Protective effect against Parkinson's disease-related insults through the activation of XBP1.

The accumulation of misfolded and unfolded proteins in endoplasmic reticulum (ER) induces ER stress, activating the unfolded protein response (UPR). Recent evidence has suggested the relationship between UPR and dopaminergic neuronal cell death in Parkinson's disease (PD); however, it remains unclear whether it makes sense to modulate UPR, to mitigate the progression of PD. In this study, we investigated a role of the IRE1 alpha-XBP1 pathway in the survival of dopaminergic cells, under stress induced by PD-related insults.

The effect of aripiprazole on prepulse inhibition of the startle response in normal and hyperdopaminergic states in rats.

This study compared the D(2) partial agonists, aripiprazole, (R(+)-terguride; S(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [S(-)-3-PPP]; 7-[3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy]-2(1H)-quinolinone [OPC-4392]) and D(2) antagonists (haloperidol, olanzapine, clozapine, risperidone, and quetiapine) on prepulse inhibition (PPI) of the startle response, and the ability to reverse apomorphine-induced deficits in the PPI response. Aripiprazole did not essentially affect PPI in naïve rats but dose-dependently restored apomorphine-induced PPI disruption. R(+)-terguride restored PPI disruption but suppressed PPI significantly in naïve rats, S(-)-3-PPP partially restored whereas OPC-4392 did not restore PPI disruption.

Age-related severity of dopaminergic neurodegeneration to MPTP neurotoxicity causes motor dysfunction in C57BL/6 mice.

This study investigated the influence of advancing age on dopaminergic neuronal degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication from the perspective concerning the relationship between dopaminergic function and behavioral features. Young (10 weeks) and older (14-15 months) C57BL/6 mice were treated with one to four injections of MPTP (20 mg/kg at 2h intervals). Although young mice showed no mortality in either MPTP treatment, older mice exhibited mortality from only two injections of MPTP during the experimental period.

Reduction of NR1 and phosphorylated Ca2+/calmodulin-dependent protein kinase II levels in Alzheimer's disease.

Ca2+ influx through the N-methyl-D-aspartate-type glutamate receptor leads to activation and postsynaptic accumulation of Ca2+/calmodulin-dependent protein kinase II. NR1 and NR2B subunits of N-methyl-D-aspartate receptor serve as high-affinity Ca2+/calmodulin-dependent protein kinase II docking sites in dendritic spines on autophosphorylation of Ca2+/calmodulin-dependent protein kinase II. By comparative Western blot analysis, we show a reduction of NR1 and phosphorylated Ca2+/calmodulin-dependent protein kinase II levels in the frontal cortex and hippocampus of Alzheimer's disease brains.

Neural mechanisms underlying motor dysfunction as detected by the tail suspension test in MPTP-treated C57BL/6 mice.

Contradictory data on behavioral changes in MPTP-treated C57BL/6 mice have been reported, even though the toxin-treated mice have been widely used for non-clinical studies as an in vivo model of Parkinson's disease (PD). We found that the duration of immobility in the tail suspension test (TST) was significantly increased in MPTP-treated C57BL/6 mice as compared with control mice without a significant change in the locomotor activity (LA). Dopamine (DA) contents and protein levels of tyrosine hydroxylase and dopamine transporter in the striatum were profoundly decreased in the toxin-treated mice.

Differential effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the olfactory bulb and the striatum in mice.

The present study was undertaken to examine whether 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes damage of dopaminergic glomerular cells of the olfactory bulb (OB) in C57BL/6 mice. At 3 days after MPTP treatment, dopamine level in the striatum and the OB decreased to 13% and 84% of the control mice, respectively. While a small reduction of tyrosine hydroxylase protein level was observed in the OB of MPTP-treated mice, dopamine transporter (DAT) was undetectable at the protein level in this region.

Mechanism of action of aripiprazole predicts clinical efficacy and a favourable side-effect profile.

The antipsychotic efficacy of aripiprazole is not generally associated with extrapyramidal symptoms, cardiovascular effects, sedation or elevations in serum prolactin that characterize typical or atypical antipsychotics. The aim of this study was to clarify the mechanism of action of aripiprazole that underlies its favourable clinical profiles. The preclinical efficacy and side-effect profiles of aripiprazole were evaluated using several pharmaco-behavioural test systems in mice and rats, both in vivo and ex vivo, and compared with those of other conventional and atypical antipsychotics.

The novel antipsychotic aripiprazole is a partial agonist at short and long isoforms of D2 receptors linked to the regulation of adenylyl cyclase activity and prolactin release.

Aripiprazole is a novel antipsychotic with a unique mechanism of action, which differs from currently marketed typical and atypical antipsychotics. Aripiprazole has been shown to be a partial agonist at the D(2) family of dopamine (DA) receptors in biochemical and pharmacological studies. To demonstrate aripiprazole's action as a partial D(2) agonist in pituitary cells at the molecular level, we retrovirally transduced the short (D(2S)) and the long (D(2L)) form of the human DA D(2) receptor gene into a rat pituitary cell line, GH4C1.

A neuron-specific EGF family protein, NELL2, promotes survival of neurons through mitogen-activated protein kinases.

NELL2 is a neuron-specific thrombospondin-1-like extracellular protein containing six epidermal growth factor-like domains. NELL2 is highly expressed in the hippocampus and cerebral cortex. Although the involvement of NELL2 in neural functions has been inferred from its expression and biochemical profiles, biological roles of NELL2 remain uncertain.

1-methyl-4-phenylpyridinium (MPP+) decreases mitochondrial oxidation-reduction (REDOX) activity and membrane potential (Deltapsi(m)) in rat striatum.

Mitochondrial dysfunction has long been implicated in the death of nigrostriatal dopaminergic neurons in Parkinson's disease (PD) and its experimental models. Here we further analyzed changes in the mitochondrial oxidation-reduction (REDOX) activity and membrane potential (Deltapsi(m)) of striatal synaptosomes after the infusion of 1-methyl-4-phenylpyridinium (MPP+) into rat striatum. MPP+ (40 nmol) treatment produced decreases in mitochondrial REDOX activity and Deltapsi(m) at 18 h, as measured by fluorometric analysis with both Alamar blue and JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl-carbocyanine iodide) dyes.