In mice studies, it has been found to stimulate the growth of dopaminergic neurons and increase gene expression of severalneurotrophic factors in both dopamine-depleted and normal brain cultures.[2]
It has been proposed for further investigation in the treatment ofParkinson's disease.[3]
9-Me-BC also inhibited the oxidation of the neurotoxinprecursorMPTP to the dopaminergic neurotoxinMPP+in vitro[5] and displayed protective effects against the neurotoxin2,9-DiMe-BC+ (2,9-dimethyl-β-carbolinium);[1] although there are concerns about its chemical similarity to 9-Me-BC itself. These findings suggest that it could potentially defend against other dopaminergicneurotoxins as well.
The administration of the dopamine antagonistsulpiride which antagonizes D2 and D3 receptors did not have a significant effect on the observed increase of dopaminergic TH+ neurons after treatment with the chemical, suggesting that the neurostimulative effect of 9-Me-BC functions independently of these two receptors.[2]
When theDAT by which 9-Me-BC is taken up into and subsequently enters the neuron through is blocked, the observed proliferation of dopaminergic neurons was abolished, but neurite outgrowth was not.[1] This leads to the hypothesis that the neurite outgrowth perhaps functions through a separate mechanism such as through the uptake of 9-Me-BC into dopaminergicastrocyte cells via anorganic cation transporter (OCT),[2] rather than the DAT. The former result further substantiates that 9-Me-BC is indeed a substrate for the dopamine transporter.
Rodent studiesin vivo demonstrated elevatedhippocampaldopamine levels, improvedspatial learning performance in aradial maze test, and increaseddendrite outgrowth in thedentate gyrus of the hippocampus,[6] as well as restoration of the number of tyrosine hydroxylase expressing neurons in the leftstriatum after an injection of MPP+ had reduced the number of such cells by 50% in an animal model ofParkinsonism.[7]
Inin-vitro murinemidbrain cell cultures, a maximum 33% increase in the number of dopaminergic tyrosine hydroxylase neurons (TH+) after 48 hours of treatment with 9-Me-BC was observed. These effects were found at 90 μM of 9-Me-BC, while higher concentrations of 125 μM and 150 μM progressively decreased the number ofdopaminergic neurons.
In cortical dopaminergicastrocytes taken from mice, it significantly increased the gene expression ofbrain-derived neurotrophic factor (BDNF) by 2-fold. The study also found an increase in the expression ofNCAM1,TGF-β2,Skp1,neurotrophin 3, andartemin factors by 1.4-fold, 1.4-fold, 1.5-fold, 1.8-fold, and 3.2-fold respectively.[2] Skp1 may increase the turnover rate of theα-synuclein protein, whose accumulation is associated with Parkinson's disease.
Administration ofLY-294002, an inhibitor of thePi3K/Akt pathway, completely blocked the neurostimulative properties of 9-Me-BC to TH+ neurons, implying that this pathway is critical to its effect on neuronal growth.[2]
9-Me-BC is a knowninhibitor ofmonoamine oxidase A andmonoamine oxidase B, with IC50 values of 1 μM for MAO-A and 15.5 μM for MAO-B, suggesting that it is more selective for MAO-A like other beta-carbolines.[2]
^Polanski W, Reichmann H, Gille G (2011). "Stimulation, protection and regeneration of dopaminergic neurons by 9-methyl-β-carboline: a new anti-Parkinson drug?".Expert Rev Neurother.11 (6):845–860.doi:10.1586/ern.11.1.PMID21651332.S2CID24899640.
^Hamann J, Wernicke C, Lehmann J, Reichmann H, Rommelspacher H, Gille G (2008). "9-Methyl-β-carboline up-regulates the appearance of differentiated dopaminergic neurones in primary mesencephalic culture".Neurochem. Int.52 (4–5):688–700.doi:10.1016/j.neuint.2007.08.018.PMID17913302.S2CID24226033.
^Herraiz T, Guillén H (2011). "Inhibition of the bioactivation of the neurotoxin MPTP by antioxidants, redox agents and monoamine oxidase inhibitors".Food Chem. Toxicol.49 (8):1773–1781.doi:10.1016/j.fct.2011.04.026.hdl:10261/63126.PMID21554916.
^Wernicke C, Hellmann J, Zieba B, Kuter K, Ossowska K, Frenzel M, Bencher NA, Rommelspacher H (2010). "9-Methyl-beta-carboline has restorative effects in an animal model of Parkinson's disease".Pharmacol Rep.62 (1):35–53.doi:10.1016/s1734-1140(10)70241-3.PMID20360614.S2CID16729205.
^Vignoni M, Rasse-Suriani FA, Butzbach K, Erra-Balsells R, Epe B, Cabrerizo FM (2013). "Mechanisms of DNA damage by photoexcited 9-methyl-β-carbolines".Org Biomol Chem.11 (32):5300–9.doi:10.1039/c3ob40344k.hdl:11336/2178.PMID23842892.
