TY - JOUR
T1 - Comparison of neuroprotective and neurorestorative capabilities of rasagiline and selegiline against lactacystin-induced nigrostriatal dopaminergic degeneration
AU - Zhu, Wen
AU - Xie, Wenjie
AU - Pan, Tianhong
AU - Jankovic, Joseph
AU - Li, Jun
AU - Youdim, Moussa B.H.
AU - Le, Weidong
PY - 2008/6
Y1 - 2008/6
N2 - Nigrostriatal neurodegeneration in Parkinson's disease (PD) has been postulated to be caused by various pathological conditions, such as mitochondrial defects, oxidative stress, and ubiquitin-proteasome system (UPS) dysfunction. Pharmacological strategies designed to interfere with these pathological pathways may effectively counteract the degeneration. Rasagiline and selegiline are selective and irreversible monoamine oxidase-B inhibitors that possess significant protective properties on dopamine neurons in various pre-clinical models of PD. In the present study, the neuroprotective and neurorestorative effects of rasagiline and selegiline were compared in an animal model of PD produced by inhibition of the UPS. C57BL/6 male mice were microinjected bilaterally with UPS inhibitor lactacystin (1.25 μg/side), into the medial forebrain bundle. Administration of rasagiline (0.2 mg/kg, i.p. once per day) or selegiline (1 mg/kg, i.p. once per day), started 7 days before or after (up to 28 days) after lactacystin microinjection. We found that both rasagiline and selegiline exerted a significant neuroprotective effect against lactacystin-induced neurodegeneration; but only rasagiline managed to restore the nigrostriatal degeneration. Furthermore, rasagiline showed a modest protection against lactacystin-induced inhibition of proteasomal activity. Our study indicates that compared with selegiline, rasagiline is more potent in protecting neurodegeneration induced by UPS impairment and may, therefore, exert disease-modifying effects in PD.
AB - Nigrostriatal neurodegeneration in Parkinson's disease (PD) has been postulated to be caused by various pathological conditions, such as mitochondrial defects, oxidative stress, and ubiquitin-proteasome system (UPS) dysfunction. Pharmacological strategies designed to interfere with these pathological pathways may effectively counteract the degeneration. Rasagiline and selegiline are selective and irreversible monoamine oxidase-B inhibitors that possess significant protective properties on dopamine neurons in various pre-clinical models of PD. In the present study, the neuroprotective and neurorestorative effects of rasagiline and selegiline were compared in an animal model of PD produced by inhibition of the UPS. C57BL/6 male mice were microinjected bilaterally with UPS inhibitor lactacystin (1.25 μg/side), into the medial forebrain bundle. Administration of rasagiline (0.2 mg/kg, i.p. once per day) or selegiline (1 mg/kg, i.p. once per day), started 7 days before or after (up to 28 days) after lactacystin microinjection. We found that both rasagiline and selegiline exerted a significant neuroprotective effect against lactacystin-induced neurodegeneration; but only rasagiline managed to restore the nigrostriatal degeneration. Furthermore, rasagiline showed a modest protection against lactacystin-induced inhibition of proteasomal activity. Our study indicates that compared with selegiline, rasagiline is more potent in protecting neurodegeneration induced by UPS impairment and may, therefore, exert disease-modifying effects in PD.
KW - Lactacystin
KW - Neuroprotection
KW - Neurorestoration
KW - Rasagiline
KW - Selegiline
KW - Ubiquitin-proteasome system
UR - http://www.scopus.com/inward/record.url?scp=43549107707&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=43549107707&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2008.05330.x
DO - 10.1111/j.1471-4159.2008.05330.x
M3 - Article
C2 - 18399960
AN - SCOPUS:43549107707
SN - 0022-3042
VL - 105
SP - 1970
EP - 1978
JO - Journal of neurochemistry
JF - Journal of neurochemistry
IS - 5
ER -