Current Neuropharmacology - Online First

Phenibut, a GABAB receptor agonist, is used for anxiety and insomnia but is limited by side effects like drowsiness and withdrawal symptoms. This study aimed to identify a novel GABAB receptor modulator with improved efficacy and safety.

A drug database of 15,000 compounds was screened using the Tanimoto similarity coefficient, identifying three candidates. Molecular docking and dynamics simulations assessed their binding affinity and stability with the GABAB receptor. The lead compound, 3-[(2-oxo-2-phenylethyl)amino]benzoic acid (C1), was tested in vivo using a stress-induced Wistar rat model (n=20, male, 200–250 g), with phenibut as a reference. Anxiety-like behaviour was evaluated via the elevated plus maze, and pharmacokinetic properties were analyzed.

C1 exhibited superior binding affinity (ΔGbind = -8.5 kcal/mol) and stability compared to phenibut (-8.0 kcal/mol). In vivo, C1 significantly increased open-arm time (110.80 ± 26.10 min) compared to phenibut (57.80 ± 9.40 min, p<0.05), indicating reduced anxiety-like behaviour. C1 also showed favourable oral bioavailability and blood-brain barrier permeability.

Consistently, C1 demonstrated superior performance compared to phenibut, suggesting its potential as a more effective alternative for GABAB receptor modulation.

C1 is a promising alternative to phenibut, demonstrating enhanced anxiolytic effects and a favourable safety profile. Further studies are warranted to confirm its clinical potential.

Opicapone is a peripheral catechol-O-methyltransferase inhibitor (COMT), approved an add on to levodopa in Parkinson's disease (PD) patients with motor fluctuations. We carried out a retrospective cohort study to evaluate gender differences in efficacy and tolerability of opicapone.

PD patients with motor fluctuations who started opicapone and who were followed up for at least 6 months were retrospectively enrolled. Total daily OFF (at baseline and follow-up), presence or worsening of dyskinesia, or presence of other adverse events (AE) at follow-up, were recorded.

Seventy-seven PD patients (51 men; 66.2%) with a disease duration of 11.0 ± 4.2 years were enrolled. At follow-up, a significant reduction of the total daily OFF time was observed in men with PD. Overall, 41.6% of PD patients reported some AEs, of which the presence or worsening of dyskinesia was the most common. Incidence of AEs was significantly higher among women (65.4% versus 29.4%; p-value 0.002) and at multivariate analysis, female sex was significantly associated with the presence of AEs (OR 4.08; 95% CI 1.46-11.4; p-value 0.007); At 6 months 27.3% patients discontinued opicapone and women had significantly higher odds of discontinuation (OR 3.00; p-value 0.04).

Opicapone is highly effective for the treatment of motor fluctuations. The occurrence of AEs is more frequent among women may be attributed to a higher levodopa bioavailability. To avoid an early discontinuation due to AEs, levodopa dosage should be reduced in women before the introduction of opicapone.

Our study provides novel insights regarding gender differences in PD treatment.

Depression is a common mental disorder, often accompanied by suicidal ideation (SI). Modified electroconvulsive therapy (MECT) is widely used as an effective treatment for severe depression, especially when pharmacotherapy has failed. However, concerns regarding the potential cardiovascular effects of MECT have prompted further investigation.

A total of 100 patients with depressive disorders undergoing MECT were recruited in this study. Among them, 70 had suicide ideation (SI group) and 30 did not (non-SI group). Electrocardiogram (ECG) recordings were obtained before MECT and on the second day after several sessions of MECT treatment.

After treatment with MECT, no significant differences were observed in ECG parameters, including PR intervals, QT intervals, and heart rates. However, a significant interaction between time and group on PR intervals was observed (F(1,98)=5.5, p=0.02). Specifically, patients in the non-SI group exhibited a slight increase in PR intervals compared with baseline values, whereas those in the SI group showed a slight decrease. More importantly, significant differences were observed between the SI and non-SI groups (Z= 2.3, p=0.02). Further linear regression analysis showed that, after controlling for gender and medication types (antidepressants versus antipsychotics), the presence of suicide ideation was independently associated with changes in PR intervals following MECT treatment (β= 0.20, t= 2.04, p= 0.04).

Our findings suggested a significant interaction between time and group on PR intervals after treatment with MECT in patients.

Considering that the within-group changes did not reach statistical significance, future research with a large sample size is warranted to focus on the differential effects of MECT on ECG indicators in depressed patients with or without suicide ideation.

Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive intervention that could effectively enhance the cognitive function in patients with amnestic mild cognitive impairment (aMCI). However, the mechanism and predictive biomarkers for therapeutic response remain poorly understood.

Fifty-three aMCI patients underwent either neuro-navigated rTMS (n=28) or sham stimulation (n=25) targeting the left angular gyrus over four weeks (registered in 2021: ChiCTR2100050496). Multimodal MRI and comprehensive neuropsychological assessments were conducted pre- and post-intervention. Changes in brain communication networks and their correlation with cognitive improvements were analysed, with random forest models applied to predict treatment efficacy.

Episodic memory (p<0.001) and general cognitive function (p<0.05) of aMCI patients were significantly improved after intervention. Novel alterations in brain communications networks were identified in 5 sensorimotor areas, executive control regions, and emotion-cognition processing hubs. Communication alterations between the right precentral gyrus and right angular gyrus were positively correlated with the improvements in episodic memory (r=0.38, p=0.046), while the alterations between right precentral gyrus and right angular gyrus were negatively correlated with improvements in general cognitive function (MMSE, r=-0.44, p=0.019; MoCA, r=-0.43, p=0.024). Notably, the random forest model integrating communication network patterns with baseline demographic and neuropsychological data showed strong power in predicting rTMS effects.

These findings advance understanding of rTMS mechanisms by linking network plasticity to cognitive gains, addressing critical knowledge gaps.

Neuro-navigated rTMS targeting the left angular gyrus may enhance cognitive function in aMCI patients by improving inter-brain regions communication. Baseline communication patterns hold promise as predictive biomarkers, facilitating personalized treatment strategies.

The mechanisms of neurodegeneration common to many neurodegenerative diseases include oxidative stress, mitochondrial dysfunctions, excitotoxicity, and others. Beyond the broad spectrum of strategies for developing neuroprotective agents that target stage-specific mechanisms in each neurodegenerative disease, considerable attention is also being given to approaches aimed at developing compounds that can effectively modulate general pathogenic mechanisms and enhance the overall resilience of neuronal cells to cell death induction.

This review discusses some of the results on new multitarget multipharmacophore agents with neuroprotective effects, particularly through their influence on mitochondrial permeability transition and antioxidant properties. We conducted comprehensive online searches on PubMed to gather the latest data on multitarget multipharmacophore agents consisting of pre-defined pharmacophores that have already demonstrated neuroprotective properties.

To create compounds with a desirable spectrum of biological activity, an approach based on the conjugation of specific structural fragments of pharmacologically active substances into a single molecular entity could be used. Core fragments of compounds that have already demonstrated neuroprotective properties due to mitochondrial and antioxidant mechanisms of action can be used as neuroactive scaffolds.

The combination of several pharmacophores in one molecule may not only result in the mere addition of the useful properties of each component, but may also give rise to new types of biological activity. The examples of the appearance of new properties in such multipharmacophore compounds, not inherent in the reference agents, discussed in our review, may be considered a prospective approach for creating a novel generation of neuroprotective agents.

Hyperprolactinemia (HPRL) can lead to various health complications. Among patients with Schizophrenia, it may be linked to antipsychotic medications and other contributing factors. Sex-based differences in HPRL have been observed, and its association with breast cancer in this population remains unclear.

To investigate overall and sex-specific risk factors for HPRL in patients with Schizophrenia and to examine the incidence of breast cancer in this population.

A retrospective cohort study was conducted among inpatients with Schizophrenia who underwent prolactin monitoring in a Chinese hospital. Participants were categorized into HPRL and non-HPRL groups, and binary logistic regression was performed to identify factors associated with HPRL.

Among 1,425 patients analyzed, the overall incidence of HPRL was 63.37%, with higher rates in females (67.99%) compared to males (57.31%). HPRL was positively associated with thyroid-stimulating hormone levels, repetitive transcranial magnetic stimulation frequency, female sex, and the use of first-generation antipsychotics, amisulpride, olanzapine, risperidone, paliperidone, perospirone, and trihexyphenidyl. Negative associations were found with aspartate aminotransferase, fasting plasma glucose, total bilirubin levels, and aripiprazole use. Sex-specific factors included thyroid-stimulating hormone and sulpiride use in men; olanzapine use in women; and differing associations of aspartate aminotransferase, direct bilirubin, age, and urea nitrogen depending on sex. Four female patients developed breast cancer.

Multiple pharmacological and non-pharmacological factors contribute to HPRL in patients with Schizophrenia, with notable sex-specific differences. The potential role of HPRL in breast cancer development among female patients requires further investigation.