Novel Sites of Neuroprotective Action of Dimebon (Latrepirdine)

Abstract

Dimebon (latrepirdine) is an anti-histaminergic agent which belongs to a fast-growing group of "old" medicines suggested to be of therapeutic utility for pathological conditions different from their original design ("repositioning"). Here, we overview the most recent studies on Dimebon directed to pathological processes in the brain-involving in vivo models of proteinopathies. In the latter, neurodegenerative effects are attributed to a group of aggregate-prone proteins such as γ-synuclein, hyperphosphorylated tau, and fused in sarcoma (FUS), which are engaged in numerous neurological diseases. We also focus on in vitro models comprised of cultured SH-SY5Y neuroblastoma cells expressing mutant forms of transactive response DNA binding protein 43 kDa (TDP-43) and showing a reduced number of TDP-43 inclusion-containing cells upon Dimebon treatment along with activation of autophagy markers. Finally, we discuss Dimebon's action in improving cellular energy balance, stabilizing mitochondrial function by increasing the threshold for nonselective mitochondrial pore opening, as well as increasing the calcium retention capacity of mitochondria and reducing lipid peroxidation. Our results, together with data from other laboratories, warrant re-evaluation of the therapeutic potential of Dimebon and its newly designed analogs as promising disease-modifying agents to treat neurodegenerative disorders. Further, emerging data favor a possible anti-aging effect and application of Dimebon for the treatment of depression, anxiety, and ischemia. The most pronounced effect of Dimebon is observed when treatment starts early in disease onset. This is a major factor which needs to be taken into account when planning future clinical trials.