9-Methyl-beta-carboline has restorative effects in an animal model of Parkinson's disease.
In a previous study, a primary culture of midbrain cells was exposed to 9-methyl-beta-carboline for 48 h, which caused an increase in the number of tyrosine hydroxylase-positive cells. Quantitative RT-PCR revealed increased transcription of genes participating in the maturation of dopaminergic neurons. These in vitro findings prompted us to investigate the restorative actions of 9-methyl-beta-carboline in vivo. The compound was delivered for 14 days into the left cerebral ventricle of rats pretreated with the neurotoxin 1-methyl-4-phenyl-pyridinium ion (MPP+) for 28 days applying a dose which lowered dopamine by approximately 50%. Interestingly, 9-methyl-beta-carboline reversed the dopamine-lowering effect of the neurotoxin in the left striatum. Stereological counts of tyrosine hydroxylase-immunoreactive cells in the substantia nigra revealed that the neurotoxin caused a decrease in the number of those cells. However, when treated subsequently with 9-methyl-beta-carboline, the number reached normal values. In search of an explanation for the restorative activity, we analyzed the complexes that compose the respiratory chain in striatal mitochondria by 2-dimension gel electrophoresis followed by MALDI-TOF peptide mass fingerprinting.We found no changes in the overall composition of the complexes. However, the activity of complex I was increased by approximately 80% in mitochondria from rats treated with MPP+ and 9-methyl-beta-carboline compared to MPP+ and saline and to sham-operated rats, as determined by measurements of nicotinamide adenine dinucleotide dehydrogenase activity. Microarray technology and single RT-PCR revealed the induction of neurotrophins: brain-derived neurotrophic factor, conserved dopamine neurotrophic factor, cerebellin 1 precursor protein, and ciliary neurotrophic factor. Selected western blots yielded consistent results. The findings demonstrate restorative effects of 9-methyl-beta-carboline in an animal model of Parkinson's disease that improve the effectiveness of the respiratory chain and promote the transcription and expression of neurotrophin-related genes.
Wernicke
Catrin
C
Department of Psychiatry, CCM, Charité-University Medicine Berlin, Dorotheenstr. 94, 10117 Berlin, Germany. catrin.wernicke@charite.de
Hellmann
Julian
J
Zieba
Barbara
B
Kuter
Katarzyna
K
Ossowska
Krystyna
K
Frenzel
Monika
M
Dencher
Norbert A
NA
Rommelspacher
Hans
H
D000465:Algorithms; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D002243:Carbolines / Q000627:therapeutic use*; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D007150:Immunohistochemistry; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D017072:Neostriatum / Q000378:metabolism / Q000473:pathology; D009414:Nerve Growth Factors / Q000096:biosynthesis; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010302:Parkinson Disease, Secondary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013378:Substantia Nigra / Q000201:enzymology / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C529608:9-methyl-beta-carboline; D000978:Antiparkinson Agents; D002243:Carbolines; D009414:Nerve Growth Factors; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine