Therapeutic effects of valproate combined with lithium carbonate on MPTP-induced parkinsonism in mice: possible mediation through enhanced autophagy.

In order to investigate the mechanisms and therapeutic effects of valproate combined with lithium carbonate on mouse model of Parkinson's disease (PD), male C57BL/6 mice were injected into intraperitoneal with valproate (20 µg/ml) combined with lithium carbonate (10 µg/ml) for 7 days following 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) (30 mg/kg) administration, and the effects on motor function were analyzed. Immunohistochemistry and Western blotting were used to detect alterations in the expression of PD biomarkers, including tyrosine hydroxylase (TH), and the level of autophagy was evaluated by the detection of microtubule-associated protein light chain 3 (LC3). In addition, the levels of monoamine neurotransmitters were measured in the striatum using high performance liquid chromatography (HPLC). After MPTP exposure, all groups manifested decreased rolling bar latency and spontaneous activity, in addition to increased pole-climbing time. The combined treatment group exhibited a recovery of rolling bar latency and pole-climbing time. The number of dopaminergic neurons in the substantia nigra following MPTP treatment was higher in the combined treatment group compared with the positive control group (p = .003). Immunoreactivity for LC3 was higher in the combined treatment group than in the controls (p = .003). The concentrations of both striatal dopamine and the dopamine metabolite dihydroxyphenyl acetic acid (DOPAC) were decreased in both MPTP-treated groups compared with the controls. The loss of DOPAC was less severe in the combined treatment group relative to the positive control group (p = .001). Therefore, we infer that valproate combined with lithium carbonate can rescue dopaminergic neurons and ameliorate the loss of DOPAC following MPTP treatment, likely via activation of autophagic/lysosomal pathways.

Effects of IL-6 secreted from astrocytes on the survival of dopaminergic neurons in lipopolysaccharide-induced inflammation.

The role of astrocytes in microglia-induced neuronal death remains controversial. In this study, astrocytes and astrocyte-derived conditioned media (ACM) supported the survival of dopaminergic neurons, and the former was more effective than the latter. In the presence of astrocytes, low concentrations of LPS enhanced the survival of dopaminergic neurons, while high concentrations attenuated survival. LPS dramatically induced astrocytes to secrete IL-6 in a dose-dependent manner with no effect on secretion of GDNF. Neuron-astrocyte cultures had highest secretion of GDNF, followed by ACM-treated neuron-enriched cultures. After neuron-astrocyte cultures treated with IL-6-neutralizing antibody, both effects of the enhanced and attenuated survival of dopaminergic neurons were abolished. Our results indicate that astrocytes play a protective role in the LPS-induced damage of dopaminergic neurons in certain circumstances, and the interaction between astrocytes and dopaminergic neurons may enhance the protective effect of astrocytes. Suitable activation of astrocytes increases the protective effect while excessive activation attenuates it, and IL-6 might mediate this dual action. The underlying mechanisms related to the secretion of GDNF and proinflammatory factors warrant further investigation.

[A dual effect on the growth of astrocytes of lipopolysaccharide].

AIM: To investigate the changes of growth of astrocytes administrated with lipopolysaccharide (LPS) and the probable mechanisms. METHODS: LPS was administrated to rat astrocytes for 1 h, 6 h, 24 h and 48 h, and the changes of growth of astrocytes were detected by MTT method. Meanwhile, the long-term changes of growth of astrocytes after administration with LPS for 24 h were also studied. Moreover, the effects of inhibitor of NF-kappaB(SN50) on proliferation of astrocytes were observed. RESULTS: Changes of astrocytes growth were observed only when LPS had been administrated for 24 h. LPS of low concentration could promote proliferation of astrocytes and increase the cell viability(P<0.05 vs control), while LPS of high concentration inhibited the proliferation of astrocytes. Being administrated for 24 h, LPS could promote the proliferation of astrocytes in short-term. As for the long-term effects, LPS inhibited the proliferation of astrocytes in a concentration-dependent manner. Pretreatment with SN50 could block the effects of LPS on astrocytes. CONCLUSION: LPS of low concentration could promote the proliferation of astrocytes in short-term and LPS of high concentration could inhibit it. The molecular mechanism of the changes might be related to the activation of NF-kappaB.