Találati lista | Tudóstér

001-es BibID:	BIBFORM107302
035-os BibID:	(scopus)85141712265 (wos)000882982200001
Első szerző:	Reddiar, Sanjeevini Babu
Cím:	A Biodistribution Study of the Radiolabeled Kv1.3-Blocking Peptide DOTA-HsTX1[R14A] Demonstrates Brain Uptake in a Mouse Model of Neuroinflammation / Reddiar Sanjeevini Babu, de Veer Michael, Paterson Brett M., Sepehrizadeh Tara, Wai Dorothy C. C., Csoti Agota, Panyi Gyorgy, Nicolazzo Joseph A., Norton Raymond S.
Dátum:	2023
ISSN:	1543-8384 1543-8392
Megjegyzések:	The voltage-gated potassium channel Kv1.3 regulates the pro-inflammatory function of microglia and is highly expressed in the post-mortem brains of individuals with Alzheimer's and Parkinson's diseases. HsTX1[R14A] is a selective and potent peptide inhibitor of the Kv1.3 channel (IC50 ? 45 pM) that has been shown to decrease cytokine levels in a lipopolysaccharide (LPS)-induced mouse model of inflammation. Central nervous system exposure to HsTX1[R14A] was previously detected in this mouse model using liquid chromatography with tandem mass spectrometry, but this technique does not report on the spatial distribution of the peptide in the different brain regions or peripheral organs. Herein, the in vivo distribution of a [64Cu]Cu-labeled DOTA conjugate of HsTX1[R14A] was observed for up to 48 h by positron emission tomography (PET) in mice. After subcutaneous administration to untreated C57BL/6J mice, considerable uptake of the radiolabeled peptide was observed in the kidney, but it was undetectable in the brain. Biodistribution of a [68Ga]Ga-DOTA conjugate of HsTX1[R14A] was then investigated in the LPS-induced mouse model of neuroinflammation to assess the effects of inflammation on uptake of the peptide in the brain. A control peptide with very weak Kv1.3 binding, [68Ga]Ga-DOTA-HsTX1[R14A,Y21A,K23A] (IC50 ? 6 ?M), was also tested. Significantly increased uptake of [68Ga]Ga-DOTA-HsTX1[R14A] was observed in the brains of LPS-treated mice compared to mice treated with control peptide, implying that the enhanced uptake was due to increased Kv1.3 expression rather than simply increased blood?brain barrier disruption. PET imaging also showed accumulation of [68Ga]Ga-DOTA-HsTX1[R14A] in inflamed joints and decreased clearance from the kidneys in LPS-treated mice. These biodistribution data highlight the potential of HsTX1[R14A] as a therapeutic for the treatment of neuroinflammatory diseases mediated by overexpression of Kv1.3.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk Biodistribution Central nervous system Inflammation Peptides and proteins Rodent models
Megjelenés:	Molecular Pharmaceutics. - 20 : 1 (2023), p. 255-266. -
További szerzők:	de Veer, Michael Paterson, Brett M. Sepehrizadeh, Tara Wai, Dorothy C. C. Csóti Ágota (1989-) (biológus) Panyi György (1966-) (biofizikus) Nicolazzo, Joseph A. Norton, Raymond S.
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
Borító:
Saját polcon:

001-es BibID:	BIBFORM100131
Első szerző:	Reddiar, Sanjeevini Babu
Cím:	Lipopolysaccharide influences the plasma and brain pharmacokinetics of subcutaneously-administered HsTX1[R14A], a KV1.3-blocking peptide / Reddiar Sanjeevini Babu, Jin Liang, Wai Dorothy C. C., Csoti Agota, Panyi Gyorgy, Norton Raymond S., Nicolazzo Joseph A.
Dátum:	2021
ISSN:	0041-0101
Megjegyzések:	KV1.3 is a voltage-gated potassium channel that is upregulated in neuroinflammatory conditions, such as Alzheimer's disease and Parkinson's disease. HsTX1[R14A] is a potent and selective peptide blocker of KV1.3 with the potential to block microglial KV1.3, but its brain uptake is expected to be limited owing to the restrictive nature of the blood-brain barrier. To assess its peripheral and brain exposure, a LC-MS/MS assay was developed to quantify HsTX1[R14A] concentrations in mouse plasma and brain homogenate that was reliable and reproducible in the range of 6.7?66.7 nM (r2 = 0.9765) and 15?150 pmol/g (r2 = 0.9984), respectively. To assess if neuroinflammation affected HsTX1[R14A] disposition, C57BL/6 mice were administered HsTX1[R14A] subcutaneously (2 mg/kg) 24 h after an intraperitoneal dose of Escherichia coli lipopolysaccharide (LPS), which is commonly used to induce neuroinflammation; brain and plasma concentrations of HsTX1[R14A] were then quantified over 120 min. LPS treatment significantly retarded the decline in HsTX1[R14A] plasma concentrations, presumably as a result of reducing renal clearance, and led to substantial brain uptake of HsTX1[R14A], presumably through disruption of brain inter-endothelial tight junctions. This study suggests that HsTX1[R14A] may reach microglia in sufficient concentrations to block KV1.3 in neuroinflammatory conditions, and therefore has the potential to reduce neurodegenerative diseases.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk
Megjelenés:	Toxicon. - 195 (2021), p. 29-36. -
További szerzők:	Jin, Liang Wai, Dorothy C. C. Csóti Ágota (1989-) (biológus) Panyi György (1966-) (biofizikus) Norton, Raymond S. Nicolazzo, Joseph A.
Pályázati támogatás:	K119417 OTKA EFOP-3.6.1-16-2016-00022 EFOP GINOP-2.3.2-15-2016-00015 GINOP
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
Borító:
Saját polcon: