TY - JOUR
T1 - Prevention and restoration of lactacystin-induced nigrostriatal dopamine neuron degeneration by novel brain-permeable iron chelators
AU - Zhu, Wen
AU - Xie, Wenjie
AU - Pan, Tianhong
AU - Xu, Pingyi
AU - Fridkin, Mati
AU - Zheng, Hailin
AU - Jankovic, Joseph
AU - Youdim, Moussa B.H.
AU - Le, Weidong
PY - 2007/12
Y1 - 2007/12
N2 - 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 μg/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 lactacystin-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.
AB - 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 μg/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 lactacystin-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.
KW - M30
KW - Parkinson's disease
KW - Ubiquitin-proteasome system
KW - VK-28
UR - http://www.scopus.com/inward/record.url?scp=36849044036&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=36849044036&partnerID=8YFLogxK
U2 - 10.1096/fj.07-8386com
DO - 10.1096/fj.07-8386com
M3 - Article
C2 - 17690154
AN - SCOPUS:36849044036
SN - 0892-6638
VL - 21
SP - 3835
EP - 3844
JO - FASEB Journal
JF - FASEB Journal
IS - 14
ER -