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REG3A inhibits KCNA3. 44 / 46
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"A potentially better option is the small molecule PAP-1, which inhibits Kv1.3 with high specificity, crosses the blood–brain barrier, and has demonstrated preclinical efficacy for treating neuroinflammation in neurodegenerative disease."
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"We speculate that Kv1.3KO (or chronic Kv1.3 inhibition), but not acute inhibition of Kv1.3 by PAP-1, may cause a long-lasting change of synaptic release mechanism, which endows the Schaffer collateral-CA1 synapses with resistance to LPS-mediated acute effect on the STP."
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"Furthermore, pharmacological inhibition of Kv1.3 by PAP-1 attenuated renal inflammation and fibrosis with decreased infiltration of macrophage infiltration and M2 polarization by employing the unilateral ureteral obstruction (UUO) renal fibrosis model."
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"PAP-1 also blocked Kv1.3 currents (37) (Fig. 3I and Supplemental Fig. S2A) confirming the identity of the overexpressed Kv1.3 channels in BV-2 cells."
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"The selective Kv1.3 blocker PAP-1 reduces airway hyperresponsiveness, inflammatory cell counts in bronchoalveolar lavage fluid and serum, and alleviates airway inflammation (reducing IL-4 and IL-17 levels) by inhibiting the ERK-NF-κB signaling pathway (Zhou et al., 2018)."
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"To determine whether Kv1.3 regulates activation of the NLRP3 inflammasome, the selective Kv1.3 blocker PAP-1 was used [19]."
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"A more recent study showed that PAP-1 inhibition of Kv1.3 channels in AD model APP/PS1 transgenic mice from 9 to 14 months of age resulted in decreased neuroinflammation and cerebral amyloid load, increased hippocampal neuronal plasticity, and improved behavioral deficits of treatment group mice with respect to the control group ( xref )."
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"All of the compounds were compared to the known Kv1.3 blocker PAP-1."
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"Although acting at different regions of the channel than Bax and MgTx (Cahalan & Chandy, xref ), PAP-1, Psora-4 and clofazimine also inhibit Kv1.3 and induce cytochrome c release and mitochondrial membrane depolarization."
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"These data suggest that the PAP-1 derivatives efficiently block the Kv1.3 channel in intact cells even without MDRi.The IC 50 of PAPTP for the Kv1.3 current measured in Jurkat T lymphocytes by patch-c[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"KV1.3 blocker PAP-1 impaired intracellular Ca2+ signaling of neutrophils and their recruitment during inflammation (Immler et al., 2022)."
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"Since Kv1.3 blockade reduces the cytokine secretion by these cells [14, 33, 35], in this work, we used the selective Kv1.3 blocker PAP1 as immunomodulator."
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"Additionally, we also combined BG with PAP-1 to treat MCAO mice, and the results showed that the combination further alleviated post-stroke brain injury and improved neurobehavioral function, which wa[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"For example, voltage dependence was observed for a highly potent immunosuppressant, 5-(4-phenoxybutoxy) psoralen (PAP-1), which blocks Kv1.3 channels in lymphocytes [27] ."
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"Taken together, the Kv1.3 blocker PAP-1 dramatically ameliorated KA-induced hippocampal neuronal damage and epileptic seizures."
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"To investigate a possible role of Kv1.3 channels on motor sign progression and survival in hSOD1G93A mice, animals were treated with the brain penetrant Kv1.3 antagonist PAP-1 (40mg/kg, i.p."
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"The flow cytometry results showed that both BmKK2 and PAP-1 significantly suppressed the increase of F4/80 + Kv1.3 + positive cells in the peripheral blood of LPS-treated mice ( Fig. 5 D and E)."
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"The most potent is PAP-1, which inhibits Kv1.3 with an EC50 of 2 nM and displays excellent selectivity over other potassium channels [18]."
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"PAP-1 inhibits Kv1.3 with an IC 50 of 2 nM ( xref ), has a half-life of 3 hours in rodents, is orally available, brain penetrant and does not exhibit any long-term toxicity in rodents or primates ( xref ; xref ; xref )."
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"For example, the inhibition of Kv1.3 by PAP-1 in multiple animal models of Parkinson’s disease leads to the decreased degeneration of dopaminergic neurons and improved behavioral outcomes [19]."
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"Especially, selective Kv1.3 blockers PAP-1 and ShK-186 showed significant protective effect on OVA induced airway hyperresponsiveness and inflammation (Koshy et al., 2014; Lin et al., 2015; Ohya and Kito, 2018; Zhou et al., 2018)."
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"A highly potent Kv1.3 blocker PAP-1 is an example of such a candidate that would probably be filtered out unless a ternary complex model was taken into consideration.Another important problem is drug [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"The small molecule with the best properties to date is PAP-1, which blocks Kv1.3 with an IC 50 = 2 nM, and is at least 23-fold selective over other channels [43] ."
