Neuroscience
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MiR-7-1 potentiated estrogen receptor agonists for functional neuroprotection in VSC4.1 motoneurons.
Protection of motoneurons is an important goal in the treatment of spinal cord injury (SCI). We tested whether neuroprotective microRNAs (miRs) like miR-206, miR-17, miR-21, miR-7-1, and miR-106a could enhance efficacy of estrogen receptor (ER) agonists such as 1,3,5-tris (4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT, ERα agonist), Way200070 (WAY, ERβ agonist), and estrogen (EST, ERα and ERβ agonist) in preventing apoptosis in the calcium ionophore (CI)-insulted ventral spinal cord 4.1 (VSC4.1) motoneurons. We determined that 200 nM CI induced 70% cell death. ⋯ The same therapeutic strategy increased expression of the Ca(2+)/calmodulin-dependent protein kinase II beta (CaMKIIβ) and the phosphorylated cAMP response element binding protein (p-CREB) so as to promote Bcl-2 transcription. Whole cell membrane potential and mitochondrial membrane potential studies indicated that miR-7-1 highly potentiated EST to preserve functionality in the CI-insulted VSC4.1 motoneurons. In conclusion, our data indicated that miR-7-1 most significantly potentiated efficacy of EST for functional neuroprotection and this therapeutic strategy could be used in the future to attenuate apoptosis of motoneurons in SCI.
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α-Synuclein is the major component of Lewy bodies. α-Synuclein phosphorylated at Ser 129 (Phospho-α-Syn) is the most common synuclein modification observed in Parkinson's disease pathology and transgenic animal models. Polo-like kinase 2 (PLK2) was previously proposed as an important kinase in α-synuclein phosphorylation at Ser129. To better understand the role of PLK2 in α-synuclein phosphorylation in vivo, we further evaluated the effect of PLK2 genetic knockdown and pharmacological inhibition on Phospho-α-Syn levels in different brain regions of PLK2 knockout (KO), heterozygous (Het) and wild-type (WT) mice. ⋯ Whereas BI 2536 reduced Phospho-α-Syn levels in WT mice, it did not further reduce the residual endogenous Phospho-α-Syn levels in PLK2 KO and Het mice, suggesting that a kinase other than PLK1-3 accounts for the remaining PLK inhibitor-resistant pool in the mouse brain. Moreover, PLK3 KO in mice had no effect on both Total- and Phospho-α-Syn brain levels. These results support a significant role for a PLK kinase in phosphorylating α-synuclein at Ser129 in the brain, and suggest that PLK2 is responsible for this activity under physiological conditions.
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Tinnitus is a bothersome phantom sound percept and its neural correlates are not yet disentangled. Previously published papers, using [(18)F]-fluoro-deoxyglucose positron emission tomography (FDG-PET), have suggested an increased metabolism in the left primary auditory cortex in tinnitus patients. This unilateral hyperactivity has been used as a target in localized treatments such as transcranial magnetic stimulation. ⋯ Nevertheless, the activity in the left primary auditory cortex was higher than in the right primary auditory cortex, but this asymmetry was present in both tinnitus patients and control subjects. In contrast, the lateralization in secondary auditory cortex was opposite, with higher activation in the right hemisphere. These data show that hemisphere asymmetries in the metabolic resting activity of the auditory cortex are present, but these are not associated with tinnitus and are a normal characteristic of the normal brain.
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Kainic acid (KA) administration is known to cause seizures and neuronal death in the hippocampus. High-frequency stimulation (HFS) of the hippocampus can be a promising method in the treatment of epilepsy while the mechanism of action is unknown yet. It remains unknown whether HFS is neuroprotective for hippocampal neurons following KA-induced seizures in macaques, although HFS has neuroprotective effects in animal models of Parkinson's disease. ⋯ In addition, administration of KA led to marked neuronal apoptosis in the hippocampus, accompanied by increased levels of Bax, activated caspase-3 and decreased levels of Bcl-2. HFS was found to attenuate changes in apoptosis-related proteins and robustly decreased neuronal loss following KA administration. These data indicate that hippocampal HFS can protect hippocampal neurons against KA neurotoxicity, and that HFS neuroprotection is likely to operate with inhibition of apoptosis.
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During a study of spinal cord injury (SCI), mice in our colony were treated with the anthelmintic fenbendazole to treat pinworms detected in other mice not involved in the study. As this was not part of the original experimental design, we subsequently compared pathological and functional outcomes of SCI in female C57BL/6 mice who received fenbendazole (150 ppm, 8 mg/kg body weight/day) for 4 weeks prior to moderate contusive SCI (50 kdyn force) as compared to mice on the same diet without added fenbendazole. The fenbendazole-treated mice exhibited improved locomotor function, determined using the Basso mouse scale, as well as improved tissue sparing following contusive SCI. ⋯ Autoantibodies produced following SCI contribute to the axon damage and locomotor deficits. Fenbendazole pretreatment reduced the injury-induced CD45R-positive B cell signal intensity and IgG immunoreactivity at the lesion epicenter 6 weeks after contusive SCI in mice, consistent with a possible effect on the immune response to the injury. Fenbendazole and related benzimadole antihelmintics are FDA approved, exhibit minimal toxicity, and represent a novel group of potential therapeutics targeting secondary mechanisms following SCI.