竞争对手
陶氏病
药理学
乳酸脱氢酶
化学
内科学
内分泌学
丙酮酸脱氢酶复合物
医学
生物化学
痴呆
疾病
多奈哌齐
神经退行性变
酶
作者
Renato X. Santos,Valeria Melis,Elizabeth A Goatman,Michael Leith,Thomas C. Baddeley,John M. D. Storey,Gernot Riedel,Claude M. Wischik,Charles R. Harrington
出处
期刊:Biomedicines
[MDPI AG]
日期:2022-04-07
卷期号:10 (4): 867-867
标识
DOI:10.3390/biomedicines10040867
摘要
The tau protein aggregation inhibitor hydromethylthionine mesylate (HMTM) was shown recently to have concentration-dependent pharmacological activity in delaying cognitive decline and brain atrophy in phase 3 Alzheimer's disease (AD) clinical trials; the activity was reduced in patients receiving symptomatic therapies. The methylthionine (MT) moiety has been reported to increase the clearance of pathological tau and to enhance mitochondrial activity, which is impaired in AD patients. In line 1 (L1) mice (a model of AD), HMTM (5/15 mg/kg) was administered either as a monotherapy or as an add-on to a chronic administration with the cholinesterase inhibitor rivastigmine (0.1/0.5 mg/kg) to explore mitochondrial function and energy substrate utilization as potential targets of drug interference. Compared with wild-type NMRI mice, the L1 mice accumulated greater levels of l-lactate and of the LDH-A subunit responsible for the conversion of pyruvate into l-lactate. In contrast, the levels of LDH-B and mitochondrial ETC subunits and the activity of complexes I and IV was not altered in the L1 mice. The activity of complex I and complex IV tended to increase with the HMTM dosing, in turn decreasing l-lactate accumulation in the brains of the L1 mice, despite increasing the levels of LDH-A. The chronic pre-dosing of the L1 mice with rivastigmine partially prevented the enhancement of the activity of complexes I and IV by HMTM and the increase in the levels of LDH-A while further reducing the levels of l-lactate. Thus, HMTM in combination with rivastigmine leads to a depletion in the energy substrate l-lactate, despite bioenergetic production not being favoured. In this study, the changes in l-lactate appear to be regulated by LDH-A, since neither of the experimental conditions affected the levels of LDH-B. The data show that HMTM monotherapy facilitates the use of substrates for energy production, particularly l-lactate, which is provided by astrocytes, additionally demonstrating that a chronic pre-treatment with rivastigmine prevented most of the HMTM-associated effects.
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