Cell-Permeable Calpain Inhibitor SJA6017 Provides Functional Protection to Spinal Motoneurons Exposed to MPP.

Extra-nigral central nervous system sites have been found to be affected in Parkinson's disease (PD). In addition to substantia nigra, degeneration of spinal cord motor neurons may play a role in the motor symptoms of PD. To this end, hybrid rodent VSC 4.

Functional role of PPARδ in corneal epithelial wound healing.

The peroxisome proliferator-activated receptor (PPAR) δ is involved in tissue repair. In this study, we investigated the functional role of PPARδ in corneal epithelial wound healing. In an in vivo corneal wound-healing model, the changes of PPARδ expression in corneal epithelia were examined by immunofluorescence microscopy, and the effect of topical administrations of a PPARδ agonist on corneal wound healing was also evaluated.

Contribution of calpains to photoreceptor cell death in N-methyl-N-nitrosourea-treated rats.

The purpose of the present study was to determine if proteolysis by the calcium-dependent enzyme calpains (EC 3.4.22.

Amelioration of retinal degeneration and proteolysis in acute ocular hypertensive rats by calpain inhibitor ((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester.

Background: Our recent study suggested involvement of calpain-induced proteolysis in retinal degeneration and dysfunction in acute ocular hypertensive rats. The purpose of the present study was to determine if an orally available form of calpain inhibitor, ((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester (SNJ-1945), ameliorated retinal degeneration induced by acute hypertension in rats. To help extrapolate the effect of SNJ-1945 from the rat model to the human glaucomatous patient, in vitro inhibition of calpain-induced proteolysis by SNJ-1945 in monkey and human retinal proteins was compared with proteolysis in rat proteins.

Presence of calpain-induced proteolysis in retinal degeneration and dysfunction in a rat model of acute ocular hypertension.

The purpose of this study was to determine if calpain-induced proteolysis was associated with retinal degeneration or dysfunction in the rat acute ocular hypertensive model. Acute glaucoma was produced by elevation of IOP to 120 mm Hg for 1 hr. Retinal degeneration was evaluated by H&E staining and apoptosis was determined by TUNEL staining in histologic sections of retina.

Structure-activity relationship study and drug profile of N-(4-fluorophenylsulfonyl)-L-valyl-L-leucinal (SJA6017) as a potent calpain inhibitor.

Novel N-arylsulfonyldipeptidyl aldehyde derivatives were prepared by DMSO oxidation from the corresponding dipeptide alcohol, and their potencies as calpain inhibitors were evaluated in vitro. Among them, N-(4-fluorophenylsulfonyl)-l-valyl-l-leucinal (8, SJA6017) potently inhibited calpains. 8 also inhibited cathepsin B and L but did not inhibit other cysteine proteases (interleukin 1beta-converting enzyme), serine proteases (trypsin, chymotrypsin, thrombin, factor VIIa, factor Xa), or proteasome.

Drug delivery to the eye with a transdermal therapeutic system.

A matrix-type transdermal therapeutic system was developed for treating diseases of the eye where it is difficult for drug molecules to reach with conventional topical instillation. Prednisolone was employed as a model drug. An in vivo study using rats showed that the daily application of the patch maintained a constant plasma concentration of the drug, which was equivalent the therapeutic plasma level following three times daily oral administration (30 mg), for approximately 24 h.

A two-step, one-pot synthesis of diverse N-pyruvoyl amino acid derivatives using the Ugi reaction.

A 100-member combinatorial library of alpha-ketoamides, which was designed to search potent cysteine protease inhibitors, was generated by a parallel solution-phase synthesis. A two-step one-pot synthesis, in which the Ugi reaction followed by pyridinium dichromate (PDC) oxidation was employed in the same reaction vessel, easily afforded the alpha-ketoamides in a short time.

Synthesis and aldose reductase inhibitory activities of novel N-nitromethylsulfonanilide derivatives.

A novel series of 14 N-nitromethylsulfonanilide derivatives were synthesized and evaluated for their ability to inhibit recombinant aldose reductase. Computational docking simulations provided a good explanation for the observed structure-activity relationships. Kinetic analysis of (2-fluoro-5-methyl-N-methyl)-N-nitromethylsulfonanilide, 11, one of the most potent compounds in this series with an IC50 = 0.

Syntheses and SH-enzyme inhibitory activities of new epoxysuccinic acid piperazine derivatives against mu-calpain and cathepsin B.

New chiral epoxysuccinic acid derivatives 5 approximately 23 bearing various amino acids and N-substituted piperazines were synthesized to evaluate their inhibitory activities against mu-calpain and cathepsin B. After screening these compounds, 1-[(2S,3S)-epoxysuccinyl-L-leucyl]-4-(2-chlorophenyl)piperazine 9 proved to exhibit fairly strong inhibitory activity against both cysteine proteases. L-Valyl derivative 19 exhibited selective inhibitory activity against cathepsin B in comparison with that against mu-calpain.

[Delivery of macromolecular drugs to the vitreous and its peripheral tissues].

We evaluated the release behavior of FITC-dextran with an average molecular weight of 4,400(FD4), as a model peptide drug, from poly(DL-lactic acid) (PLA) implant. The drug level in the vitreous and its peripheral tissues were measured following the implantation in the rabbit vitreous. The release profile of FD4 from the PLA implant was biphasic; a fraction of the drug molecules incorporated in the polymer implant was swiftly released; then slowly or even negligibly for a certain period of time and finally complete bursting release probably due to bulk erosion of the polymer.

Intravitreous delivery of dexamethasone sodium m-sulfobenzoate from poly(DL-lactic acid) implants.

Biodegradable intravitreal rod-shaped implants containing dexamethasone sodium m-sulfobenzoate (DMSB) were prepared from blends of poly(DL-lactic acid) (PLA) with number-average molecular weight 2000 (PLA2000) and 4000 (PLA4000). The effect of the fraction of PLA2000 on the release of DMSB from the implant was investigated after implantation in the vitreous body of rabbit eyes. After the initial burst, the drug was released slowly from the blended PLA implants with a PLA2000 fraction of below 30 wt% in normal eyes within a period of 28 d.

Polymer blend implant for ocular delivery of fluorometholone.

Ocular implants containing fluorometholone (FLM) were prepared using blends of poly (DL-lactic acid) (PLA) and polyvinyl pyrrolidone (PVP). The effect of the fraction of PVP content on the release of FLM from the implant was investigated in vitro. The drug was released from the device by approximately following first order kinetics within the period of 40 d.