Our recent studies demonstrated that
propargylamine derivatives such as
rasagiline (
Azilect, Food and Drug Administration-approved anti-Parkinson
drug) and its S-isomer
TVP1022 protect cardiac and neuronal cell cultures against apoptotic-inducing stimuli. Studies on structure-activity relationship revealed that their
neuroprotective effect is associated with the
propargylamine moiety, which protects mitochondrial viability and prevents apoptosis by activating Bcl-2 and
protein kinase C-epsilon and by down-regulating the proapoptotic
protein Bax. Based on the established cytoprotective and neuroprotective efficacies of
propargylamine derivatives, as well as on our recent study showing that
TVP1022 attenuates serum
starvation-induced and
doxorubicin-induced apoptosis in neonatal rat ventricular myocytes (NRVMs), we tested the hypothesis that
TVP1022 will also provide protection against
doxorubicin-induced NRVM functional derangements. The present study demonstrates that pretreatment of NRVMs with
TVP1022 (1 microM, 24 h) prevented
doxorubicin (0.5 microM, 24 h)-induced elevation of diastolic [Ca(2+)](i), the slowing of [Ca(2+)](i) relaxation kinetics, and the decrease in the rates of myocyte contraction and relaxation. Furthermore, pretreatment with
TVP1022 attenuated the
doxorubicin-induced reduction in the
protein expression of sarco/endoplasmic reticulum
calcium (Ca(2+))
ATPase,
Na(+)/Ca(2+) exchanger 1, and total
connexin 43. Finally,
TVP1022 diminished the inhibitory effect of
doxorubicin on gap junctional intercellular coupling (measured by means of
Lucifer yellow transfer) and on conduction velocity, the amplitude of the activation phase, and the maximal rate of activation (dv/dt(max)) measured by the Micro-
Electrode-Array system. In summary, our results indicate that
TVP1022 acts as a novel
cardioprotective agent against
anthracycline cardiotoxicity, and therefore potentially can be coadmhence, theinistered with
doxorubicin in the treatment of
malignancies in humans.