The overexpression of α-synuclein
(α-syn) and its aggregation
is the hallmark of Parkinson’s disease. The α-syn aggregation
results in the formation of Lewy bodies that causes neuronal cell
death. Therefore, the small molecules that can protect neuronal cells
from α-syn toxicity or inhibit the aggregation of α-syn
could emerge as anti-Parkinson agents. Herein, a library of methoxy-stilbenes
was screened for their ability to restore the cell growth from α-syn
toxicity, using a yeast strain that stably expresses two copies of
a chromosomally integrated human α-syn gene. Tetramethoxy-stilbene
4s
, a nonantioxidant, was the most capable of restoring cell
growth. It also rescues the more toxic cells that bear three copies
of wild-type or A53T-mutant α-syn, from cell growth block. Its
EC
50
values for growth restoration of the 2-copy wild-type
and the 3-copy mutant α-syn strains are 0.95 and 0.35 μM,
respectively. Stilbene
4s
mitigates mitochondrial membrane
potential loss, negates ROS production, and prevents nuclear DNA-fragmentation,
all hallmarks of apoptosis. However,
4s
does not rescue
cells from the death-inducing effects of Bax and βA4, which
suggest that
4s
specifically inhibits α-syn-mediated
toxicity in the yeast. Our results signify that simultaneous use of
multiple yeast-cell-based screens can facilitate revelation of compounds
that may have the potential for further investigation as anti-Parkinson’s
agents.
Methylphenidate (MPH) is among the main drugs prescribed to treat patients with attention-deficit and hyperactivity disease (ADHD). MPH blocks both the norepinephrine and dopamine reuptake transporters (NET and DAT, respectively). Our study was aimed at further understanding the mechanisms by which MPH could modulate neurotransmitter efflux, using ex vivo radiolabelled neurotransmitter assays isolated from rats. Here, we observed significant dopamine and norepinephrine efflux from the prefrontal cortex (PFC) after MPH (100 µM) exposure. Efflux was mediated by both dopamine and norepinephrine terminals. In the striatum, MPH (100 µM) triggered dopamine efflux through both sodium- and vesicular-dependent mechanisms. Chronic MPH exposure (4 mg/kg/day/animal, voluntary oral intake) for 15 days, followed by a 28-day washout period, increased the firing rate of PFC pyramidal neurons, assessed by in vivo extracellular single-cell electrophysiological recordings, without altering the responses to locally applied NMDA, via micro-iontophoresis. Furthermore, chronic MPH treatment resulted in decreased efficiency of extracellular dopamine to modulate NMDA-induced firing activities of medium spiny neurons in the striatum, together with lower MPH-induced (100 µM) dopamine outflow, suggesting desensitization to both dopamine and MPH in striatal regions. These results indicate that MPH can modulate neurotransmitter efflux in brain regions enriched with dopamine and/or norepinephrine terminals. Further, long-lasting alterations of striatal and prefrontal neurotransmission were observed, even after extensive washout periods. Further studies will be needed to understand the clinical implications of these findings.
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