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.