Current Neuropharmacology - Volume 23, Issue 5, 2025

Age-related neurodegenerative diseases (NDs) pose a formidable challenge to healthcare systems worldwide due to their complex pathogenesis, significant morbidity, and mortality.

This comprehensive review aims to elucidate the central role of the microbiota-gut-brain axis (MGBA) in ND pathogenesis. Specifically, it delves into the perturbations within the gut microbiota and its metabolomic landscape, as well as the structural and functional transformations of the gastrointestinal and blood-brain barrier interfaces in ND patients. Additionally, it provides a comprehensive overview of the recent advancements in medicinal and dietary interventions tailored to modulate the MGBA for ND therapy.

Accumulating evidence underscores the pivotal role of the gut microbiota in ND pathogenesis through the MGBA. Dysbiosis of the gut microbiota and associated metabolites instigate structural modifications and augmented permeability of both the gastrointestinal barrier and the blood-brain barrier (BBB). These alterations facilitate the transit of microbial molecules from the gut to the brain via neural, endocrine, and immune pathways, potentially contributing to the etiology of NDs. Numerous investigational strategies, encompassing prebiotic and probiotic interventions, pharmaceutical trials, and dietary adaptations, are actively explored to harness the microbiota for ND treatment. This work endeavors to enhance our comprehension of the intricate mechanisms underpinning ND pathogenesis, offering valuable insights for the development of innovative therapeutic modalities targeting these debilitating disorders.

Psychotic disorders, characterized by altered brain function, significantly impair reality perception. The neurodevelopmental hypothesis suggests these disorders originate from early brain development disruptions. Glial-derived neurotrophic factor (GDNF) is crucial for neuronal survival and differentiation, especially in dopaminergic neurons, and shows promise in neurodegenerative and neuropsychiatric conditions.

This scoping review aims to examine the role of GDNF in schizophrenia spectrum disorders and substance-induced psychoses, integrating knowledge on the neurobiological mechanisms and therapeutic potential of GDNF.

A comprehensive literature search was conducted using PubMed and Scopus databases from January 2001 onwards. Data extraction focused on GDNF levels, cognitive function, antipsychotic treatment effects, and genetic studies.

The review included 25 studies (18 human, 7 animal). While some studies demonstrated inconsistent results regarding GDNF serum levels in schizophrenic patients, the majority reported correlations between GDNF levels and cognitive functions. Animal studies underscored GDNF's role in stress response, drug-induced neurotoxicity, and dopamine signaling abnormalities. Genetic studies revealed potential associations between GDNF gene polymorphisms and schizophrenia susceptibility, though findings were mixed.

GDNF plays a significant role in cognitive functions and neuroprotection in schizophrenia. The variability in study results underscores the complexity of GDNF's involvement. The therapeutic potential of GDNF in psychotic disorders remains unclear, necessitating further research to clarify its efficacy and safety.

This review emphasizes the importance of integrated biomarker strategies, gene therapy approaches, and precision medicine in advancing the understanding and treatment of psychotic disorders.

Worldwide, three million deaths each year are reported due to the harmful use of alcohol. To date, only a few drugs have been approved for the treatment of Alcohol Use Disorder (AUD). This systematic review and meta-analysis aim to assess the long-term efficacy and safety of sodium oxybate (SMO) treatment in patients with AUD.

We followed the PRISMA statement guidelines and searched PubMed and ISI Web of Science to retrieve the studies of interest. In total, 13 studies on long-term (>12 weeks) SMO administration in patients with AUD were included in this systematic review, and 7 were included in the meta-analysis.

Overall, the abstinence rate after 12 weeks of treatment was similar in the SMO and placebo groups, while it was significantly in favour of SMO compared to Naltrexone (NTX). The completion rate was similar in all three conditions. Mean corpuscular volume (MCV) levels favoured SMO over NTX, while Alcohol Craving Scale (ACS) scores did not favour SMO. The incidence of adverse reactions varied widely between studies.

