9-Me-BC powder (9-methyl-beta-carboline)

A screen of β-carbolines for neurotoxicity. 9-Me-BC turned out to be the first member of the class with the opposite profile: it lowered basal lactate dehydrogenase release, reduced the number of propidium iodide-stained cells, decreased caspase-3 activity and raised ATP content while total protein stayed unchanged. The number of differentiated dopaminergic neurons rose significantly, and transcription of Shh, Wnt1, Wnt5a, En1, En2, Nurr1, Pitx3, Th, Dat and Aldh1a1 increased. Expression of inflammation-related genes fell. Dopamine uptake capacity rose; dopamine content rose non-significantly. An anti-proliferative effect was seen in SH-SY5Y neuroblastoma.

TH expression rose in pre-existing DOPA decarboxylase-positive neurons together with the transcription factors Gata2, Gata3, Creb1 and Crebbp, and neurite outgrowth increased. The compound protected cultures against 2,9-dimethyl-β-carbolinium toxicity and restored neurons after chronic rotenone exposure. The anti-inflammatory component was suppression of activated microglial proliferation and reduced expression of inflammatory cytokine and receptor genes. α-Synuclein protein fell despite increased expression of its gene, which the authors attribute to faster protein turnover. Blocking the dopamine transporter abolished the gain in neuron number but further increased neurite outgrowth.

Animals received the neurotoxin MPP⁺ for 28 days at a dose that lowered dopamine by roughly 50%. 9-Me-BC was then delivered into the left cerebral ventricle for 14 days. It reversed the dopamine loss in the left striatum, and stereological counts of TH-immunoreactive cells in the substantia nigra returned to normal values. Complex I activity in striatal mitochondria was about 80% higher than in the MPP⁺ plus saline group and in sham-operated animals. GDNF and BDNF expression increased.

Ten days of treatment improved spatial learning in the radial maze, raised dopamine levels in the hippocampal formation, and produced longer, more complex dendritic trees with more spines on dentate gyrus granule neurons. A five-day course produced none of these effects — the result depends on duration, not dose alone.

IC₅₀ was 1 µM for MAO-A and 15.5 µM for MAO-B (rasagiline, for comparison, gives 412 nM and 4.43 nM). The maximum gain in TH-positive neurons was 33 ± 8% at 90 µM; at 70 µM the 27 ± 7% gain was unaffected by sulpiride, so D2/D3 receptors are not involved. The PI3K inhibitor LY294002 abolished the effect completely. In cortical astrocytes, 90 µM raised Artn expression 3.2-fold, Bdnf twofold, Ntf3 1.8-fold, Skp1 1.5-fold, and Tgfb2 and Ncam1 1.4-fold. There was no toxicity: viability rose 12% at 90 µM and 20% at 150 µM, and LDH release fell to 73% of control. Astrocyte proliferation was instead suppressed — BrdU incorporation dropped by 39 ± 4% at 90 µM and 71 ± 6% at 150 µM.