Single Administration of the T-Type Calcium Channel Enhancer SAK3 Reduces Oxidative Stress and Improves Cognition in Olfactory Bulbectomized Mice.

Dian Yuan,Ichiro Kawahata,Kohji Fukunaga,Jing Xu,Hisanao Izumi,An Cheng

doi:10.3390/ijms22020741

Abstract

Alzheimer’s disease (AD), characterized by cognitive impairments, is considered to be one of the most widespread chronic neurodegenerative diseases worldwide. We recently introduced a novel therapeutic agent for AD treatment, the T-type calcium channel enhancer ethyl-8-methyl-2,4-dioxo-2-(piperidin-1-yl)-2H-spiro[cyclopentane-1,3-imidazo[1,2-a]pyridin]-2-ene-3-carboxylate (SAK3). SAK3 enhances calcium/calmodulin-dependent protein kinase II and proteasome activity, thereby promoting amyloid beta degradation in mice with AD. However, the antioxidative effects of SAK3 remain unclear. We investigated the antioxidative effects of SAK3 in olfactory bulbectomized mice (OBX mice), compared with the effects of donepezil as a positive control. As previously reported, single oral administration of both SAK3 (0.5 mg/kg, p.o.) and donepezil (1.0 mg/kg, p.o.) significantly improved cognitive and depressive behaviors in OBX mice. Single oral SAK3 administration markedly reduced 4-hydroxy-2-nonenal and nitrotyrosine protein levels in the hippocampus of OBX mice, which persisted until 1 week after administration. These effects are similar to those observed with donepezil therapy. Increased protein levels of oxidative stress markers were observed in the microglial cells, which were significantly rescued by SAK3 and donepezil. SAK3 could ameliorate oxidative stress in OBX mice, like donepezil, suggesting that the antioxidative effects of SAK3 and donepezil are among the neuroprotective mechanisms in AD pathogenesis.

Highlights

Alzheimer’s disease (AD) is one of the most common progressive neurodegenerative disorders worldwide and is the most common form of dementia
Vehicle-treated OBX mice had a reduced percentage of alternation (53.78 ± 2.434, p = 0.034) than the vehicle-treated sham mice; this alteration was significantly restored by SAK3 administration (0.5 mg/kg, 67.79 ± 2.977, p = 0.0318) or donepezil (1.0 mg/kg, 62.45 ± 6.411, p = 0.2161) (Figure 1B)
We propose that SAK3 acts competitively to rescue AD pathogenesis, benefiting from its efforts to suppress oxidative stress

Summary

Introduction

Alzheimer’s disease (AD) is one of the most common progressive neurodegenerative disorders worldwide and is the most common form of dementia. Over the past few years, a large number of studies have indicated that oxidative stress is closely associated with the etiology and pathology of neuronal degeneration and cell death in the brain of patients with AD [4]. In early AD, which is characterized by mild cognitive impairment, protein oxidation is significantly increased in the hippocampus prior to the deposition of Aβ [5]. Previous investigations have reported that donepezil plays a key role in restoring redox homeostasis by inhibiting the activation of the enzyme, acetylcholinesterase, displaying antioxidative effects in patients with AD [6]. Our previous research revealed that oral administration of glutathione, a potent antioxidant drug, ameliorated elevated oxidative stress in the brains of AD mice and rescued cognitive impairments observed in behavioral tests [7]

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Results

Conclusion