Prevention and restoration of lactacystin-induced nigrostriatal dopamine neuron degeneration by novel brain-permeable iron chelators

Dysfunction of the ubiquitin- proteasome system ( UPS) and accumulation of iron in substantia nigra ( SN) are implicated in the pathogenesis of Parkinson's disease ( PD). UPS dysfunction and iron misregulation may reinforce each other's contribution to the degeneration of dopamine ( DA) neurons. In the present study, we use a new brain- permeable iron chelator, VK- 28 [ 5-( 4-( 2- hydroxyethyl) piperazin- 1- yl ( methyl)- 8- hydroxyquinoline], and its derivative M30 [ 5-( N- methyl- N- propargyaminomethyl)- 8- hydroxyquinoline] in vivo to test their neuroprotective and neurorestorative properties against proteasome inhibitor ( lactacystin) - induced nigrostriatal degeneration. Bilateral microinjections of lactacystin ( 1.25 mu g/side) into the mouse medial forebrain bundle were performed. Administration of VK- 28 ( 5 mg/ kg, once a day) or M30 ( 5 mg/ kg, once a day) was applied intraperitoneally 7 days before or after the lactacystin microinjection until the mice were sacrificed 28 days after microinjection. We found that VK- 28 and M30 both significantly improved behavioral performances and attenuated lacta-cystin-induced DA neuron loss, proteasomal inhibition, iron accumulation, and microglial activation in SN. In addition, M30 restored the Bcl-2 level, which was suppressed after lactacystin injection. These findings suggest that brain- permeable iron chelators can improve DA neuron survival under UPS impairment. Furthermore, M30, a derivative of VK- 28 and neuroprotective agent rasagiline, may serve as a better neuroprotective therapy for PD.