PF-9601N

The current treatments for advanced prostate adenocarcinoma (PAC) include the androgen receptor antagonist enzalutamide and docetaxel‐based chemotherapy. Elevated monoamine oxidase‐A (MAO‐A) mRNA expression and activity in tumorous prostate positively correlate with disease progression and therapy resistance. While MAO‐B mRNA expression was also demonstrated in PAC cell lines, its role remained unclear. Therefore, this study evaluates the effects of the irreversible MAO‐B inhibitor selegiline and rasagiline and their combinations with conventional therapies on androgen‐insensitive (PC‐3, DU145) and androgen‐sensitive (22Rv1, LNCaP, VCaP) PAC cell lines. MAO activity was determined by the MAO‐Glo luminescence assay, viability by the ATP‐based chemiluminescence method, proliferation by the Luna‐II automated cell counter, and mRNA expressions by RT‐qPCR. MAO‐B mRNA was stably expressed by all PAC cell lines, with the highest expression in 22Rv1 and LNCaP cells. Selegiline reduced MAO‐B activity by 75%–80% and decreased cell counts by 40%–50% at 100 μM in PC‐3 and 22Rv1 cells. Selegiline concentration‐dependently inhibited cell proliferation (100 μM–10 mM) and reduced viability (1–10 mM) similar to rasagiline in all cell lines. Combination with enzalutamide in 22Rv1, and with docetaxel in PC‐3 demonstrated potentiating and additive effects, respectively. Selegiline reduced FOXA1 and GLUT1 mRNA expressions related to cancer progression and metabolism in both cell lines, increased the apoptosis‐related BAX in PC‐3, and decreased AR, EGFR, and SNAI2 in 22Rv1 linked to proliferation and metastasis. These findings suggest potential for selegiline repurposing in both androgen‐sensitive and ‐insensitive PAC therapy by promoting apoptosis and inhibiting cancer growth and survival signals, respectively.

Despite advances in disease‐modifying drugs, better treatments for symptomatic Alzheimer's disease (AD) are needed, with dopaminergic neurotransmission representing a potential target. The objective of this systematic review and meta‐analysis was to evaluate the efficacy of drugs with predominantly dopaminergic action in improving cognitive symptoms in AD.

The MEDLINE, Embase, and ClinicalTrials.gov databases were searched from 1980 to January 2023. We used random effect models to generate pooled effect estimates

We included 19 prospective randomized controlled AD trials (1408 total participants), of which 7 were of “good” quality, 8 “fair,” and 4 “poor.” All were included in the analysis. The overall pooled effect was small but showed a significant positive effect of dopaminergic drugs compared to placebo (standardized mean difference [SMD]: 0.33, 95% confidence interval [CI]: 0.08 to 0.59, P = 0.01; I2 = 79%). Significance remained after removing outliers to account for heterogeneity. When exploring subgroups (divided by mechanism of action), 5 trials of dopamine reuptake inhibitors did not show a significant effect on cognition, whereas 12 monoamine oxidase B (MAO‐B) inhibitor trials showed a moderately significant positive effect (SMD: 0.52, 95% CI: 0.13 to 0.90, P = 0.01; I2 = 84%).

We show evidence of the benefit of dopaminergic medications, specifically MAO‐B inhibitors, on cognitive symptoms in AD. Several studies included here also used drugs with both noradrenergic and dopaminergic action, highlighting a potential dual stimulation that could lead to better clinical efficacy. Trials targeting well‐defined patient populations, ideally supported by biomarker evidence of dopaminergic dysfunction, are needed to compare noradrenergic and dopaminergic agents—both separately and in combination—on cognitive function to maximize treatment effects. Particularly, further research should explore the impact of MAO‐B drugs on specific aspects of cognitive function to better understand their mechanism given the upregulation of MAO‐B expression in AD.

We conducted a meta‐analysis investigating the efficacy of dopaminergic drugs in improving cognitive symptoms in Alzheimer's disease (AD).Our findings highlight the potential cognitive benefits of dopaminergic medications, particularly monoamine oxidase B inhibitors, in AD.Future trials are warranted and could focus on biomarker‐defined patient groups to enhance effectiveness.