Protection of Dopaminergic Cells From 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/ 1-methyl-4-phenylpyridinium Toxicity by Histone Deacetylase Inhibitors
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the depletion of dopaminergic cells in the substantia nigra pars compacta (SNpc) and the decrease of striatal dopamine (DA) levels. The observance of classical parkinsonian symptoms (bradykinesia, rigidity and tremor) does not occur until the nigrostriatal DA levels are severely depleted making it difficult to identify events responsible for the initiation of neurodegeneration and the mechanism(s) by which DA neurons are lost in PD. However, the use of animal models of Parkinson-like DA neuron degeneration such as the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model and the use of its active metabolite, 1-methyl-4-phenylpyridinium (MPP+), in cell culture have provided some insight into the possible pathological processes that may be involved in PD. While the exact mechanism of dopaminergic (DAergic) cell death in PD is unknown, apoptotic cell death has been described in the post-mortem PD brain as well as in various animal and in vitro studies. Apoptotic cell death in the SNpc of mice exposed to sub-acute MPTP administration is associated with caspase activation and in vitro data suggests that caspase activation may result in hypoacetylation of histone tails. This change in the acetylation state of histones does not favor active transcription and may limit the cells ability to respond to the toxic insult (i.e. MPP +) through the transcriptional upregulation of free radical scavengers and anti-apoptotic proteins. Administration of drugs that are capable of inhibiting the class of enzymes responsible for the removal acetyl groups from proteins, histone deacetylases (HDACs), has been shown to potentiate the acetylation of target proteins including histones. Inhibition of HDACs using these drugs (HDACis) protects both neurons and cell lines exhibiting neuronal phenotypes from a variety of toxic insults including excitotoxicity, oxidative stress and inflammation making this family of drugs an intriguing candidate to protect against cell death in both in vitro and in vivo models of PD-like DAergic loss. We examined the ability of three HDACis (sodium butyrate, NaB, valproate, VPA, and suberoylanilide hydroxamic acid, SAHA) to protect against MPP + toxicity in both human derived SK-N-SH and rat derived MES 23.5 DAergic cell lines. While all three HDACis showed some degree of protection, only NaB and VPA did not interfere with the ability of MPP+ to enter the cells and were further examined. In order to evaluate the in vivo efficacy of HDACis in a sub-acute MPTP mouse model, the spatio-temporal dynamics of histone acetylation as a result of HDAC inhibition were examined in the C57B/l6 mouse. We found that that neither NaB nor VPA was able to produce a long-lasting hyperacetylation. However, VPA was able to induce a prolonged hyperacetylation in both FVBn and Swiss Webster mice compared to C57Bl/6 mice. Valproate was then tested in the sub-acute MPTP mouse model of PD using FVBn mice. We detected a partial protection of both striatal DA and DAergic cell bodies in the SNpc. The cumulative results of the work presented suggest that HDAC inhibition and in particular VPA may represent an effective disease modifying therapy in the treatment of PD.
Kidd, Sarah K, "Protection of Dopaminergic Cells From 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/ 1-methyl-4-phenylpyridinium Toxicity by Histone Deacetylase Inhibitors" (2012). ETD Collection for Thomas Jefferson University. AAI3498698.