Chronic Administration of Dimebon does not Ameliorate Amyloid-β Pathology in 5xFAD Transgenic Mice

Abstract

Dimebon has been tested as a potential modifier of Alzheimer's disease (AD), resulting in mixed clinical trial outcomes. Originally utilized as an antihistamine, Dimebon was later found to ameliorate AD symptoms in initial human trials. Although subsequent trials have reportedly failed to replicate these finding, there is a growing body of evidence that Dimebon might be neuroprotective in certain models of neurodegeneration. The precise mechanism by which Dimebon is thought to act in AD is unclear, though changes in receptor activity, mitochondria function, and autophagy activity have been proposed. It is thus necessary to test Dimebon in transgenic animal model systems to determine if and how the drug affects development and manifestation of pathology, and which pathogenic processes are altered. In the present study we treated mice harboring five familial mutations associated with hereditary AD (5xFAD line) with a chronic regime of Dimebon. The compound was not found to improve the general health or motor behavior of these mice, nor prevent accumulation of Aβ peptides in the brain. Modest changes in response to an anxiogenic task were, however, detected, suggesting Dimebon might improve behavioral abnormalities and cognition in disease in a mechanism independent of protecting against amyloidosis.

Voluntary running does not reduce neuroinflammation or improve non-cognitive behavior in the 5xFAD mouse model of Alzheimer’s disease

“…This may reflect the typical phenotypical differences that this AD model displays compared to wild-type mice in these two tests in sedentary control settings 35,36 . At 8 months of age, 5xFAD mice typically develop increased exploratory behavior in the Elevated plus maze, which correlates with the deposition of Aβ in the brain [35][36][37] . This increased exploratory behavior has been suggested to reflect disinhibitory tendencies, similar to what is seen in AD patients 35 .…”

Mitochondrial dysfunction in neurodegenerative diseases and the potential countermeasure

“…Several antioxidants such as creatine, coenzyme Q10, and mitochondrially‐targeted antioxidants/peptides seems to improve the patient's ankle mobility in PD clinical trials . However, most of the antioxidants, such as dimebon, seem to have beneficial effects in the AD preclinical research, but failed in the AD clinical trials . Since mitochondrial dysfunction occurs at the early stage of diseases, the method of pharmacological interventions should be considered.…”

“…78 However, most of the antioxidants, such as dimebon, seem to have beneficial effects in the AD preclinical research, but failed in the AD clinical trials. 79,80 Since mitochondrial dysfunction occurs at the early stage of diseases, the method of pharmacological interventions should be considered.…”

Mitochondria are an Important Target in the Search for new Drugs for the Treatment of Alzheimer′s Disease and Senile Dementia

“…Учитывая данные о митопротекторном и антиоксидантном эффектах димебона мы предположили и затем экспериментально подтвердили в опытах in vivo геропротекторные свойства димебона [67]. Димебон оказывает положительное влияние на метаболизм мозга стареющих крыс, в том числе и нормализуя потребление глюкозы [68]. Несмотря на имеющиеся в литературе данные об отсутствии снижения нерастворимых амилоидных агрегатов в мозге трансгенных животных с 5xFAD (модель БА), даже в этом исследовании была выявлена коррекция поведенческих нарушений -снижение тревожности у этих животных под влиянием димебона [69].…”