmission mediated mainly through C fibers. Although 250 Hz stimulation activates both Aδ and Aβ fibers, tactile sensation would not be perceived when painful sensation is produced at the same time. Therefore, 250 Hz was effective stimulus frequency for activation of Aδ fibers initiating noxious sensation. Thus, the transcutaneous sine-wave stimulation can be applied to evaluate functional changes of sensory transmission by comparing thresholds with the three stimulus frequencies

Hydrogen in Drinking Water Reduces Dopaminergic Neuronal Loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Mouse Model of Parkinson's Disease

It has been shown that molecular hydrogen (H2) acts as a therapeutic antioxidant and suppresses brain injury by buffering the effects of oxidative stress. Chronic oxidative stress causes neurodegenerative diseases such as Parkinson's disease (PD). Here, we show that drinking H2-containing water significantly reduced the loss of dopaminergic neurons in PD model mice using both acute and chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The concentration-dependency of H2 showed that H2 as low as 0.08 ppm had almost the same effect as saturated H2 water (1.5 ppm). MPTP-induced accumulation of cellular 8-oxoguanine (8-oxoG), a marker of DNA damage, and 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation were significantly decreased in the nigro-striatal dopaminergic pathway in mice drinking H2-containing water, whereas production of superoxide (O2•−) detected by intravascular injection of dihydroethidium (DHE) was not reduced significantly. Our results indicated that low concentration of H2 in drinking water can reduce oxidative stress in the brain. Thus, drinking H2-containing water may be useful in daily life to prevent or minimize the risk of life style-related oxidative stress and neurodegeneration

Neuronal Orphan G-Protein Coupled Receptor Proteins Mediate Plasmalogens-Induced Activation of ERK and Akt Signaling.

The special glycerophospholipids plasmalogens (Pls) are enriched in the brain and reported to prevent neuronal cell death by enhancing phosphorylation of Akt and ERK signaling in neuronal cells. Though the activation of Akt and ERK was found to be necessary for the neuronal cells survival, it was not known how Pls enhanced cellular signaling. To answer this question, we searched for neuronal specific orphan GPCR (G-protein coupled receptor) proteins, since these proteins were believed to play a role in cellular signal transduction through the lipid rafts, where both Pls and some GPCRs were found to be enriched. In the present study, pan GPCR inhibitor significantly reduced Pls-induced ERK signaling in neuronal cells, suggesting that Pls could activate GPCRs to induce signaling. We then checked mRNA expression of 19 orphan GPCRs and 10 of them were found to be highly expressed in neuronal cells. The knockdown of these 10 neuronal specific GPCRs by short hairpin (sh)-RNA lentiviral particles revealed that the Pls-mediated phosphorylation of ERK was inhibited in GPR1, GPR19, GPR21, GPR27 and GPR61 knockdown cells. We further found that the overexpression of these GPCRs enhanced Pls-mediated phosphorylation of ERK and Akt in cells. Most interestingly, the GPCRs-mediated cellular signaling was reduced significantly when the endogenous Pls were reduced. Our cumulative data, for the first time, suggest a possible mechanism for Pls-induced cellular signaling in the nervous system