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Rifampicin, an antibacterial drug, is highly effective in the treatment of tuberculosis and leprosy. Recently, it has been reported to have neuroprotective effects in in vitro and in vivo models. This study was designed to elucidate its neuroprotective effects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity (known as an in vivo mouse model of Parkinson's disease). Mice were injected intraperitoneally (i.p.) with MPTP (10 mg/kg) four times at 1- h intervals, and brains were analyzed 3 or 7 days later. Rifampicin at 20 mg/kg (i.p., twice) had protective effects against MPTP-induced neuronal damage (immunohistochemical changes in tyrosine hydroxylase) in both the substantia nigra and striatum. Rifampicin also protected against the MPTP-induced depletions of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in the striatum. The maximal concentrations of rifampicin between 30 and 240 min after a single rifampicin injection (20 mg/kg, i.p.) were 2.6 μM (at 30 min) in plasma and 0.77 μM (at 60 min) in striatum. Next, the effects of rifampicin on oxidative stress [lipid peroxidation in mouse brain homogenates and free radical-scavenging activity against diphenyl- p -picrylhydrazyl (DPPH)] were evaluated to clarify the underlying mechanism. At 1 μM or more, rifampicin significantly inhibited both lipid peroxidation in the striatum and free radical production. These findings suggest that in mice, rifampicin can reach brain tissues at concentrations sufficient to attenuate MPTP-induced neurodegeneration in the nigrostriatal dopaminergic neuronal pathway, and that an inhibitory effect against oxidative stress may be partly responsible for its observed neuroprotective effects.

Pd(II)-catalyzed hydroesterification of various enol esters smoothly proceeded upon the combined use of pressurized carbon monoxide and methanol to give the α-or β-acetoxy esters with the regioselectivity highly depending on the size of the α-substituent.

The palladium(II)-catalyzed carbonylation of various enol esters in the presence of methanol under pressurized carbon monoxide was investigated. As typical results, the carbonylation of isopropenyl acetate afforded a cyclocarbonylation product, 2-methoxy-2,5,5-trimethyl-1,3-dioxolan-4-one, in 46% yield under carbon monoxide of 150 atm at 100 °C, whereas vinyl acetate selectively gave an α-hydroesterification product, methyl 2-acetoxypropionate, in 56% yield under 250 atm at 100 °C. On the contrary, the reaction of 3,3-dimethyl-1-buten-2-yl acetate gave exclusively a β-hydroesterification product, methyl 3-acetoxy-4,4-dimethylpentanoate, in 64% yield. The yields of these products show a maximum as a function of the base/palladium ratio and of the carbon monoxide pressure. The effects of the reaction variables, such as the MeOH/substrate ratio, the structure of the base, the base/Pd ratio, the CO pressure, and the reaction temperature, were examined for optimizing the process. The mechanisms for the unique ...

The palladium(II)-catalyzed carbonylation of various enol esters in the presence of methanol under pressurized carbon monoxide was investigated. As typical results, the carbonylation of isopropenyl acetate afforded a cyclocarbonylation product, 2-methoxy-2,5,5-trimethyl-1,3-dioxolan-4-one, in 46% yield under carbon monoxide of 150 atm at 100 °C, whereas vinyl acetate selectively gave an α-hydroesterification product, methyl 2-acetoxypropionate, in 56% yield under 250 atm at 100 °C. On the contrary, the reaction of 3,3-dimethyl-1-buten-2-yl acetate gave exclusively a β-hydroesterification product, methyl 3-acetoxy-4,4-dimethylpentanoate, in 64% yield. The yields of these products show a maximum as a function of the base/palladium ratio and of the carbon monoxide pressure. The effects of the reaction variables, such as the MeOH/substrate ratio, the structure of the base, the base/Pd ratio, the CO pressure, and the reaction temperature, were examined for optimizing the process. The mechanisms for the unique ...

