NeuropharmacologyValproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity
Section snippets
Materials
LPS (strain O111:B4) was purchased from Calbiochem (San Diego, CA, USA). Cell culture ingredients were obtained from Invitrogen (San Diego, CA, USA). [3H]-Dopamine (DA; 28 Ci/mmol) was purchased from PerkinElmer Life Sciences (Boston, MA, USA). The polyclonal antibody against tyrosine hydroxylase (TH) was a kind gift from Dr. John Reinhard of Glaxo Wellcome (Research Triangle Park, NC, USA) and the antibody diluent was a product of DAKO (Carpinteria, CA, USA). Biotinylated horse anti-mouse and
Treatment with VPA or other HDACIs triggers microglial apoptosis
To investigate whether VPA decreases the number of microglia by inducing apoptosis (Peng et al., 2005), we examined multiple parameters of apoptotic cell death in VPA-treated rat microglia-enriched cultures. The VPA-treated microglial cells showed a significant dose-dependent reduction in cell viability in the range of 0.3 mM to 1.2 mM, as determined by the MTT assay (Fig. 1A). Moreover, VPA treatment triggered the externalization of PS, an early hallmark of apoptosis, and increased the
Discussion
In this study, we demonstrated that VPA induce the apoptosis of the cultured rat microglia. The microglial apoptosis is characterized by PS externalization, internucleosomal DNA fragmentation, and appearance of TUNEL-positive cells. The apoptosis of microglia is likely responsible for the reduction in the number of microglia in VPA-treated neuron–glia cultures (Peng et al., 2005). The finding that VPA exerted little effect on the proliferation of microglia further supports this notion. Evidence
Conclusion
In conclusion, the present study provides strong evidence that VPA and other HDACIs markedly induce the apoptosis of the microglia. This apoptosis-inducing effect is associated with a loss of microglial mitochondrial transmembrane potential and an increase in histone hyperacetylation. The HDACI-induced microglial apoptosis likely contributes to their neuroprotective effects in response to pro-inflammatory stimuli. Since microglia could potentially act as both protector and attacker, future in
Acknowledgments
We are grateful to Ms. Belinda Wilson and Mr. Robert N. Wine for their technical assistance, and Drs. Sung-Jen Wei, Ms. Michelle L. Block, and Mr. Chiou-Feng Lin for their invaluable comments regarding this manuscript. This work was also supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH.
References (41)
- et al.
Histone deacetylase inhibitors: new drugs for the treatment of inflammatory diseases?
Drug Discov Today
(2005) - et al.
Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis
J Neuroimmunol
(2005) - et al.
Valproic acid induces caspase 3-mediated apoptosis in microglial cells
Neuroscience
(2006) - et al.
Ibuprofen and apigenin induce apoptosis and cell cycle arrest in activated microglia
Neurosci Lett
(2005) - et al.
Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic mouse model of Huntington’s disease
J Biol Chem
(2005) - et al.
Valproic acid, a mood stabilizer and anticonvulsant, protects rat cerebral cortical neurons from spontaneous cell death: a role of histone deacetylase inhibition
FEBS Lett
(2003) - et al.
Sodium butyrate suppresses interferon-gamma-, but not lipopolysaccharide-mediated induction of nitric oxide and tumor necrosis factor-alpha in microglia
J Neuroimmunol
(2004) - et al.
T-helper types 1, 2, and 3 cytokine interactions in symptomatic manic patients
Psychiatry Res
(2004) - et al.
CYP2E1-mediated modulation of valproic acid-induced hepatocytotoxicity
Clin Biochem
(2001) - et al.
Repression of interferon-gamma-induced inducible nitric oxide synthase (iNOS) gene expression in microglia by sodium butyrate is mediated through specific inhibition of ERK signaling pathways
J Neuroimmunol
(2005)
Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures: role of microglia
Brain Res Mol Brain Res
Additive neuroprotective effects of a histone deacetylase inhibitor and a catalytic antioxidant in a transgenic mouse model of amyotrophic lateral sclerosis
Neurobiol Dis
Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen
J Biol Chem
Microglial distribution and apoptosis in fetal rat brain
Brain Res Dev Brain Res
Linear relationship of valproate serum concentration to response and optimal serum levels for acute mania
Am J Psychiatry
Microglia-mediated neurotoxicity: uncovering the molecular mechanisms
Nat Rev
Anticancer activities of histone deacetylase inhibitors
Nat Rev Drug Discov
Phagocytosis of apoptotic inflammatory cells by microglia and modulation by different cytokines: mechanism for removal of apoptotic cells in the inflamed nervous system
Glia
Phagocytosis of apoptotic inflammatory cells by microglia and its therapeutic implications: termination of CNS autoimmune inflammation and modulation by interferon-beta
Glia
Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes
Mol Psychiatry
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These two authors contribute equally to this work.