The protective effect of TND1128, with self-redox ability, on Ca2+
overloaded mouse brain slice and its comparison with β-NMN.
Abstract
Background and purpose: We have no definitive treatment for dementia
characterized by prolonged neuronal death due to cerebrovascular
degeneration or the enormous accumulation of foreign matters, such as
β-amyloid. Since these diseases develop slowly, we may be able to delay
the onset and improve these symptoms by enhancing the energy metabolism
of individual neurons to assist their viabilities. We examined the
effect of TND1128, a derivative of 5-deazaflavin, proven to have the
self-redox ability as a possible candidate for a direct activator for
mitochondrial energy synthesis. Experimental Approach: We prepared brain
slices obtained from mice 22 ± 2 hours pretreated with TND1128 or β−ΝΜΝ
used as an active control. We measured Ca2+ concentrations in the
cytoplasm ([Ca2+]cyt) and mitochondria ([Ca2+]mit) by using
fluorescence Ca2+ indicators, Fura4F, and X-rhod-1, respectively, and
examined the protective effects of TND1128 and β−ΝΜΝ on overloaded
cytosolic and mitochondrial Ca2+ by repeating 80K exposure. Key Results:
TND1128 (0.01, 0.1, and 1 mg/kg s.c.) mitigates the dynamics of both
[Ca2+]cyt and [Ca2+]mit in a dose-dependent manner. β−ΝΜΝ (10,
30, and 100mg/kg s.c.) showed significant dose-dependent facilitatory
effects on the recovery of [Ca2+]cyt during washing for 5 minutes.
However, there was no significant effect on the [Ca2+]mit dynamics.
Conclusion and implications: TND1128 works as a cofactor for activating
cellular energy production machinery. TND1128 would rescue deteriorating
neurons in various cerebrovascular disorder-related diseases, including
Alzheimer’s disease and Parkinson’s disease. Furthermore, TND1128 will
rescue patients with disorders of respiratory organs, such as pulmonary
emphysema and COVID-19, which causes respiratory disability