Journal of molecular neuroscience : MN
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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive neuronal loss, caused by misfolding and accumulation of tau and Amyloid β-42. Cellular mechanisms involving phosphatases, chaperones, ubiquitin proteasome system (UPS) and aggresomes solubilize or remove these toxic aggregates. Chaperones such as Hsp70 and Hsp90 functions in folding tau to its native form or in the downstream degrade and eliminated tau from the cell. ⋯ In this scenario, inhibiting the chaperone activity would aid in overcoming AD. Small molecules inhibitors against chaperone activity are known to be effective in the clearance of aberrant tau from cell. In this review, the aspects of inhibition and prevention of tau aggregates formation are discussed in terms of chaperone activity and their small molecule modulators.
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Ferroptosis is a recently defined form of cell death with the involvement of iron and reactive oxygen species (ROS), which is distinct from apoptosis, autophagy and other forms of cell death. Emerging evidence suggested that iron accumulation and lipid peroxidation can be discovered in various neurological diseases, accompanied with reduction of glutathione (GSH) and glutathione peroxidase 4 (GPX4). ⋯ This review summarizes the mechanisms underlying ferroptosis and reviews the contributions of ferroptosis in neurodegenerative diseases (i.e. Alzheimer's disease and Parkinson's disease), traumatic brain injury, as well as hemorrhagic and ischemic stroke, to provide the current understanding of this novel form of cell death in neurological disorders.
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Acid-sensing ion channel 3 (ASIC3) is abundant in the trigeminal nervous system and is most sensitive to a slight pH decrease. Recent studies have indicated that ASIC3 in the peripheral trigeminal ganglia is likely involved in the pathogenesis of migraine pain. However, it is unclear whether this receptor plays a role in recurrent migraine, namely, migraine chronicity. ⋯ ASIC3 was primarily expressed in neurons but not in astrocytes of the TNC. Moreover, APETx2 attenuated tactile allodynia and significantly decreased the expression of c-Fos, CGRP and RAMP1, while GMQ aggravated these effects compared to those observed in the IS + vehicle group. These findings indicate a critical role of ASIC3 channels in the pathophysiology of RM, and ASIC3 might represent a potential therapeutic target to prevent the progression of migraine.
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Opioid receptor like 1 (ORL1) receptor activation displayed an anti-nociceptive effect at spinal level for acute and neuropathic pain. SCH221510, an orally active non-peptide ORL1 agonist, was reported to be effective in treating neuropathic pain. The present study used ORL1 antagonist and siRNA to investigate that ORL1 activation mediates intrathecal SCH221510 analgesia in neuropathic pain induced by chronic constrictive injury (CCI) to rat sciatic nerve. ⋯ Intrathecal siRNA blocked SCH221510 analgesia in neuropathic pain at spinal level. Conclusively, ORL1 activation mediates SCH221510 analgesia in neuropathic pain at spinal level. The results warrant a potential clinically applicable drug in treating neuropathic pain.
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Postoperative cognitive dysfunction in elderly patients has been related to neurodegenerative disorders and mortality. Sevoflurane anesthesia has been implicated in both postoperative cognitive dysfunction and neurotoxicity. Given the advantages of using inhaled anesthetics like sevoflurane, it is important to understand how their usage results in neurotoxicity and subsequently devise ways to circumvent or attenuate the anesthetic-mediated induction in neurotoxicity. ⋯ Sevoflurane inhalation resulted in significant inhibition of brain-derived neurotrophic factor (BDNF) and cognitive impairment. Treatment with a combination of siRNAs targeting HOTAIR rescued BDNF expression and improved cognitive responses. Taken together, our results suggest that sevoflurane-mediated brain function impairment is at least in part mediated by the HOTAIR lncRNA.