Current Neuropharmacology - Volume 23, Issue 10, 2025

Mediterranean diet may enhance cognitive function and delay the progression of Alzheimer's disease (AD). We conducted a systematic review to investigate the effect of oleocanthal (OC) from extra-virgin olive oil (EVOO) on amyloid-β (Aβ) burden in preclinical models of AD, considering the anti-inflammatory and neuroprotective effects of EVOO biophenols, which are key components of the Mediterranean dietary model.

The literature was searched through six electronic databases until February 2023. Screening of 52 retrieved articles for inclusion criteria resulted in 7 preclinical reports evaluating the effect of an OC-supplemented diet on AD trajectories by means of Aβ load or clearance in affected models. Reports were appraised for risk of bias using the SYRCLE's RoB tool. A protocol was registered on PROSPERO.

Case control prevailed over the case-crossover design, and the geographical distribution was uniformly American. The study population mostly included 5xFAD, otherwise TgSwDI or wild-type C57BL/6 mouse models. We found a role of OC in reducing Aβ load in the hippocampal parenchyma and microvessels compared with controls. An increased cerebral clearance of Aβ through the blood-brain barrier and a substantial improvement in metabolic and behavioral parameters were also reported in preclinical models under an OC-enriched diet. The risk of bias was shown to be moderate overall.

Preclinical data are promising about the effects of OC from the Mediterranean diet's EVOO in relieving the burden of Aβ in AD; however, further evidence is needed to corroborate the efficacy of this biophenol and strengthen the speculated causal pathway.

Glutamate is implicated in playing a crucial role in modulating the complex pathophysiological mechanisms of migraines, including central or peripheral sensitization, cortical spreading depression, and pain transmission. With expanding knowledge over the last three decades, glutamate receptors have become focal points in neurological drug research. Altered plasma glutamate levels during migraines suggest a potential avenue for effective therapies targeting glutamate reduction. Furthermore, glutamate is believed to play a vital role in modulating the complex pathophysiological mechanisms underlying migraines.

This study aims to provide an overview of the ionotropic glutamate receptor antagonists (NMDA, AMPA, and Kainate receptors) and metabotropic glutamate receptors in the context of migraines. We explore the advantages and disadvantages of these receptor modulators as alternative treatments, considering efficacy, tolerability, and safety.

We conducted comprehensive online searches across various electronic databases, with a primary focus on PubMed and clinicaltrials.gov, to gather the latest treatment approaches and emerging concepts.

A total of 371 articles were identified from PubMed, along with 69 articles from clinicaltrials.gov. After refinement, 113 articles were included. We summarize seven different medications currently in clinical practice for migraines and highlight six items for migraine therapy in preclinical trials and their potential value.

It's crucial to note that these agents pose certain challenges in specific drug research due to their intricate influence and mechanisms of action within multiple neuronal pathways. Therefore, further studies are warranted to elucidate more specific glutamatergic signaling pathways for migraine therapy while minimizing interference with normal neuronal functions.

The objective of this study is to determine the characteristics of peripheral inflammatory profiles and their correlations with the clinical features in patients with cerebellar ataxia.

We conducted a cross-sectional study on a cohort of 140 cerebellar ataxia patients, including 74 patients with spinocerebellar ataxia (SCA), 66 patients with multiple system atrophy with predominant cerebellar ataxia (MSA-C), and 145 healthy controls (HCs). Inflammatory profiles (PLT, MPV, NLR, PLR, MLR, SII, AISI and ESR) were measured in peripheral blood, and were compared by ANOVA and Kruskal-Wallis test. The receiver operating characteristic (ROC) curve and the area under curve (AUC) were performed to determine the sensitivity and specificity of the inflammatory markers. Spearman correlation and partial correlation analysis were performed to detect the association between inflammatory profiles and clinical scales in cerebellar ataxia.

Inflammatory profiles from peripheral blood showed significant difference between different groups. Significant variations were observed in MPV, NLR, MLR, SII, AISI and ESR between cerebellar ataxia and HCs groups (p<0.05). NLR and ESR in both SCA and MSA-C groups were increased compared with HCs (p<0.05). The difference of MHR between SCA and MSA-C groups was observed based on HDL variation (p<0.05). The combination of ESR and PLT distinguished SCA from MSA-C (AUC=0.800). In addition, MLR was significantly corelated with clinical scales, including SARA and ICARS in SCA group as well as UMSARS and FAB in MSA-C group (r>0.3/r<-0.3).

Significant variation in peripheral inflammatory profiles was firstly identified in Chinese genetic ataxias and non-genetic cerebellar ataxia cohort, which showed the potential clinical correlations between peripheral inflammatory phenotype and severity of ataxia.

