The Sirtuin-2 Inhibitor AK7 Is Neuroprotective in Models of Parkinson’s Disease but Not Amyotrophic Lateral Sclerosis and Cerebral Ischemia

Sirtuin deacetylases regulate diverse cellular pathways and influence disease processes. Our previous studies identified the brain-enriched sirtuin-2 (SIRT2) deacetylase as a potential drug target to counteract neurodegeneration. In the present study, we characterize SIRT2 inhibition activity of the brain-permeable compound AK7 and examine the efficacy of this small molecule in models of Parkinson’s disease, amyotrophic lateral sclerosis and cerebral ischemia. Our results demonstrate that AK7 is neuroprotective in models of Parkinson’s disease; it ameliorates alpha-synuclein toxicity in vitro and prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine depletion and dopaminergic neuron loss in vivo. The compound does not show beneficial effects in mouse models of amyotrophic lateral sclerosis and cerebral ischemia. These findings underscore the specificity of protective effects observed here in models of Parkinson’s disease, and previously in Huntington’s disease, and support the development of SIRT2 inhibitors as potential therapeutics for the two neurodegenerative diseases

Effects of AK7 in SOD1-G93A mouse model of ALS.

<p>Kaplan-Meier probability curves show no significant effects of AK7 treatment on (<b>A</b>) symptom onset (118 ± 10.0 days for AK7, 117 ± 8.6 days for vehicle-treated controls) or (<b>B</b>) survival (169 ± 12.7 days for AK7, 175 ± 12.4 days for controls) of SOD1-G93A mice in this study. Values are median age ± SD; n = 23 for AK7, n = 27 for vehicle-treated controls.</p

Protective effects of AK7 in acute MPTP mouse model of PD.

<p>Mice received a single injection (<i>i.p.</i>) of MPTP at 40 mg/kg or saline. AK7 30 mg/kg was injected <i>i.p.</i> 10 min before and 50 min after MPTP administration. Animals were sacrificed 7 days after the injection. Striatal DA (A) and metabolite DOPAC (B) were detected by HPLC-ECD (A&B, n = 8–10, *<i>p</i><0.05 vs CON; # <i>p</i><0.05 vs MPTP). (C) For determination of MPTP metabolism, mice were injected with MPTP and AK7 (10 min before and 50 min after MPTP) at indicated doses and sacrifice 90 min after MPTP treatment. MPP⁺ was detected in the striatum by HPLC (C, n = 5–6, ** ##, <i>p</i><0.01 vs corresponding MPTP control groups).</p

SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models.

There are currently no disease-modifying therapies for the neurodegenerative disorder Huntington's disease (HD). This study identified novel thiazole-containing inhibitors of the deacetylase sirtuin-2 (SIRT2) with neuroprotective activity in ex&nbsp;vivo brain slice and Drosophila models of HD. A systems biology approach revealed an additional SIRT2-independent property of the lead-compound, MIND4, as an inducer of cytoprotective NRF2 (nuclear factor-erythroid 2 p45-derived factor 2) activity. Structure-activity relationship studies further identified a potent NRF2 activator (MIND4-17) lacking SIRT2 inhibitory activity. MIND compounds induced NRF2 activation responses in neuronal and non-neuronal cells and reduced production of reactive&nbsp;oxygen species and nitrogen intermediates. These drug-like thiazole-containing compounds represent an exciting opportunity for development of multi-targeted agents with potentially synergistic therapeutic benefits in HD and related disorders