Current Neuropharmacology - Online First

This study investigates the relationship between National Cancer Institute Common Terminology Criteria (NCI-CTC) for grading bortezomib-induced peripheral neuropathy (BIPN) and objective motor/sensory nerve dysfunctions assessed by nerve conduction studies (NCS). It also evaluates the correlation between specific nerve conduction abnormalities and progression-free survival (PFS).

Thirty-three patients with multiple myeloma developing peripheral neuropathy during bortezomib treatment were enrolled. Participants were grouped based on NCI-CTC toxicity scores (< 2, n=17; ≥ 2, n=16). Comprehensive NCS were performed, assessing compound muscle action potentials (CMAP), motor conduction velocities (MCV), sensory nerve action potentials (SNAP), and sensory conduction velocities (SCV) across ulnar, median, tibial, peroneal, sural, and superficial peroneal nerves. Correlation analyses were used to examine the association between NCS parameters and PFS.

Patients with higher NCI-CTC grades (≥ 2) exhibited significant reductions in motor and sensory nerve conduction parameters. Notably, the peroneal nerve showed significant decreases in CMAP (p=0.0059) and MCV (p=0.0223). The superficial peroneal nerve displayed a significant reduction in SCV (p=0.0189). A strong positive correlation was found between median nerve SNAP and longer PFS (r=0.558, p=0.001).

The findings indicate that higher clinical grades of BIPN (NCI-CTC ≥ 2) are associated with objective neurophysiological evidence of worsened nerve function, with the peroneal nerve being particularly affected. The correlation between median nerve SNAP and PFS suggests that NCS parameters could potentially serve as prognostic markers in patients with BIPN.

Bortezomib-induced neurotoxicity leads to significant impairments in both motor and sensory nerve conduction. Median nerve SNAP shows promise as a predictor for PFS, underscoring the potential value of NCS in monitoring neurotoxicity and guiding clinical management in patients receiving bortezomib.

Multiple Sclerosis (MS) is characterized by the infiltration of leukocytes into the nervous tissue, and disruption of the Blood-Brain Barrier (BBB) is one of the main factors in the progression of MS and its model, Experimental Autoimmune Encephalomyelitis (EAE). Furthermore, some anti-lymphocytic drugs against MS may inherently produce BBB disruption as their side effect. This study hypothesized that drugs restoring the BBB may be useful for the treatment of MS and EAE, as well as for ameliorating the side effects of modern anti-lymphocytic drugs.

EAE was induced in SJL/J mice. EAE progression was evaluated by a severity score and a plasma cytokine profile, while a BBB condition was evaluated by the Evans dye method, Tight Junction Proteins (TJPs) content, and leukocyte infiltration.

The mice with EAE demonstrated neurological symptoms, a cytokine response, and BBB deterioration, which was associated with upregulation of the NADPH oxidases NOX1 and NOX4 in the brain. Administration of the anti-lymphocyte drug fingolimod to EAE mice caused lymphopenia, improved animal health, enhanced the BBB function during the administration period, and decreased the pro-inflammatory response, but it was accompanied by a “withdrawal effect,” defined as a sharp increase in the IL-17 and IFN-gamma to levels higher than those in untreated animals, lymphocyte hyperactivation, worsening symptoms, and increasing BBB permeability after discontinuation of fingolimod. Administration of peroxiredoxin 6 (Prdx6) to EAE mice also improved BBB, decreased lymphocyte infiltration and NADPH oxidase expression, and ameliorated symptoms. Preliminary administration of Prdx6 before the fingolimod treatment eliminated the “withdrawal effect” of fingolimod and led to full recovery of the EAE mice. This Prdx6 effect was associated with the activation of anti-proliferative and pro-apoptotic signaling cascades in lymphocytes.

Conclusion: Both fingolimod and Prdx6 produced beneficial effects, while Prdx6 may be useful for ameliorating the side effects of anti-lymphocytic drugs. Accounting for literature data that discontinuation of MS treatment is very likely to lead to a severe MS rebound, a drug that prevents the rebound should be useful.

