Neuroscience
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Theiler's murine encephalomyelitis virus (TMEV) induces demyelination in susceptible strains of mice through a CD4(+) Th1 T cell-mediated immunopathological process. TMEV infection produces a syndrome in mice that resembles multiple sclerosis. In this work, we focused on the increased expression of the genes encoding voltage-gated Ca(2+) channel subunits in SJL/J mouse astrocytes infected in culture with a BeAn strain of TMEV. ⋯ TMEV infection in mouse astrocytes induced a Ca(2+) current with a density proportional to the amount of viral particles used for infection. The use of Ca(2+) channel blockers, nimodipine and ω-conotoxin-GVIA, showed that both functional L- and N-type Ca(2+) channels were upregulated in infected astrocytes. The upregulation of Ca(2+) channels in astrocytes after TMEV infection provides insight into the molecular processes and potential role of astrocyte Ca(2+) dysregulation in the pathophysiology of encephalomyelitis and is important for the development of novel therapeutic strategies leading to prevention of neurodegeneration.
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Adult neurogenesis occurs throughout life; however the majority of new neurons do not survive. Enhancing the survival of these new neurons will increase the likelihood that these neurons could return function following injury. Inhibition of Rho kinase is known to increase neurite outgrowth and regeneration. ⋯ These mice also demonstrated enhanced spatial memory as tested by the Y maze with no significant changes in anxiety or novel object recognition. Rho kinase inhibition enhanced the survival of new born neurons in the dentate gyrus with a specific dosage effect. These results suggest that inhibition of Rho kinase following injury could be beneficial for increasing the survival of new neurons that may aid recovery.
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Increasing evidence has linked membrane cholesterol to amyloid precursor protein (APP) processing. β-Sitosterol (BS) is one of the most common forms of plant sterols, with the structure very similar to that of cholesterol. Using HT22 mouse hippocampal cells, this study investigated whether the substitution of membrane cholesterol with BS influences APP metabolism. ⋯ Additional experiments suggest that the effect of membrane BS on APP metabolism is associated with the migration of APP from lipid rafts toward non-raft regions. Given that dietary BS can enter the brain and accumulates in the plasma membrane of brain cells, these results suggest a potential use of BS in the prevention of Alzheimer's disease.
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Pain from cancer can be severe, difficult to treat, and greatly diminishes patients' quality of life. It is therefore important to gain new information on the mechanisms of cancer pain and develop new treatment strategies. We have used a murine model of bone cancer pain to investigate underlying peripheral neural mechanisms and novel treatment approaches. ⋯ These effects were inhibited by prior intraplantar administration of selective CB1 (AM281) or CB2 (AM630) receptor antagonists but not by vehicle. These results indicate that activation of either CB1 or CB2 receptors reduced the spontaneous activity of C-fiber nociceptors associated with tumor growth as well as their evoked responses. Our results provide further evidence that activation of peripheral cannabinoid receptors may be a useful target for the treatment of cancer pain.
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Central neuropathic pain (CNP) in the spinal cord, such as chronic pain after spinal cord injury (SCI), is an incurable ailment. However, little is known about the spinal cord mechanisms underlying CNP. Recently, reactive oxygen species (ROS) have been recognized to play an important role in CNP of the spinal cord. ⋯ Furthermore, in the presence of a transient receptor potential ankyrin 1 (TRPA1) channel antagonist (HC-030031) or a transient receptor potential vanilloid 1 (TRPV1) channel antagonist (capsazepine or AMG9810), the t-BOOH-induced increase in the frequency of sEPSCs was inhibited. These results indicate that ROS enhance the spontaneous release of glutamate from presynaptic terminals onto SG neurons through TRPA1 and TRPV1 channel activation. Excessive activation of these ion channels by ROS may induce central sensitization in the spinal cord and result in chronic pain such as that following SCI.