Medicinal plants belonging to the Verbenaceae family demonstrated antidepressant effects in preclinical studies. Depression is one of the largest contributors to the global health burden of all countries. Plants from the Aloysia genus are traditionally used for affective disorders, and some of them have proven anxiolytic and antidepressant activity. The aim of this work was to evaluate the antidepressant effect of the ethanolic extract of Aloysia gratissima var. gratissima (Agg) and Aloysia virgata var. platyphylla (Avp) in mice. A tail suspension test (TST) and forced swimming test (FST) were conducted after three doses in a period of 24 h and after 7 days of treatment. Imipramine was used as an antidepressant drug. The main results demonstrated that Agg extract reduced the immobility time in mice treated orally for 7 consecutive days when compared to the control group (reduced by about 77%, imipramine 70%). Animals treated with three doses of Avp in a 24-h period had reduced immobility time in the FST (60%), and after 7 days of treatment the reduction was greater (Avp 50, 100, and 200 about 85%; Avp 400, 96.5%; p < 0.0001, imipramine, 77%). LCMS analysis showed the presence of verbascoside, hoffmaniaketone, and hoffmaniaketone acetate in both, A. virgata var. platyphylla and A. gratissima var gratissima. The flavonoids nepetin and 6-hydroxyluteolin were also found in Agg. Both tested extracts demonstrated promising antidepressant-like activity in mice.

Humanity is facing a vast prevalence of neurodegenerative diseases, with Alzheimer’s disease (AD) being the most dominant, without efficacious drugs, and with only a few therapeutic targets identified. In this scenario, we aim to find molecular entities that modulate imidazoline I₂ receptors (I₂-IRs) that have been pointed out as relevant targets in AD. In this work, we explored structural modifications of well-established I₂-IR ligands, giving access to derivatives with an imidazole-linked heterocycle as a common key feature. We report the synthesis, the affinity in human I₂-IRs, the brain penetration capabilities, the in silico ADMET studies, and the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of this new bunch of I₂-IR ligands. Selected compounds showed neuroprotective properties and beneficial effects in an in vitro model of Parkinson’s disease, rescued the human dopaminergic cell line SH-SY5Y from death after treatment with 6-hydroxydopamine, and showed crucial anti-inflammatory effects in a cellular model of neuroinflammation. After a preliminary pharmacokinetic study, we explored the action of our representative 2-(benzo[b]thiophen-2-yl)-1H-imidazole LSL33 in a mouse model of AD (5xFAD). Oral administration of LSL33 at 2 mg/Kg for 4 weeks ameliorated 5XFAD cognitive impairment and synaptic plasticity, as well as reduced neuroinflammation markers. In summary, this new I₂-IR ligand that promoted beneficial effects in a well-established AD mouse model should be considered a promising therapeutic strategy for neurodegeneration.

Background: Medicinal plants are part of traditional medicine and should be considered a therapeutic alternative for mental diseases. Several plants belonging to the Verbenaceae family have proved useful in treating general anxiety disorders, the most prevalent psychiatric disorders. Objective: This research aimed to verify the extract’s safety, the effect on general behavior, and the effect on sleeping time, as well as to evaluate the anxiolytic-like effect of the methanol extract of Aloysia virgata var. platyphylla (Avp), in mice. Methodology: The toxicity test was done according to the OECD guide (mice groups n=5), and general behavior was observed during the assay. Sleeping time was assessed using the pentobarbital-induced hypnosis method (n=8). Male Swiss albino mice (n=6) were treated with 50 to 400 mg/kg of Avp extract and diazepam as a control. The anxiolytic-like effect was tested through the hole board and elevated plus-maze test. Results: The Avp extract has no side effects in tested doses, and no central nervous system depressant activity was noted. A. virgata var. platyphylla increased exploration (number and time) in the hole board. In the elevated plus-maze, increased number and time into open arms were evidenced compared to the control group. Conclusion: With all these results, we concluded that the Avp extract is safe and has a potential anxiolytic-like activity in the animal model used.

Neurodegenerative diseases such as Alzheimer’s (AD) and Huntington’s (HD) remain major therapeutic challenges due to limited treatment efficacy. Imidazoline I2 receptor (I2-IR) ligands have recently emerged as promising neuroprotective agents, with reported roles in modulating oxidative stress, neuroinflammation, and protein aggregation. This study evaluates the therapeutic potential of several I2-IR ligands, including Idazoxan, CR4056, and novel compounds, using Caenorhabditis elegans (C. elegans) models of AD and HD. Transgenic strains CL2006 (expressing human Aβ1-42) and EAK103 (expressing Ht513) were employed to assess locomotor activity, oxidative stress tolerance, Aβ and Ht aggregation, and sod-1 gene expression. Several ligands significantly improved movement, reduced Aβ and Ht aggregates, and enhanced antioxidant gene expression, particularly Idazoxan, LSL42, and PIP01. Notably, some compounds exhibited prooxidant effects, highlighting the utility of C. elegans for early in vivo toxicity screening. Importantly, this study provides the first in vivo evidence of the efficacy of I2-IR ligands in HD models and reinforces their potential as therapeutic candidates for HD. Overall, these findings suggest a potential role for modulation of I2-IR-related pathways in neurodegeneration and support the utility of C. elegans as a rapid, cost-effective platform for preclinical drug evaluation.