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"Arterial rings were incubated with 20 % FBS alone or with the Kv1.3 blocker PAP-1 (100 nmol/L)."
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"After we found that Kv1.3 blockade attenuated KA-induced epilepsy in mice, we explored how Kv1.3 blocker PAP-1 mitigated seizures and alleviated neuronal damage."
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"Some experimental groups were treated with the Kv1.3 blocker PAP-1 (5-(4-phenoxybutoxy) psoralen) or the mTOR blocker everolimus (EVL).2.3 Morphometric studies."
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"Given the indispensable role of microglia in epilepsy, we examined the proliferation and inflammatory activation of microglia and related proinflammatory cytokine production with the treatment of Kv1.3 blocker PAP-1 in KA-induced epileptic mice.We first quantitate microgliosis with marker Iba-1."
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"These data indicated that Kv1.3 selective blockers such as margatoxin (MgTx) or PAP-1 (5-(4-phenoxybutoxy)psoralen) [12] could be used for the treatment of vascular diseases associated with PM of VSMC[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Variations of the PAP-1 structure have already been shown to reduce Kv1.3 blocking potency ( Bodendiek et al., 2009 )."
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"These coatings represent a good strategy for the development of a next generation of DES, and in fact drug loaded ELRs have been used as advanced delivery systems with promising results in diseases su[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Experimental conditions include the presence of the Kv1.3 blocker PAP-1 in the 20%FBS medium or in the different ELR formats (grids or beads) as indicated."
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"Using young male mice and rats we previously demonstrated that the Kv1.3 blocker PAP-1 when started 12 h after reperfusion dose-dependently reduces infarction and improves neurological deficit on day 8. However, these proof-of-concept findings are of limited translational value because the majority of strokes occur in patients over 65 and, when considering overall lifetime risk, in females."
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"This could be a result of a concentration-dependent effect of HsTX1[R14A], similar to that reported in another study where the expression of IL-1β was reduced only with a relatively higher concentrati[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"After we found that blockade of Kv1.3 could suppress proinflammatory microglia in vivo and in vitro, we then investigated the underlying molecular mechanism of the anti-inflammatory effect of Kv1.3 blocker PAP-1 in epilepsy."
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"Therefore, blockade of Kv1.3 on these cells may promote neurogenesis, thereby providing benefit to brain health [19], in addition to the benefits of blockade of microglial Kv1.3.Given the non-selective nature of Kv1.3 blockers such as PAP-1, development of Kv1.3 blockers with higher selectivity is essential for realising the therapeutic potential of Kv1.3 blockade in AD."
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"Treatment with the Kv1.3 blocker PAP-1 as a cytoprotectant started 12 h after reperfusion benefits both young and old female mice."
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"First, we explored the effect of T2DM in the remodeling of human vessels using organ culture of hMA samples, to determine that these vessels exhibited larger IH lesions, increased Kv1.3 mRNA expression, and elevated sensitivity to the Kv1.3 blocker PAP-1, compared to non-T2DM vessels."
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"For example, the inhibition of Kv1.3 by PAP-1 in multiple animal models of Parkinson’s disease leads to the decreased degeneration of dopaminergic neurons and improved behavioral outcomes [ xref ]."
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"In this study, the specific Kv1.3 blocker PAP-1 showed great potential in the inhibition of the expressions of Kv1.3, NLRP3, ASC, Caspases-1p20, pro-IL-1 β and IL-1 β in colon with colitis, suggesting[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Another Kv1.3 blocker PAP-1 also protects animals against DSS-induced colitis possibly through inhibition of NLRP3 inflammasome pathway downstream of Kv1.3 signaling (Mei et al., 2019)."
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"This has been confirmed for Kv1.3 channel blockers such as PAP-1 in different preparations including human vessels ([8,11]."
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"A Kv1.3 blocker PAP-1 (IC  = 2 nM) [13] reduced microglia-mediated neuroinflammation in 5 × FAD and APP/PS1 mice (another model of familial AD), and inhibited microglia-mediated neurotoxicity in 5 × FAD mice [7, 14, 15] and in APP/PS1 mice [12]."
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"Interestingly, in a study using the middle cerebral artery occlusion model, a model of ischemic stroke that involves the formation of occlusive platelet thrombi in response to combined thrombotic and inflammatory stimuli[71], the selective Kv1.3 blocker Pap-1 dose-dependently reduced the infarct area in rodents, reducing microglial activation and improving neuronal survival[72]."
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"Overall, Kv1.3 blocker PAP-1 inhibited microglial activation and reduced proinflammatory cytokine production via the Ca /NF-κB signaling pathway."
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