Maternal chronic immune and inflammatory conditions may predispose newborns to atypical developmental trajectories, identifying pregnancy as a key period for the etiopathogenesis of neurodevelopmental disorders. The possible long-term impact of maternal multiple sclerosis (MS) on the offspring’s cognitive and behavioral development and its pharmacological treatment during pregnancy is mostly unknown. This study aims to delineate the cognitive and behavioral profile of offsprings exposed to maternal MS, untreated or treated with Natalizumab throughout pregnancy, in comparison to a control group.

We retrospectively enrolled 39 children (23 males; 16 females; mean age 45.82 ± 35.46 months) exposed to maternal MS, untreated or treated with Natalizumab throughout pregnancy, and 36 children (24 males; 12 females, mean age 38.03 ± 21.52 months) of healthy mothers. All offspring underwent a standardized evaluation of their intellectual or developmental quotient, adaptive functioning, and behavioral issues, including symptoms of autism.

The clinical profile of the included offspring was characterized by an adequate cognitive profile and a good level of adaptive skills (MS offspring: Griffiths III mean total DQ (N = 30) 114.57; WISC-IV mean Full IQs (N= 9) 115.44; mean ABAS GAC 97.28/Control offspring: Griffiths III mean total DQ (N = 31) 105.42; WISC-IV mean Full IQs (N= 4) 119.25 ± 11.32; mean ABAS GAC 97.82 ± 21.4). Furthermore, no significant behavioural problems or autism symptoms emerged in the entire group, regardless of MS treatment.

Offspring's developmental and behavioral phenotypes do not appear to be influenced by maternal treatment with Natalizumab until late pregnancy, nor by maternal variables directly related to MS (age at the time of MS diagnosis, disease duration, and severity).

Advances in mass spectrometry-based proteomic analysis have generated extensive protein data from cells involved in neurodegenerative diseases. The field of neuroproteomics is expanding to include the study of extracellular vesicles (EVs) to identify potential biomarkers for disease prevention and endogenous factors involved in neuroprotection.

In this study, rat cortical astrocytes in normoxia were cultured under normoxic conditions and subsequently exposed to hypoxia. Astrocyte-derived EVs released into the supernatant were collected separately from both conditions. Label-free mass spectrometry-based proteomics was then performed to assess the effects of hypoxia on the EV protein cargo. A meta-analysis comparing the results with previously published EV proteomic datasets was also conducted.

This study revealed a differential expression of 83 upregulated proteins under hypoxic conditions and 61 downregulated proteins under normoxic conditions, highlighting the protective protein signatures elicited by astrocytes. The dataset has been deposited in the ProteomeXchange Consortium with the identified PXD050160.

The present study makes a novel contribution by employing proteomic techniques to characterize the protein cargo of EVs isolated from primary rat astrocytes. This approach enables a more refined analysis of astrocyte-specific intercellular signaling under hypoxic conditions and provides valuable insights into the roles of astrocytes in maintaining brain homeostasis and contributing to pathological processes.

This systematic review intends to find out how neurodevelopmental disorders, including Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD), are influenced by the gut microbiota throughout early childhood. The study looks at the variety and types of microbes that a child is exposed to, the particular microbiome profiles associated with neurodevelopmental outcomes, and the molecular processes that underlie these relationships.

We performed a thorough search of PubMed, Scopus, the WHO Global Health Library (GHL), and ISI Web of Science. After screening 2,744 original studies based on predetermined eligibility criteria, 19 studies were included. Microbial groupings, presence (high/low), and related neurodevelopmental disorders were among the primary areas of data extraction. The methodological quality of the studies was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS).

The investigated literature repeatedly showed a strong correlation between dysbiosis of the gut microbiota and neurodevelopmental disorders. Cases of ASD were associated with both a high number of Clostridium species and a low number of Bifidobacterium species. On the other hand, a Low number of E. coli and a high number of the class Clostridia, phylum Firmicute, genus Bifidobacterium, and Akkermansia, as well as the species Listeria monocytogenes, Toxoplasma gondii, Streptococcus mutans, and Mycobacterium tuberculosis have been linked to ADHD. The NOS evaluation showed variation in the quality of the methodology; some studies had high scores, suggesting sound technique, while other studies had lower scores, indicating serious methodological flaws.

The results highlight the potential impact of the gut microbiome throughout early life on neurodevelopmental outcomes, indicating that microbial imbalances may play a role in the onset of disorders like ASD and ADHD. However, to improve the quality of data, larger-scale longitudinal studies would be required.