In vitro studies with dopaminergic neuron cell cultures demonstrated
increased expression of tyrosine hydroxylase and associated
transcription factors, increased neurite outgrowth, regeneration of
neurons after chronic rotenone administration, and reduced expression of
inflammatory cytokines. In studies of primary mesencephalic
dopaminergic neuron cell cultures, the substance increased the number of
differentiated dopaminergic neurons and produced higher levels of
transcription factors associated with dopaminergic differentiation.[2]
9-Me-BC also inhibited the oxidation of the neurotoxin precursor MPTP to
the dopaminergic neurotoxin MPP+ in vitro.
Rodent studies in vivo demonstrated elevated hippocampal dopamine
levels, improved spatial learning performance in a radial maze test, and
increased dendrite outgrowth in the dentate gyrus of the hippocampus,
as well as restoration of the number of tyrosine hydroxylase expressing
neurons in the left striatum after an injection of MPP+ had reduced the
number of such cells by 50% in an animal model of Parkinsonism.
ß-Carbolines (BCs) belong to the heterogenous family of carbolines,
which have been found exogenously, that is, in various fruits, meats,
tobacco smoke, alcohol and coffee, but also endogenously, that is,
blood, brain and CSF. These exogenous and endogenous BCs and some of
their metabolites can exert neurotoxic effects, however, an unexpected
stimulatory effect of 9-methyl-ß-carboline (9-me-BC) on dopaminergic
neurons in primary mesencephalic cultures was recently discovered. The
aim of the present study was to extend our knowledge on the stimulatory
effects of 9-me-BC and to test the hypothesis that 9-me-BC may act as a
cognitive enhancer. We found that 10 days (but not 5 days) of
pharmacological treatment with 9-me-BC (i) improves spatial learning in
the radial maze, (ii) elevates dopamine levels in the hippocampal
formation, and (iii) results after 10 days of treatment in elongated,
more complex dendritic trees and higher spine numbers on granule neurons
in the dentate gyrus of 9-me-BC-treated rats. Our results demonstrate
that beyond its neuroprotective/neurorestorative and anti-inflammatory
effects, 9-me-BC acts as a cognitive enhancer in a hippocampus-dependent
task, and that the behavioral effects may be associated with a
stimulatory impact on hippocampal dopamine levels and dendritic and
synaptic proliferation.
