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Effects of the KCNQ channel opener ezogabine on functional connectivity of the ventral striatum and clinical symptoms in patients with major depressive disorder.
Tan, A, Costi, S, Morris, LS, Van Dam, NT, Kautz, M, Whitton, AE, Friedman, AK, Collins, KA, Ahle, G, Chadha, N, et al
Molecular psychiatry. 2020;(6):1323-1333
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Abstract
Major depressive disorder (MDD) is a leading cause of disability worldwide, yet current treatment strategies remain limited in their mechanistic diversity. Recent evidence has highlighted a promising novel pharmaceutical target-the KCNQ-type potassium channel-for the treatment of depressive disorders, which may exert a therapeutic effect via functional changes within the brain reward system, including the ventral striatum. The current study assessed the effects of the KCNQ channel opener ezogabine (also known as retigabine) on reward circuitry and clinical symptoms in patients with MDD. Eighteen medication-free individuals with MDD currently in a major depressive episode were enrolled in an open-label study and received ezogabine up to 900 mg/day orally over the course of 10 weeks. Resting-state functional magnetic resonance imaging data were collected at baseline and posttreatment to examine brain reward circuitry. Reward learning was measured using a computerized probabilistic reward task. After treatment with ezogabine, subjects exhibited a significant reduction of depressive symptoms (Montgomery-Asberg Depression Rating Scale score change: -13.7 ± 9.7, p < 0.001, d = 2.08) and anhedonic symptoms (Snaith-Hamilton Pleasure Scale score change: -6.1 ± 5.3, p < 0.001, d = 1.00), which remained significant even after controlling for overall depression severity. Improvement in depression was associated with decreased functional connectivity between the ventral caudate and clusters within the mid-cingulate cortex and posterior cingulate cortex (n = 14, voxel-wise p < 0.005). In addition, a subgroup of patients tested with a probabilistic reward task (n = 9) showed increased reward learning following treatment. These findings highlight the KCNQ-type potassium channel as a promising target for future drug discovery efforts in mood disorders.
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Stretch-activated ion channel Piezo1 directs lineage choice in human neural stem cells.
Pathak, MM, Nourse, JL, Tran, T, Hwe, J, Arulmoli, J, Le, DT, Bernardis, E, Flanagan, LA, Tombola, F
Proceedings of the National Academy of Sciences of the United States of America. 2014;(45):16148-53
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Abstract
Neural stem cells are multipotent cells with the ability to differentiate into neurons, astrocytes, and oligodendrocytes. Lineage specification is strongly sensitive to the mechanical properties of the cellular environment. However, molecular pathways transducing matrix mechanical cues to intracellular signaling pathways linked to lineage specification remain unclear. We found that the mechanically gated ion channel Piezo1 is expressed by brain-derived human neural stem/progenitor cells and is responsible for a mechanically induced ionic current. Piezo1 activity triggered by traction forces elicited influx of Ca(2+), a known modulator of differentiation, in a substrate-stiffness-dependent manner. Inhibition of channel activity by the pharmacological inhibitor GsMTx-4 or by siRNA-mediated Piezo1 knockdown suppressed neurogenesis and enhanced astrogenesis. Piezo1 knockdown also reduced the nuclear localization of the mechanoreactive transcriptional coactivator Yes-associated protein. We propose that the mechanically gated ion channel Piezo1 is an important determinant of mechanosensitive lineage choice in neural stem cells and may play similar roles in other multipotent stem cells.
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Dose effects of oxaliplatin on persistent and transient Na+ conductances and the development of neurotoxicity.
Park, SB, Lin, CS, Krishnan, AV, Goldstein, D, Friedlander, ML, Kiernan, MC
PloS one. 2011;(4):e18469
Abstract
BACKGROUND Oxaliplatin, a platinum-based chemotherapy utilised in the treatment of colorectal cancer, produces two forms of neurotoxicity--acute sensorimotor neuropathic symptoms and a dose-limiting chronic sensory neuropathy. Given that a Na(+) channelopathy has been proposed as the mechanism underlying acute oxaliplatin-induced neuropathy, the present study aimed to determine specific mechanisms of Na(+) channel dysfunction. METHODOLOGY/PRINCIPAL FINDINGS Specifically the function of transient and persistent Na(+) currents were followed during treatment and were investigated in relation to oxaliplatin dose level. Eighteen patients were assessed before and after a single oxaliplatin infusion with motor and sensory axonal excitability studies performed on the median nerve at the wrist. While refractoriness (associated with Na(+) channel inactivation) was significantly altered post-oxaliplatin infusion in both motor (Pre: 31.7±6.4%; Post: 68.8±14.5%; P≤.001) and sensory axons (Pre: 31.4±5.4%; Post: 21.4±5.5%; P<.05), strength-duration time constant (marker of persistent Na(+) conductances) was not significantly altered post-infusion (Motor Pre: 0.395±0.01 ms; Post: 0.394±0.02 ms; NS; Sensory Pre:0.544±0.03 ms; Post: 0.535±0.05 ms; NS). However, changes in strength-duration time constant were significantly correlated with changes in refractoriness in motor and sensory axons (Motor correlation coefficient = -.65; P<.05; Sensory correlation coefficient = .67; P<.05). CONCLUSIONS/SIGNIFICANCE It is concluded that the predominant effect of acute oxaliplatin exposure in human motor and sensory axons is mediated through changes in transient rather than persistent Na(+) conductances. These findings are likely to have implications for the design and trial of neuroprotective strategies.
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Activation of the CFTR Cl- channel by trimethoxyflavone in vitro and in vivo.
Fischer, H, Illek, B
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 2008;(5-6):685-92
Abstract
The flavone apigenin has been previously selected as a potent pharmacological activator of the CFTR Cl(-) channel, however, its utility for the activation of CFTR in vivo is expected to be limited because flavonoids are readily metabolized. We therefore investigated the poorly metabolizable methylether of apigenin, 5,7,4'-trimethoxyflavone (TMF) as a CFTR activator using transepithelial short-circuit current measurements, whole cell and single cell patch clamp techniques, and nasal potential difference (PD) measurements. Transepithelial Cl(-) secretion by Calu-3 epithelia was stimulated by TMF with a halfmaximal concentration of 64+/-5 microM to 55+/-15% of maximal currents achieved by subsequent addition of cAMP agonist forskolin (10 microM). In forskolin-prestimulated tissues, TMF showed small effects and stimulated Cl(-) secretion by an additional 6%. Single channel and whole cell patch clamp techniques were used to verify these effects and identify CFTR as the target of TMF. TMF increased the open probability of silent CFTR (to 0.31+/-0.06) but showed small effects once CFTR had been prestimulated with forskolin. In nasal PD measurements in humans, perfusion of TMF onto the nasal mucosa activated nasal PD by -9.5+/-1.1 mV, which was 69% of the effect of TMF+isoproterenol (-13.8+/-3.9 mV). These data show that TMF is an activator of CFTR in both in vitro and in vivo assays that targets mainly the unstimulated CFTR.