Neuroscience
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Repeated mild traumatic brain injury (r-mTBI) can potentially manifest into chronic traumatic encephalopathy (CTE). The apolipoprotein E (APOE4) genotype, a well-recognized potent genetic risk factor in age-related neurodegenerative diseases such as Alzheimer's disease, has been linked to worse outcome after TBI in individuals who carry this allele. The underlying molecular modifications triggered by APOE genotype following r-mTBI remain elusive. ⋯ APOE4 mice showed significant increases in the tau conformational marker MC1, neurofilament H, brain phospholipids, and endothelial specific oxidized low density lipoprotein receptor in cortical homogenates obtained from injured mice compared to sham counterparts. This pilot work suggests APOE3 and APOE4 specific effects following injury in a mouse model of r-mTBI. These changes may underlie the molecular changes that trigger the vulnerability and increased risk of developing neurodegenerative diseases in aged individuals exposed to repetitive mTBI.
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Recent studies on the impact of Parkinson's disease (PD) on the thalamostriatal pathway have mainly focused on the structural and functional changes in the thalamus projection to the striatum. Alterations in the electrophysiological activity of the thalamostriatal circuit in PD have not been intensively studied. To further investigate this circuit, parafascicular nucleus (PF) single-unit spikes and dorsal striatum local field potential (LFP) activities were simultaneously recorded in control and 6-hydroxydopamine (6-OHDA)-lesioned rats during inattentive rest or treadmill walking states. ⋯ During rest state, after dopamine loss, increased PF I spike and striatal LFP coherence was observed in the beta-frequency (12-35 Hz), with changed PF I neuronal firing pattern and unchanged firing rates of the two neuron subtypes. However, in a treadmill walking state, PF II neurons displayed markedly increased coherence to striatal beta oscillations in the dopamine-depleted rats, as well as an altered PF II neuronal firing pattern and significantly decreased firing rates of the two neuron subtypes. The results indicate that in PD animals, state transition from rest to moving, such as treadmill walking, is associated with different PF neuron types and increased spike-LFP synchronization, which may provide new paradigms for understanding and treating PD.
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Cerebral edema in ischemic stroke can lead to increased intracranial pressure, reduced cerebral blood flow and neuronal death. Unfortunately, current therapies for cerebral edema are either ineffective or highly invasive. During the development of cytotoxic and subsequent ionic cerebral edema water enters the brain by moving across an intact blood brain barrier and through aquaporin-4 (AQP4) at astrocyte endfeet. ⋯ Additional functional assays were used to validate AQP4 inhibition and identified a promising structural series for medicinal chemistry. These efforts improved potency and revealed a compound we designated AER-270, N-[3,5-bis (trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide. AER-270 and a prodrug with enhanced solubility, AER-271 2-{[3,5-Bis(trifluoromethyl) phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, improved neurological outcome and reduced swelling in two models of CNS injury complicated by cerebral edema: water intoxication and ischemic stroke modeled by middle cerebral artery occlusion.