Delayed treatment with arundic acid reduces the MPTP-induced neurotoxicity in mice.

The authors investigated the protective effects of a novel astrocyte-modulating agent, arundic acid, in a 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP) mouse model of Parkinson's disease. Male mice received four intraperitoneal (i.p.) injections of MPTP (20 mg/kg) at 2 h intervals. The content of dopamine and its metabolites in the striatum was reduced markedly 7 days after MPTP treatment. The delayed treatment with arundic acid (30 mg/kg, i.p.) administered 3, 4, 5 and 6 days after MPTP treatment did not affect the depletion of dopamine and its metabolites in the striatum. Our immunohistochemical study with anti-tyrosine hydroxylase antibody, anti-neuronal nuclei antibody, anti-glial fibrillary acidic protein antibody, anti-S 100beta antibody and anti-nestin antibody showed that the delayed treatment with arundic acid had a protective effect against MPTP-induced neuronal damage in the striatum and the substantia nigra of mice. Furthermore, this agent ameliorated the severe reductions in number of isolectin reactive microglia in the striatum and the substantia nigra 7 days after MPTP treatment. These results demonstrate that the inhibition of S 100beta synthesis in astrocytes may be the major component of the beneficial effect of arundic acid. Thus, our present findings provide that the therapeutic strategies targeted to astrocytic modulation with arundic acid offers a great potential for restoring the functional capacity of the surviving dopaminergic neurons in individuals affected with Parkinson's disease.

Effects of chronic administration with nilvadipine against immunohistochemical changes related to aging in the mouse hippocampus.

We investigated the effect of Ca2+ antagonist nilvadipine on age-related immunohistochemical alterations in ubiquitin and S100beta protein of the hippocampal CA1 sector in mice using 8-, 18-, 40-, and 59-week-old mice. No significant changes in the number of neuronal cells were observed in the hippocampal CA1 sector up to 59 weeks after birth. The administration of nilvadipine did not affect the number of the hippocampal CA1 cells of 40-week-old mice. Age-dependent increases in ubiquitin immunoreactivity were observed in the hippocampal CA1 neurons up to 59 weeks after birth. The administration of nilvadipine prevented dose-dependently the increases in the number of ubiquitin-immunoreactive neurons in the hippocampal CA1 sector of 40-week-old mice. S100,beta immunoreactivity was unchanged in the hippocampal CA1 sector up to 40 weeks after birth. In 59-week-old mice, the level of staining of S100beta-immunoreactive cells increased significantly in the hippocampal CA1 sector. The administration of nilvadipine decreased dose-dependently the number of S 100beta-immunoreactive cells in the hippocampal CA1 sector of 40-week-old mice. The present study demonstrates that age-related increases in ubiquitin system may play a pivotal role in protecting neuronal cell damage during aging. In contrast, our results suggest that expression of S 100beta protein in the hippocampal CA1 sector may play an exacerbating factor in some neuronal cells damaged by aging. Our results also demonstrate that nilvadipine, a dihydropyridine-type calcium channel blocker, can prevent dose-dependently the increases in the ubiquitin immunoreactive neurons and decrease the number of S100beta immunoreactive cells in the hippocampal CA1 neurons of aged mice. These results suggest that nilvadipine may offer a new approach for the treatment of neuronal dysfunction in aged humans.

Arundic acid, an astrocyte-modulating agent, protects dopaminergic neurons against MPTP neurotoxicity in mice.

We examined the neuroprotective effects of a novel astrocyte-modulating agent, arundic acid (ONO-2506), in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Male C57BL/6 mice received four intraperitoneal injections of MPTP (20 mg/kg) at 2 h intervals. Dopamine content in the striatum was reduced to 21% of the normal control after 7 days. Treatment with arundic acid (30 mg/kg, i.p.) administered 1 min, 6 h, 24 h, 48 h, and 72 h after the last MPTP injection prevented the dopamine depletion (52% of the control, p<0.01). In addition, this treatment resulted in behavioral benefits. Behavioral testing showed that MPTP-injected mice exhibited motor deficits in the pole test and catalepsy test after 7 days, but arundic acid prevented the appearance of motor abnormalities in these tests. The MPTP-injected animals exhibited an 87% loss of tyrosine hydroxylase-containing dopaminergic neurons in the substantia nigra after 7 days, but the arundic acid-treated mice showed only a 56% reduction (p<0.01). GFAP-positive reactive astrocytes were accumulated in the striatum and substantia nigra 7 days after the MPTP injection, whereas arundic acid treatment induced an earlier appearance of reactive astrocytes by 3 days. The reactive astrocytes increased the production of S-100 protein, which is thought to promote neuronal damage, but arundic acid suppressed the expression of S-100. Thus, arundic acid protected dopaminergic neurons against MPTP neurotoxicity in mice and ameliorated neurological deficits. The results suggest that the neuroprotection is mediated through the modulation of astrocytic activation, including the inhibition of S-100 protein synthesis.