3-(1-azepanylsulfonyl)-n-(3-bromphenyl)benzamide and Parkinsonian-Disorders

Aging is a prominent risk factor for the occurrence and progression of Parkinson disease (PD). Aging animals are more significant for PD research than young ones. It is promising to develop effective treatments for PD through modulation of aging-related molecules. Sirtuin 2 (SIRT2), a strong deacetylase highly expressed in the brain, has been implicated in the aging process. In our present study, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 12mg/kg once daily) was observed to bring about significant behavioral deficits and striatal dopamine depletion in aging male and female mice, while it did not do so in young animals. MPTP did not cause significant reduction in striatal 5-hydroxytryptamine content in aging male and female mice. Furthermore, we observed that MPTP treatment resulted in significant reduction in GSH content and significant increase in MDA content and SIRT2 expression in the substantia nigra (SN) of aging mice, while it did not do so in young animals. Importantly, we observed that AK-7 (a selective SIRT2 inhibitor) significantly improved behavior abnormality and neurochemical deficits in aging male and female mice treated with MPTP. Significant increase in GSH content and significant decrease in MDA content were also observed in the SN of aging male and female mice co-treated with MPTP and AK-7 compared with the MPTP-treated animals. Our results indicated that MPTP induce aging-related neurochemical and behavioural deficits and dysfunction of redox network in male and female mice and AK-7 may be neuroprotective in PD through modulating redox network.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Aging; Animals; Behavior Rating Scale; Benzamides; Corpus Striatum; Disease Models, Animal; Dopaminergic Neurons; Female; Glutathione; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Oxidation-Reduction; Parkinsonian Disorders; Sirtuin 2; Substantia Nigra; Sulfonamides

Aging is one of the strongest risk factors for Parkinson's disease (PD). SIRT2 has been implicated in the aging process. It is pertinent to investigate the role of SIRT2 in aging-related dopaminergic neurotoxicity and to develop effective therapeutic strategies for PD through the use of aging animals. In this study, we observed that rotenone induced significant behavior abnormality and striatal dopamine depletion in aging rats, while it did not do so in young rats. No significant change in striatal serotonin level was observed in the aging rats after rotenone administration. There was also aging-related rotenone-induced increase in substantia nigra (SN) SIRT2 expression in the rats. In addition, there was aging-related rotenone-induced SN malondialdehyde (MDA) increase and glutathione (GSH) decrease in the rats. No significant changes in cerebellar SIRT2, MDA, or GSH levels were observed in the aging rats after rotenone administration. Striatal dopamine content was significantly inversely correlated with SN SIRT2 expression in the rats. AK-7 significantly diminished striatal dopamine depletion and improved behavior abnormality in the rotenone-treated aging rats. Furthermore, AK-7 significantly decreased MDA content and increased GSH content in the SN of rotenone-treated aging rats. Finally, the effect of AK-7 on dopaminergic neurons and redox imbalance was supported by the results from primary mesencephalic cultures. Our study helps to elucidate the mechanism for the participation of aging in PD and suggests that SN SIRT2 may be involved in PD neurodegeneration, that AK-7 may be neuroprotective in PD, and that maintaining redox balance may be one of the mechanisms underlying neuroprotection by AK-7.

Topics: Aging; Animals; Benzamides; Corpus Striatum; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Male; Neuroprotective Agents; Oxidation-Reduction; Parkinsonian Disorders; Rats; Rats, Sprague-Dawley; Rotenone; Sirtuin 2; Substantia Nigra; Sulfonamides