FK506 ameliorates cell death features in Huntington’s disease striatal cell models

• Published in: Neurochemistry international 2011-10, Vol.59 (5), p.600-609
• Main Authors: Rosenstock, Tatiana R., de Brito, Olga Martins, Lombardi, Vitoria, Louros, Susana, Ribeiro, Marcio, Almeida, Sandra, Ferreira, Ildete Luisa, Oliveira, Catarina R., Rego, A. Cristina
• Format: Article
• Language: English
• Subjects: 3-Nitropropionic acid; Animals; Apoptosis - drug effects; Biological and medical sciences; Blotting, Western; Caspase 3 - metabolism; Cell Death; Cell Line; Corpus Striatum - cytology; Corpus Striatum - drug effects; Cytosol - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA Fragmentation; FK506; Fundamental and applied biological sciences. Psychology; Humans; Huntingtin Protein; Huntington Disease - pathology; Immunosuppressive Agents - pharmacology; Medical sciences; Mice; Mice, Transgenic; Mitochondria - metabolism; Mitochondrial dysfunction; Mutant huntingtin; Necrosis; Nerve Tissue Proteins - genetics; Neurology; Neurons - drug effects; Neuroprotective Agents; Nitro Compounds - toxicity; Nuclear Proteins - genetics; Propionates - toxicity; Staurosporine - pharmacology; Striatal neurons; Subcellular Fractions - drug effects; Subcellular Fractions - metabolism; Tacrolimus - pharmacology; Vertebrates: nervous system and sense organs
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/j.neuint.2011.04.009

► FK506 effectively prevents neuroapoptosis in3-NP-treated primary striatal neurons. ► Striatal neuronswithFL-mHttare more vulnerable to toxic stimuli than wild-type. ► FK506 significantly revert caspase-3 activation in striatal cells expressing FL-mHtt. ► FK506 is neuroprotective under mild apoptotic stimulus in the presence of FL-mHtt. Huntington’s disease (HD) is a genetic neurodegenerative disorder characterized by striatal neurodegeneration, involving apoptosis. FK506, an inhibitor of calcineurin (or protein phosphatase 3, formerly known as protein phosphatase 2B), has shown neuroprotective effects in several cellular and animal models of HD. In the present study, we show the protective effects of FK506 in two striatal HD models, primary rat striatal neurons treated with 3-nitropropionic acid (3-NP) and immortalized striatal STHdh cells derived from HD knock-in mice expressing normal (STHdh7/7) or full-length mutant huntingtin (FL-mHtt) with 111 glutamines (STHdh111/111), under basal conditions and after exposure to 3-NP or staurosporine (STS). In rat striatal neurons, FK506 abolished 3-NP-induced increase in caspase-3 activation, DNA fragmentation/condensation and necrosis. Nevertheless, in STHdh111/111 cells under basal conditions, FK506 did not prevent, in a significant manner, the release of cytochrome c and apoptosis inducing factor (AIF) from mitochondria, or alter Bax/Bcl-2 ratio, but significantly reverted caspase-3 activation. In STHdh111/111 cells treated with 0.3mM 3-NP or 25 nM STS, linked to high necrosis, exposure to FK506 exerted no significant effects on caspase-3 activation. However, treatment of STHdh111/111 cells exposed to 10nM STS with FK506 effectively prevented cell death by apoptosis and moderate necrosis. The results suggest that FK506 may be neuroprotective against apoptosis and necrosis under mild cell death stimulus in the presence of FLmHtt.