SUN N8075 is a novel antioxidant with neuroprotective properties. This study was designed to elucidate its neuroprotective effects against 6-hydroxy dopamine (6-OHDA)-induced cell death and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity (known as in vitro and in vivo models of Parkinson's disease, respectively). In the in vitro study, on human neuroblastoma SH-SY5Y cells, SUN N8075 decreased the hydrogen peroxide (H2O2)-induced production of reactive oxygen species and protected against 6-OHDA-induced cell death. In the in vivo study, SUN N8075, when injected intraperitoneally (i.p.) twice with a 5-h interval, inhibited lipid peroxidation (viz. the production of thiobarbituric acid reactive substance) in the mouse forebrain at 1 h after the second injection. Mice were injected i.p. with MPTP (10 mg/kg) four times at 1-h intervals, and brains were analyzed 7 days later. SUN N8075 at 30 mg/kg (i.p., twice) exhibited a protective effect against the MPTP-induced decrease in tyrosine hydroxylase (TH)-positive fibers in the striatum. Moreover, SUN N8075 at 10 and 30 mg/kg (i.p., twice) had a similar protective effect against the MPTP-induced decrease in TH-positive cells in the substantia nigra. Further, SUN N8075 30 mg/kg (i.p. twice) markedly suppressed the MPTP-induced accumulation of 8-hydroxy-deoxyguanosine (8-OHdG) in the striatum. These findings indicate that SUN N8075 exerts protective effects, at least in part via an anti-oxidation mechanism, in these in vitro and in vivo models of Parkinson's disease.

Endoplasmic reticulum (ER) stress, which is caused by the accumulation of unfolded proteins in the ER lumen, is associated with stroke and neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. We evaluated the effect of a selective inducer of immunoglobulin heavy chain binding protein (BiP) (BiP inducer X; BIX) against both tunicamycin-induced cell death (in SH-SY5Y cells) and the effects of global transient forebrain ischemia (in gerbils). BIX significantly induced BiP expression both in vitro and in vivo. Pretreatment with BIX at 2 or 5 microM reduced the cell death induced by tunicamycin in SH-SY5Y cells. In gerbils subjected to forebrain ischemia, prior treatment with BIX (intracerebroventricular injection at 10 or 40 microg) protected against cell death and decreased TUNEL-positive cells in the hippocampal CA1 subfield. These findings indicate that this selective inducer of BiP could be used to prevent the neuronal damage both in vitro and in vivo.

(2S)-1-(4-Amino-2,3,5-trimethylphenoxy)-3-{4-[4-(4-fluorobenzyl) phenyl]-1-piperazinyl}-2-propanol dimethanesulfonate (SUN N8075) is a novel antioxidant with neuroprotective properties. We examined whether SUN N8075 inhibited the neuronal damage resulting from permanent focal cerebral ischemia, and examined its neuroprotective properties in vivo and in vitro mechanism. Focal cerebral ischemia was induced by permanent middle cerebral artery occlusion in mice, and the resulting infarction, brain swelling, and neurological deficits were evaluated after 24 h or 72 h. Brain damage was assessed histochemically using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining and antibody recognizing 4-hydroxynonenal histidine adduct (4-HNE). In the in vitro study, we examined the effects of SUN N8075 on 1) lipid peroxidation in mouse brain homogenates and 2) cell viability and caspase-3 protease activity under a hypoxic insult or FeSO(4) in rat cultured cerebrocortical neurons. SUN N8075 administered either 10 min before or at 1 h after the occlusion reduced both infarction size and neurological deficits. SUN N8075 reduced brain swelling when administered 10 min before, 1 h, or 3 h after occlusion. Furthermore, only pretreatment (administered 10 min before) decreased infarct volume and brain swelling at 72 h after middle cerebral artery occlusion. SUN N8075 reduced the number of TUNEL-positive cells and decreased the level of oxidative damage, as assessed by immunopositive staining to 4-HNE. SUN N8075 inhibited lipid peroxidation, leakage of lactate dehydrogenase, caspase-3 activation induced by in vitro hypoxia, and the neuronal damage induced by in vitro FeSO(4) exposure. These findings indicate that SUN N8075 has neuroprotective effects against acute ischemic neuronal damage in mice and may prove promising as a therapeutic drug for stroke.