Author: van den Akker, Focco ; Greenlee, William J ; Zhang, Rongli ; Anand, Puneet ; Hausladen, Alfred ; Rajavel, Malligarjunan ; Premont, Richard T ; Stomberski, Colin T ; Zhou, Hua-Lin ; Stamler, Jonathan S

Acute kidney injury (AKI) is associated with high morbidity and mortality, and no drugs are available clinically. Metabolic reprogramming resulting from the deletion of S-nitroso-coenzyme A reductase 2 (SCoR2; AKR1A1) protects mice against AKI, identifying SCoR2 as a potential drug target. Of the few known inhibitors of SCoR2, none are selective versus the related oxidoreductase AKR1B1, limiting therapeutic utility. To identify SCoR2 (AKR1A1) inhibitors with selectivity versus AKR1B1, analogs of the nonselective (dual 1A1/1B1) inhibitor imirestat were designed, synthesized, and evaluated. Among 57 compounds, JSD26 has 10-fold selectivity for SCoR2 versus AKR1B1 and inhibits SCoR2 potently through an uncompetitive mechanism. When dosed orally to mice, JSD26 inhibited SNO-CoA metabolic activity in multiple organs. Notably, intraperitoneal injection of JSD26 in mice protected against AKI through S-nitrosylation of pyruvate kinase M2 (PKM2), whereas imirestat was not protective. Thus, selective inhibition of SCoR2 has therapeutic potential to treat acute kidney injury.

01 Feb 2014·Journal of Ocular Pharmacology and TherapeuticsQ4 · MEDICINE

Polyol Effects on Growth Factors and MAPK Signaling in Rat Retinal Capillary Cells

Q4 · MEDICINE

Article

Author: Kador, Peter F. ; Zhang, Peng ; Zhang, Zifeng

PURPOSERecent studies report that growth factor and signaling changes in rat lenses do not directly result from the presence of diabetes or sorbitol/galactitol (polyol) formation/accumulation, but from secondary osmotic changes associated with the aldose reductase (AR) catalyzed polyol formation. AR is also present in rat retinal pericyte and endothelial cells; however, significant polyol formation only occurs in pericytes and this does not appear to be linked to osmotic changes. The purpose of this study was to determine whether polyol formation and AR activity are similarly linked to growth factor and signaling changes in the rat capillary cells despite the apparent absence of osmotic stress.METHODSConditionally immortalized rat retinal pericyte (TR-rPCT) and endothelial (TR-iBRB) cell lines were cultured on collagen type 1-coated dishes in the DMEM containing 5.5 mM glucose. After 24 h of initial culture, the medium was replaced with a serum-free medium containing 5.5, 25, or 50 mM glucose or galactose with/without the aldose reductase inhibitors (ARIs) AL1576 or tolrestat for periods of up to 48 h. Growth factors and transduction pathways were measured by Western blots using the antibodies against basic FGF, IGF-1, TGF-β, P-ERK1/2, P-SAPK/JNK, and P-Akt.RESULTSSorbitol accumulation was only observed in pericytes, while galactitol was present in both pericytes and endothelial cells. Pericytes cultured in high glucose showed increased expression of the growth factors basic FGF, IGF-1, TGF-β, and signaling in P-Akt, P-ERK1/2, and P-SAPK/JNK compared with those cultured in 5.5 mM glucose and these expressions were normalized by the presence of ARIs. Similar results were observed with galactose media. In contrast, endothelial cells cultured in high glucose media showed neither growth factor or signaling changes. In galactose media, endothelial cells showed increased expression of basic FGF, IGF-1, TGF-β, P-ERK1/2, and P-SAPK/JNK, which were only partially reduced by ARIs.CONCLUSIONGrowth factor and MAPK signaling expression in pericytes are linked to the presence of polyols. Pericytes, which readily accumulate sorbitol/galactitol that is inhibited by ARIs, show expression changes similar to those observed in rat lenses. In contrast, endothelial cells only show partial expression changes that are linked to galactitol accumulation.

01 Dec 2012·Journal of NeurochemistryQ2 · MEDICINE

Vesicular uptake blockade generates the toxic dopamine metabolite 3,4‐dihydroxyphenylacetaldehyde in PC12 cells: relevance to the pathogenesis of Parkinson's disease

Q2 · MEDICINE

Article

Author: Sullivan, Patti ; Goldstein, David S. ; Holmes, Courtney ; Cooney, Adele ; Gross, Daniel J. ; Kopin, Irwin J. ; Sullivan, Rachel ; Jinsmaa, Yunden ; Sharabi, Yehonatan

AbstractParkinson's disease entails profound loss of nigrostriatal dopaminergic terminals, decreased vesicular uptake of intraneuronal catecholamines, and relatively increased putamen tissue concentrations of the toxic dopamine metabolite, 3,4‐dihydroxyphenylacetaldehyde (DOPAL). The objective of this study was to test whether vesicular uptake blockade augments endogenous DOPAL production. We also examined whether intracellular DOPAL contributes to apoptosis and, as α‐synuclein oligomers may be pathogenetic in Parkinson's disease, oligomerizes α‐synuclein. Catechols were assayed in PC12 cells after reserpine to block vesicular uptake, with or without inhibition of enzymes metabolizing DOPAL—daidzein for aldehyde dehydrogenase and AL1576 for aldehyde reductase. Vesicular uptake was quantified by a method based on 6F‐ or 13C‐dopamine incubation; DOPAL toxicity by apoptosis responses to exogenous dopamine, with or without daidzein+AL1576; and DOPAL‐induced synuclein oligomerization by synuclein dimer production during DOPA incubation, with or without inhibition of L‐aromatic‐amino‐acid decarboxylase or monoamine oxidase. Reserpine inhibited vesicular uptake by 95–97% and rapidly increased cell DOPAL content (p = 0.0008). Daidzein+AL1576 augmented DOPAL responses to reserpine (p = 0.004). Intracellular DOPAL contributed to dopamine‐evoked apoptosis and DOPA‐evoked synuclein dimerization. The findings fit with the ‘catecholaldehyde hypothesis,’ according to which decreased vesicular sequestration of cytosolic catecholamines and impaired catecholaldehyde detoxification contribute to the catecholaminergic denervation that characterizes Parkinson's disease.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Complications	Phase 3	US	Alcon AG	-
Diabetes Mellitus	Phase 3	-	Alcon AG	-

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