Current Neuropharmacology - Current Issue

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.

Facial nerve injury induces autophagy and apoptosis in facial nerve nucleus motoneurons of the CNS, impairing nerve regeneration and functional recovery. The function of P2Y2R after facial nerve injury remains to be determined. This study hypothesizes that inhibiting P2Y2R may play a protective role in facial nerve injury by modulating the autophagy signaling pathway.

An in vivo mouse model of facial nerve crush injury was utilized in this study. Mice received either a P2Y2R agonist or antagonist through intrathecal injections of 10 μL/daily for 4 weeks. This study measured facial nerve function, examined fibrogenesis, and analyzed expression of autophagy regulatory proteins. In an in vitro experiment, NSC34 cells were treated with a P2Y2R agonist or an antagonist, and changes in the levels of phosphorylated PI3K, Akt, and mTOR, as well as autophagy regulatory proteins determined.

Inhibition of P2Y2R significantly increased autophagy levels and enhanced facial nerve function. These protective outcomes were linked to the suppression of phosphorylated PI3K, Akt, and mTOR signaling pathways.

The study suggests that P2Y2R inhibition may improve facial nerve function by improving autophagy, making it a promising therapeutic approach for treating facial nerve injury.

The growing prevalence of neuropsychiatric disorders is becoming a major health challenge. Traditional pharmacotherapies face limitations, making drug repurposing a valuable strategy. However, high-throughput screening approaches for these conditions are scarce.

This study leveraged exposure data from the UK Biobank Neale Lab (N = 361,141) and outcome data from the FinnGen database (N = approximately 410,000) to employ Mendelian Randomization (MR) analyses and identify potential drug repurposing candidates for neuropsychiatric disorders. Sensitivity, Linkage Disequilibrium Score Correlation (LDSC), and Bayesian Colocalization (COLOC) analyses were conducted to ensure the robustness and reliability of our findings.

Using the IVW method, seven medications with negative causal associations with neuropsychiatric disorders were identified. Pregabalin, bumetanide, and prednisolone were associated with reduced anxiety (beta = -7.28, p = 4.00e-03; beta = -2.24, p = 6.00e-03; beta = -1.74, p = 2.84e-03). Vitamin B1 preparations showed an inverse association with dementia (beta = -2.47, p = 1.51e-03), Creon E/C granules with epilepsy (beta = -4.99, p = 3.91e-03), Pentasa SR 250 mg with multiple sclerosis (beta = -3.95, p = 3.83e-03), and zolmitriptan with stroke excluding subarachnoid hemorrhage (beta = -1.61, p = 6.00e-03). Sensitivity analyses confirmed these findings, whereas the LDSC and COLOC analyses provided additional support.

MR-based drug repurposing is a promising approach for the treatment of neuropsychiatric disorders. Further validation is necessary to effectively integrate these medications into clinical practice.

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.

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.