Rescue of dying neurons: a new action for deprenyl in MPTP parkinsonism.
Deprenyl slows the progression of disabling symptoms in Parkinson's disease (PD) by an unknown mechanism. It can block the action of MPTP on substantia nigra compacta (SNc) neurons by inhibiting monoamine oxidase B necessary to mediate the conversion of MPTP to MPP+, its active metabolite, in astroglia. Mice were pretreated with saline or the PD-producing toxin, MPTP (30 mg/kg) daily for 5 days and then after a further 3 days (to allow for the metabolism and excretion of the MPTP) were treated with deprenyl (0.25 or 10 mg/kg) or saline 3 times weekly for 20 days. In three series of mice treated with MPTP alone or MPTP-saline, serial sections through the SNc showed that averages of 37-42% of tyrosine hydroxylase (TH) immunoreactive neurons were lost gradually over 20 days. Joint counts of the numbers of TH-immunoreactive and Nissl-stained SNc somata from immediately adjacent sections established that the reductions in the numbers of TH-immunoreactive somata at 20 days after MPTP treatment represented neuronal death. Deprenyl treatment reduced the loss of TH-immunoreactive SNc neurons to averages of 14-16% for the 10-mg/kg and 0.25-mg/kg doses, respectively, and joint Nissl/TH counts for adjacent sections showed that reduction in the loss of TH-immunoreactive soma represented the rescue of SNc neurons that would have died by 20 days. The gradual loss of SNc neurons over the 20 days following MPTP exposure may reflect the toxin's axotomy-like effects on SNc neurons or the prolonged action of sequestered MPP+.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Physiology, Faculty of Medicine, University of Toronto, Ontario, Canada.
W G
WG
Tatton
C E
CE
Greenwood
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D012642:Selegiline / Q000494:pharmacology*; D012965:Sodium Chloride / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D012642:Selegiline; D012965:Sodium Chloride; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase