Sirtuin 2 is a member of the sirtuin family of proteins. It is a NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and alpha-tubulin as well as many other proteins such as key transcription factors. Sirtuin 2 participates in the modulation of multiple and diverse biological processes such as cell cycle control, genomic integrity, microtubule dynamics, cell differentiation, metabolic networks, and autophagy. It also plays a major role in the control of cell cycle progression and genomic stability.
AK-7 is a Sirtuin 2 selective inhibitor with IC50 of 15.5μM. At the concentration of 10μM, AK-7 reduced cholesterol levels in naive N2a neuroblastoma cells and hippocampal slice cultures from wild-type mice. At the concentration of 1μM , AK-7 showed neuroprotective effect in striatal Huntington’s disease neurons[3]. When i.p. administrated at the dose of 10mg/kg or 20mg/kg, AK-7 improved the behavior and neuropathological phenotype and extended survival of R6/2 HD mice. At the dose of 20mg/kg, AK-7 ameliorated HD neuropathology in R6/2 mice[4]. At the dose of 20mg/kg, i.p. administrated AK7 was neuroprotective in a subacute MPTP mouse model of Parkinson’s disease and significant increase of α-tubulin aectylation in the striatum after AK7 treatment was confirmed[5].
作用机制
AK-7 is a Sirtuin 2 selective inhibitor with a NAD+ competitive mechanism. The binding of AK-7 to Sirtuin 2 was suggested through docking calculations[5].
AK-7 细胞实验
Cell Line
Concentration
Treated Time
Description
References
RAW 264.7 cells
25 µM
20 hours
To investigate the effect of SIRT2 inhibitor AK-7 on autophagy regulation in tolerant cells, results showed that AK-7 treatment increased beclin-1 and LC3b-II expression and reduced p62 accumulation.
Cells. 2021 Mar 26;10(4):731.
HEK293T cells
10 µM
24 hours
Study the effect of AK-7 on P38 acetylation level
Neoplasia. 2021 Jan;23(1):129-139.
Human ovarian teratocarcinoma (PA-1) cell line
12.5, 25, 50, 100, 200 µg/mL
24 hours
To evaluate the cytotoxic effect of AK-7 extract on the PA-1 cell line. Results showed a significant decrease in cell viability of the PA-1 cell line with increasing concentrations of AK-7 extract, with an IC50 value of 82.04 µg/mL.
Microorganisms. 2023 Oct 3;11(10):2480.
CD4+ T cells
0.1–10 µM
3 days
AK-7 increased the percentage of IL-2-producing CD4+ T cells in a dose-dependent manner.
Cell Mol Immunol. 2022 Jun;19(6):738-750.
Th17 cells
0.1–10 µM
3 days
AK-7 significantly reduced the differentiation of Th17 cells in a dose-dependent manner but did not affect the differentiation of Th1, Th2, or Treg cells or cell viability.
Cell Mol Immunol. 2022 Jun;19(6):738-750.
Neural stem/progenitor cells (NSPCs)
10 µM
every 3 days
To validate the inhibitory effect of AK-7 on ODEXs-promoted neurogenesis and synaptic protein expression
CNS Neurosci Ther. 2024 Mar;30(3):e14661.
Primary mesencephalic neuron/glia cultures
25 µM
To investigate the protective effect of AK-7 on dopaminergic neurons, results showed AK-7 significantly increased TH-IR cell counts
Drug Des Devel Ther. 2015 May 7;9:2553-63.
AK-7 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Sprague-Dawley rats
Aging-related Parkinson's disease model
Intranigral injection
1 µg/day/side or 5 µg/day/side
Administered on the first and eighth day of rotenone treatment
To investigate the protective effect of AK-7 on behavioral abnormalities and striatal dopamine depletion in aging rats, results showed AK-7 significantly improved behavioral abnormalities and striatal dopamine depletion
Drug Des Devel Ther. 2015 May 7;9:2553-63.
Mice
Huntington's disease Mice models
Intraperitoneal injection
10, 20, and 30 mg/kg
Twice daily, starting from 4 weeks of age
AK-7 treatment significantly improved motor function, extended survival, and reduced brain atrophy and mutant huntingtin aggregation in R6/2 and 140CAG mice.
Cell Rep. 2012 Dec 27;2(6):1492-7
Mice
Autoimmune encephalomyelitis (EAE) model
Intraperitoneal injection
20 mg/kg
Daily from 8 weeks of age to 16 weeks of age
AK-7 treatment significantly improved clinical scores and body weight loss in EAE mice, reduced the number of spinal cord-infiltrating CD4+ T cells and IL-17A-producing CD4+ T cells.
Cell Mol Immunol. 2022 Jun;19(6):738-750.
C57BL/6J mice
Chronic unpredictable mild stress (CUMS)-induced depression model
Intraperitoneal injection
20 mg/kg
Once daily for 2 weeks
Blocking SIRT2 reverses the antidepressant effects of ODEXs
CNS Neurosci Ther. 2024 Mar;30(3):e14661.
Sprague-Dawley rats
Hypoxic-ischemic white matter damage model
Intraperitoneal injection
20 mg/kg
Once daily for 5 consecutive days
AK-7 inhibited SIRT2 activity, reversing the protective effects of caffeine on hypoxic-ischemic white matter damage, as evidenced by reduced expression of myelinating and synaptic proteins.
CNS Neurosci Ther. 2022 Jul;28(7):1019-1032
Rats
Aging rats with increased neonatal iron intake
Intranigral injections
5 μg/side per day
Administered at postnatal days 540 and 570
AK-7 significantly diminished striatal dopamine depletion and improved behavior abnormalities
Neural Regen Res. 2014 Nov 1;9(21):1917-22
Rats
Aging rats with increased neonatal iron intake
Intranigral injections
5 μg/side per day
Injected at postnatal days 540 and 570
AK-7 significantly diminished striatal dopamine depletion and improved behavior abnormality
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