Schizophrenia (SCZ) is a debilitating mental disorder of unknown etiology. It is characterized by both positive and negative symptoms. Increasing evidence reports the role of immune abnormalities in the pathogenesis of SCZ.

This study aimed to examine the potential effect of age on the associations between clinical symptoms and immune parameters in drug-naïve first episode SCZ (DNFES).

A total of 64 young DNFES patients were recruited and divided into younger and older groups according to the median age. Immune parameters, including neutrophil (NEU), lymphocyte (LYM), and neutrophil-to-lymphocyte ratio (NLR) values, were measured and compared between the younger and older patients to investigate the potential effect of age on the correlations between immune parameters and clinical symptoms.

We found that NEU and NLR were significantly higher in patients compared to healthy controls, with even higher values observed in the younger group than in the older group. In addition, NEU count was correlated with clinical symptoms in older patients, while NLR was correlated with symptoms in younger patients. Linear regression analysis showed that NEU or NLR values were associated with the clinical symptoms in patients with SCZ after controlling confounders.

Our study suggests that young adult patients had abnormal immune parameters. Furthermore, age mediated the relationships between immune parameters and symptom severity. This study provides further evidence that abnormal immune parameters, particularly an increased innate immune response, may be involved in the pathophysiology of SCZ.

The risk of developing progressive multifocal leukoencephalopathy (PML), a rare but potentially fatal opportunistic infection of the central nervous system caused by the J.C. virus (JCV), remains a primary concern associated with natalizumab therapy in the clinical management of patients diagnosed with multiple sclerosis (MS).

This study compared two tests, STRATIFY JCV™ DxSelect™, and IMMUNOWELL™ JCV antibody tests, for assessing the risk of PML in patients diagnosed with relapsing-remitting multiple sclerosis (RRMS) who had received disease-modifying therapy (DMT) with branded natalizumab (Tysabri^®). The main objective was to determine the comparability of these tests in classifying PML risk. Eligible patients were selected from a database, and all specimens for the STRATIFY JCV™ DxSelect™ and IMMUNOWELL™ JCV antibody tests were collected on the same day. Patients were classified into three risk categories (low, intermediate, or high) based on threshold values for each test.

The analysis showed 85.5% agreement between the two tests for risk classification. Ten discordant cases were identified, mainly between intermediate- and high-risk categories. Compared to STRATIFY JCV™ DxSelect™, IMMUNOWELL™ JCV antibody test tended to categorize more patients as higher risk. No significant association was found between discordance and prior use of immunosuppressant drugs and >24 doses of natalizumab. The agreement between tests, assessed with the weighted Cohen’s Kappa coefficient, was substantial (κ=0.6222).

Compared to the STRATIFY JCV™ DxSelect™, the IMMUNOWELL™ JCV test tends to place more patients in higher risk categories. Further, longitudinal studies are needed to evaluate the clinical impact of these differences in PML risk assessment.

Esketamine is administered intranasally in combination with at least another antidepressant in patients with treatment-resistant depression. Some of these antidepressants might affect ketamine’s pharmacokinetic profile by inhibiting cytochrome-P450 (CYP450) isoforms. Our aim was to establish how different types of combined antidepressants affect serum and salivary levels of esketamine at the time of maximum plasma concentrations and afterward in TRD patients receiving esketamine in a real-world context.

Serum and salivary samples were collected from 53 patients receiving intranasal esketamine (56 mg) at baseline, after 20 min (roughly corresponding to Tmax), 7 hours (corresponding to the t½ value), 24, and 72 hours. Patients were stratified according to the combined antidepressant medication.

Salivary esketamine levels were several-fold higher than the corresponding serum levels at all time points, and showed high inter-individual variability. Serum 20-min post-esketamine levels and AUC0-72 levels were significantly higher in patients on antidepressants known to inhibit different isoforms of CYP450 (paroxetine, fluoxetine, duloxetine, venlafaxine), with respect to levels detected in patients on sertraline, citalopram, escitalopram, vortioxetine. These changes in the pharmacokinetic profile of esketamine did not affect the clinical outcome of esketamine. However, changes in systolic blood pressure in response to esketamine positively correlated with serum esketamine levels, suggesting a reduction of esketamine dose in patients with cardiovascular comorbidity under treatment with paroxetine, fluoxetine, duloxetine, venlafaxine.

The CYP450-related status of co-administered antidepressants may affect esketamine levels. However, the small sample sizes of the co-administered drug subgroups and multiple prescriptions do not allow for drawing strong conclusions.