Po-See Chen

Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons

Parkinsons disease (PD) is characterized by the selective and progressive loss of dopaminergic (DA) neurons in the midbrain substantia nigra. Currently, available treatment is unable to alter PD progression. Previously, we demonstrated that valproic acid (VPA), a mood stabilizer, anticonvulsant and histone deacetylase (HDAC) inhibitor, increases the expression of glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) in astrocytes to protect DA neurons in midbrain neuron-glia cultures. The present study investigated whether these effects are due to HDAC inhibition and histone acetylation. Here, we show that two additional HDAC inhibitors, sodium butyrate (SB) and trichostatin A (TSA), mimic the survival-promoting and protective effects of VPA on DA neurons in neuron-glia cultures. Similar to VPA, both SB and TSA increased GDNF and BDNF transcripts in astrocytes in a time-dependent manner. Furthermore, marked increases in GDNF promoter activity and promoter-associated histone H3 acetylation were noted in astrocytes treated with all three compounds, where the time-course for acetylation was similar to that for gene transcription. Taken together, our results indicate that HDAC inhibitors up-regulate GDNF and BDNF expression in astrocytes and protect DA neurons, at least in part, through HDAC inhibition. This study indicates that astrocytes may be a critical neuroprotective mechanism of HDAC inhibitors, revealing a novel target for the treatment of psychiatric and neurodegenerative diseases.

Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity

Valproic acid (VPA), a widely prescribed drug for seizures and bipolar disorder, has been shown to be an inhibitor of histone deacetylase (HDAC). Our previous study has demonstrated that VPA pretreatment reduces lipopolysaccharide (LPS)-induced dopaminergic (DA) neurotoxicity through the inhibition of microglia over-activation. The aim of this study was to determine the mechanism underlying VPA-induced attenuation of microglia over-activation using rodent primary neuron/glia or enriched glia cultures. Other histone deacetylase inhibitors (HDACIs) were compared with VPA for their effects on microglial activity. We found that VPA induced apoptosis of microglia cells in a time- and concentration-dependent manner. VPA-treated microglial cells showed typical apoptotic hallmarks including phosphatidylserine externalization, chromatin condensation and DNA fragmentation. Further studies revealed that trichostatin A (TSA) and sodium butyrate (SB), two structurally dissimilar HDACIs, also induced microglial apoptosis. The apoptosis of microglia was accompanied by the disruption of mitochondrial membrane potential and the enhancement of acetylation levels of the histone H3 protein. Moreover, pretreatment with SB or TSA caused a robust decrease in LPS-induced pro-inflammatory responses and protected DA neurons from damage in mesencephalic neuron-glia cultures. Taken together, our results shed light on a novel mechanism whereby HDACIs induce neuroprotection and underscore the potential utility of HDACIs in preventing inflammation-related neurodegenerative disorders such as Parkinsons disease.

Clozapine protects dopaminergic neurons from inflammation-induced damage by inhibiting microglial overactivation

Increasing evidence suggests a possible involvement of neuroinflammation in some psychiatric disorders, and also pharmacological reports indicate that anti-inflammatory effects are associated with therapeutic actions of psychoactive drugs, such as anti-depressants and antipsychotics. The purpose of this study was to explore whether clozapine, a widely used antipsychotic drugs, displays anti-inflammatory and neuroprotective effects. Using primary cortical and mesencephalic neuron-glia cultures, we found that clozapine was protective against inflammation-related neurodegeneration induced by lipopolysaccharide (LPS). Pretreatment of cortical or mesencephalic neuron–glia cultures with clozapine (0.1 or 1xa0μM) for 24xa0h attenuated LPS-induced neurotoxicity. Clozapine also protected neurons against 1-methyl-4-phenylpyridinium+ (MPP+)-induced neurotoxicity, but only in cultures containing microglia, indicating an indispensable role of microglia in clozapine-afforded neuroprotection. Further observation revealed attenuated LPS-induced microglial activation in primary neuron-glia cultures and in HAPI microglial cell line with clozapine pretreatment. Clozapine ameliorated the production of microglia-derived superoxide and intracellular reactive oxygen species (ROS), as well as the production of nitric oxide and TNF-α following LPS. In addition, the protective effect of clozapine was not observed in neuron-glia cultures from mice lacking functional NADPH oxidase (PHOX), a key enzyme for superoxide production in immune cells. Further mechanistic studies demonstrated that clozapine pretreatment inhibited LPS-induced translocation of cytosolic subunit p47phox to the membrane in microglia, which was most likely through inhibiting the phosphoinositide 3-kinase (PI3K) pathway. Taken together, this study demonstrates that clozapine exerts neuroprotective effect via the attenuation of microglia activation through inhibition of PHOX-generated ROS production and suggests potential use of antipsychotic drugs for neuroprotection.

Is Lacking of Energetic Motivation a Symptom in a Unique Domain for Patients with Major Depressive Disorder

Objective: The purpose of this study was to explore whether the symptoms that patients with major depressive disorder have lower energy, which is a unique symptom can be measured by the Motivation and Energy Inventory (MEI). Method: We recruited 22 outpatients with major depressive disorder. We assessed them with the Hamilton Depression Rating Scale (HAM-D), the Taiwanese Depression Questionnaire (TDQ), World Health Organization Quality of Life (WHO-QoL) and the Motivation and Energy Inventory (MEI). Results: The results showed that the MEI sub scores, except the social motivation subscale, are highly correlated with all domains of the depression scales. Conclusion: The sum of state of energetic motivation measured by the MEI might be not a unique symptom in patients with major depressive disorder. But the symptoms related to social motivation needs more attention in clinics.

Potentially Arrhythmogenic Effects of Haloperidol and Olanzapine on Cardiac Autonomic Function-A Preliminary Study

Objective: Antipsychotic medications have been linked to instances of cardio-toxicity or unexplained sudden death. Dysfunction of the cardiac autonomic nervous system may be attributable to the adverse arrhythmic effects in schizophrenic patients taking antipsychotics. Materials and Methods: Twelve schizophrenic patients with scores for the Brief Psychiatry Rating Scale of less than 40, including nine haloperidol-treated patients and three olanzapine-treated patients, were recruited from the outpatient clinic. Each patient received comprehensive measurements of cardiac autonomic nervous function changes at two time points. The first assessment was done after discontinuing the antipsychotics and anticholinergics for more than two weeks. These patients then were prescribed the antipsychotic at the previous dosage again after this first assessment. The second assessment was performed six weeks later. Results: Our study found no statistically significant differences in QTc prolongation between the nine haloperidol-treated and the three olanzapine-treated patients. None of the variables for cardiac autonomic nervous function predicted any arrythymogenic potential of the antipsychotics in our study. Conclusions: Autonomic nervous variables do not seem to be suitable indices for arrythmogenic potential in medicated schizophrenic patients. Future studies involving larger samples are needed to confirm these results.