TPT-260 (Dihydrochloride)

TPT-260 Dihydrochloride (NSC55712), a thiophene thiourea derivative, is a retromer complex stabilizer against thermal denaturation (K_d = ~5 µM). TPT-260 Dihydrochloride increases the levels of retromer proteins, shifts amyloid-precursor protein (APP) away from the endosome, and decreases the pathogenic processing of APP. TPT-260 Dihydrochloride inhibits TLR4 upregulation, IKKβ phosphorylation, NF-κB p65 nuclear translocation, and NLRP3 inflammasome formation. TPT-260 Dihydrochloride improves retromer-mediated cargo trafficking, reduces brain infarct area, and decreases amyloid plaque deposition. TPT-260 Dihydrochloride exhibits minimal cytotoxicity to primary microglia at tested concentrations. TPT-260 Dihydrochloride can be used for the research of inflammatory bowel disease, ischemic stroke and Alzheimer's disease^[1][2][3][4]. In Vitro:TPT-260 (10 μM) Dihydrochloride improves Occludin recycling and epithelial barrier function in Caco-2 cells but has no effect on VMP1-knockdown Caco-2 cells, indicating VMP1 is required for the Target Reagent's activity^[1].
TPT-260 (5-20 μM) Dihydrochloride has no cytotoxic effect on primary mouse microglia, as measured by cell viability and LDH release assays^[2].
TPT-260 (5-20 μM) Dihydrochloride protects primary mouse microglia from LPS (HY-D1056)/Nigericin (HY-127019)-induced cytotoxicity, as shown by restored cell viability and reduced LDH release^[2].
TPT-260 (5-20 μM) Dihydrochloride inhibits LPS/Nigericin-induced inflammasome formation in primary mouse microglia, as measured by reduced ASC speck formation^[2].
TPT-260 (5-20 μM) Dihydrochloride inhibits LPS/Nigericin-induced nuclear translocation of NF-κB p65 in primary mouse microglia, as measured by reduced nuclear p65 fluorescence intensity^[2].
TPT-260 (5-20 μM) Dihydrochloride inhibits LPS (HY-D1056)/Nigericin (HY-127019)-induced upregulation of pro-inflammatory gene expression (Nlrp3, Tnfa, Il1b) in primary mouse microglia^[2].
TPT-260 (5-20 μM) Dihydrochloride attenuates LPS/Nigericin-induced activation of the TLR4-IKKβ-NF-κB pathway in primary mouse microglia, as shown by reduced levels of pathway-related proteins and pro-inflammatory IL-1β^[2].
TPT-260 (5 μM; 48 h) Dihydrochloride increases plasma membrane expression of NHE3 in Caco-2/bbe cells, raising surface NHE3 to 142.4% of control^[3].
TPT-260 (5 μM; 48 h) Dihydrochloride increases levels of core retromer proteins VPS35 and VPS26 in Caco-2/bbe cells, and prevents the Cholera toxin (CT)-induced reduction in these retromer proteins when given either concurrently with CT or prior to CT exposure^[3].
TPT-260 (5 μM; 48 h) Dihydrochloride increases plasma membrane expression of NHE3 in polarized Caco-2/bbe-HA-NHE3 cells, and reverses the CT-induced reduction in NHE3 surface expression when given either concurrently with CT or prior to CT exposure^[3].
TPT-260 (5 μM; 48 h) Dihydrochloride partially reduces forskolin-induced fluid secretion in 3D human duodenal enteroids by stimulating NHE3-mediated fluid absorption^[3].
TPT-260 Dihydrochloride (R55) binds to retromer complex with a K_d of ~5 μM^[4].
TPT-260 Dihydrochloride (48 h) increases Vps35 levels with an EC₅₀ of ~3.3 μM in primary hippocampal neurons^[4].
TPT-260 Dihydrochloride (48 h) significantly reduces the levels of both endogenous Aβ40 and Aβ42 in hippocampal neurons^[4].
TPT-260 Dihydrochloride inhibits Aβ levels with an IC₅₀ of ~12 μM in hippocampal neurons^[4].
TPT-260 Dihydrochloride significantly reduces the levels of both endogenous β-CTF and sAPPβ, and increases sAPPα levels in hippocampal neurons^[4]. In Vivo:TPT-260 (5 mg/kg; i.p.; single dose 24 hours prior to MCAO surgery) Dihydrochloride significantly reduces brain infarct volume, lowers neuroinflammatory marker levels, and improves neurological function in ischemic stroke model mice by inhibiting NF-κB signaling and M1 microglial activation^[2].