SMO in the chronic treatment of patients with AUD showed no superiority to placebo in our analysis of published RCTs, although many observational studies reported its beneficial effect in the long term. On the contrary, SMO was superior to NTX treatment on abstinence. The rate of study completion was similar in the three groups. Safety was not an issue in any of the studies included. Further studies are needed to better assess SMO efficacy and safety in the long term.

Oral cancer causes intense pain at the primary site, and such pain can impair oral functions. However, the underlying mechanisms for oral cancer pain are still not fully understood. In the present study, it is investigated whether programmed cell death protein 1 (PD-1) is involved in the development of oral cancer pain.

RMP1-14, a specific anti-PD-1 antibody, was injected into spinal trigeminal nucleus caudalis (Sp5C) and measured pain behaviors using von Frey filaments and dolognawmeter. Western blotting and immunofluorescence staining were performed to analyze the expression of PD-1 and tumor necrosis factor alpha (TNFα) in the Sp5C.

It was observed that the PD-1 antibody significantly inhibited mechanical hypersensitivity and functional allodynia in our oral cancer pain mouse model. Moreover, we found that TNFα was highly upregulated in the Sp5C following the induction of oral cancer pain and that intra-Sp5C injection of the PD-1 antibody diminished the upregulation of TNFα. It was found that genetic deletion of TNFα or its receptor antagonism synergized the analgesic effect of PD-1 antibody on oral cancer pain.

Our results suggest that PD-1 in the Sp5C contributes to oral cancer pain by altering TNFα signaling in the trigeminal nociceptive system, and PD-1 could be targeted to develop a novel approach for oral cancer pain management.

The heterogenicity in Alzheimer’s Disease (AD) progression hinders individual prognosis. The present work is an observational 2-year longitudinal study in patients with mild cognitive impairment due to AD (n = 52, with positive CSF biomarkers). The aim of this study is to predict which patients are at risk of fast progression. For this, 3 neuropsychological tests based on different domains (clinical dementia, cognition, delayed memory) and the sum of them were used.

The tests were performed at diagnosis time (T1) and two years after the diagnosis time (T2). Then, the corresponding progression models were developed using each individual test and their sum as a variable response.

As a result, the model based on cognition status to predict fast decline (differences in the Z score (T2-T1) <1.5 were considered fast declining) provided satisfactory performance (AUC 0.74, 83.3% of sensibility and 70.2% of specificity); the models based on clinical dementia and delayed memory to predict fast declining showed low AUC and sensitivity. Nevertheless, the model based on the sum of the 3 tests showed the highest AUC (0.79), low sensitivity (63.6%), and high specificity.

The developed progression models could provide useful information to clinicians and AD patients regarding their fast/normal decline in general or specific domains.

Data on long-term treatment with Esketamine Nasal Spray (ESK-NS) in real-world patients with treatment resistant depression (TRD) is scarce. The primary aim of the study is to evaluate the effectiveness and tolerability of ESK-NS treatment at 6 and 12-month follow-ups.

This is part of an observational, retrospective, multicentric Italian study (REAL-ESK study). Subjects for the present study underwent psychiatric assessments after 6 and 12 months from the start of ESK-NS treatment. Repeated measures analysis of variance (ANOVA) was used to assess changes in continuous variables, such as scores on psychometric scales from baseline to follow-up time points.

Of 63 patients who maintained ESK-NS treatment for at least 6 months, 48 were responders or remitters (76.2%). Among 15 non-responders at 6 months, 4 significantly improved at 12-month follow-up. At least one side effect was reported by 71.8% of subjects with a 6-month follow-up assessment. An overall reduction of side effects was noticed as treatment progressed (42% of patients who continued the treatment reported side effects at 12 months). The most common side effects were sedation (31.7%) and dissociation (28.6%) during ESK-NS sessions. Only 2 patients discontinued ESK-NS for tolerability reasons.

The results support the effectiveness and safety of esketamine in the mid and long-term treatment of TRD patients. The late clinical response of a subgroup of patients represents a novel finding. Data needs to be confirmed in larger samples and longer observation periods.