Neurotherapeutics最新文献

Ocrelizumab (OCR) and Natalizumab (NTZ) are highly effective treatments widely used in Multiple Sclerosis (MS). However, long-term, real-world comparative data on clinical effectiveness, safety and treatment persistence are limited. This retrospective analysis included relapsing and progressive MS patients initiating treatment at two Italian Universities ("La Sapienza" and "Federico II"). Propensity-score nearest-neighbor matching with a caliper of 0.1 was conducted to adjust for between-group differences in age, sex, previous treatment status, MS phenotype, disease duration, clinical and MRI activity at baseline. Differences in follow-up duration were adjusted with pairwise censoring. Cox proportional hazard regression models were used with Evidence of disease activity (EDA-3) and its components (relapses, MRI activity, and confirmed disability progression) as outcomes. Treatment discontinuation rate and occurrence of adverse events (AEs) were tested using logistic regression. We identified 308 patients (140 on OCR, 168 on NTZ) with a mean (SD) follow-up of 75.7 (30.8) months. Patients treated with OCR were older and less active and less frequenlty naïve at baseline than NTZ-treated patients. The PS-matching procedure retained 140 patients (70 pairs) with a mean follow-up of 55.9 (14.3) months. No significant differences were found between NTZ and OCR in terms of relapses, MRI activity or confirmed disability progression. OCR treatment was associated with a higher incidence of mild to moderate AEs, and higher to comparable treatment persistence. This study provides real-world evidence of comparable effectiveness between OCR and NTZ over a 5-year observation period, with OCR being associated with a higher incidence of AEs and, possibly, higher treatment persistence.

DL-3-n-butylphthalide (NBP) exhibits promising pharmacological efficacy against ischemia-reperfusion injury, but its protective effects may involve many mechanisms that are yet to be fully understood. This study aimed to profile the metabolic alterations induced by NBP during the process of ischemia-reperfusion using spatial metabolomics. Our study found that NBP could significantly reduce the ischemic area and restore physical function by potentially modulating pathways of the citrate cycle, pyruvate metabolism, autophagy, and unsaturated fatty acid biosynthesis. During the process of ischemia-reperfusion, NBP played a therapeutic role in improving energy supply, decreasing autophagy, and improving unsaturated fatty acid biosynthesis. Subsequent studies confirmed improvements in relevant indices of mitochondrial morphology, autophagy, and ferroptosis after treatment with NBP. These findings shed light on novel mechanisms underlying the efficacy of NBP in treating cerebral ischemia/reperfusion injury associated with ischemic stroke.

Autosomal dominant Alzheimer's disease (ADAD) is driven by rare variants in APP, PSEN1, and PSEN2. Although more than 200 pathogenic variants in these genes are known to cause ADAD, other variants are benign, may act as risk factors, or may even reduce Alzheimer's disease risk (e.g. protective). Classifying novel variants in APP, PSEN1, or PSEN2 as pathogenic, risk, benign, or protective is a critical step in evaluating disease risk profiles which further impacts eligibility for clinical trials focused on the ADAD population. Here, we classify 53 novel variants in APP, PSEN1, and PSEN2 based on bioinformatic data and cell-based assays. We identified 6 benign variants, 2 risk variants, and 32 likely pathogenic variants. Thirteen variants were associated with reduced Aβ levels in cell-based assays, consistent with a potential protective effect. Together, this study highlights the complexities associated with classification of rare variants in ADAD genes.

Alzheimer's disease (AD) is characterized by progressive neurodegeneration, marked by the accumulation of amyloid-β (Aβ) plaques and tau tangles. Emerging evidence suggests that mitochondrial dysfunction plays a pivotal role in AD pathogenesis, driven by impairments in mitochondrial quality control (MQC) mechanisms. MQC is crucial for maintaining mitochondrial integrity through processes such as proteostasis, mitochondrial dynamics, mitophagy, and precise communication with other subcellular organelles. In AD, disruptions in these processes lead to bioenergetic failure, gene dysregulation, the accumulation of damaged mitochondria, neuroinflammation, and lipid homeostasis impairment, further exacerbating neurodegeneration. This review elucidates the molecular pathways involved in MQC and their pathological relevance in AD, highlighting recent discoveries related to mitochondrial mechanisms underlying neurodegeneration. Furthermore, we explore potential therapeutic strategies targeting mitochondrial dysfunction, including gene therapy and pharmacological interventions, offering new avenues for slowing AD progression. The complex interplay between mitochondrial health and neurodegeneration underscores the need for innovative approaches to restore mitochondrial function and mitigate the onset and progression of AD.

Paclitaxel (PCX) based treatments, commonly used to treat breast, ovarian and lung cancers, have the highest incidence of chemotherapy-induced neuropathic pain, affecting from 38 to 94 ​% of patients. Unfortunately, analgesic treatments are not always effective for PCX-induced neuropathic pain (PINP). This study aimed to evaluate the antinociceptive effect of clavulanic acid (CLAV), a clinically used β-lactam molecule, in both therapeutic and preventive contexts in mice with PINP. A single dose of CLAV administered after the onset of PINP significantly reduced mechanical hyperalgesia. Interestingly, preventive administration of CLAV prevented PINP development. The effect of preventive CLAV on PINP was associated with increased levels of IL-10 and IFN-β in serum, and decreased levels of IL-1β and TNF-α in both the serum and CNS. Immunostaining experiments revelated that CLAV increased the levels of glutamate transporter type 1 (GLT-1) and toll-like receptor type 4 (TLR4) in the spinal cord, while reducing levels of the astrocytic marker the glial fibrillary acidic protein (GFAP). Notably, co-incubation with CLAV and PCX in triple-negative breast cancer cells did not interfere with PCX-induced cytotoxic effects. Hence, these findings suggest that CLAV could be employed as a clinical treatment aimed at preventing PINP without compromission the cytotoxic efficacy of PCX.

Replacing cells lost during the progression of neurodegenerative disorders holds potential as a therapeutic strategy. Unfortunately, the majority of cells die post-transplantation, which creates logistical and biological challenges for cell therapy approaches. The cause of cell death is likely to be multifactorial in nature but has previously been correlated with hypoxia in the graft core. Here we use mathematical modelling to highlight that grafted cells experiencing hypoxia will also face a rapid decline in glucose availability. Interestingly, three neuron progenitor types derived from stem cell sources, and primary human fetal ventral mesencephalic (VM) cells all remained highly viable in severe hypoxia (0.1 ​% oxygen), countering the idea of rapid hypoxia-induced death in grafts. However, we demonstrate that glucose deprivation, not a paucity of oxygen, was a driver of rapid cell death, which was compounded in ischemic conditions of both oxygen and glucose deprivation. Supplementation of glucose to rat embryonic VM cells transplanted to the adult rat brain failed to improve survival at the dose administered and highlighted the problems of using osmotic minipumps in assisting neural grafting. The data shows that maintaining sufficient glucose in grafts is likely to be of critical importance for cell survival, but better means of achieving sustained glucose delivery is required.

Spinal cord injury (SCI) significantly alters gene expression, potentially impeding functional recovery. This study investigated the effects of atorvastatin, a widely prescribed cholesterol-lowering drug, on gene expression and functional recovery in a chronic murine SCI model. Female C57BL/6J mice underwent moderate 0.25 ​mm lateral compression SCI and received daily atorvastatin (10 ​mg/kg) or vehicle-only injections from two weeks post-injury for four weeks. Sensorimotor functions were assessed using the Basso Mouse Scale (BMS), its subscore, and the inclined plane test. RNA sequencing of spinal cord tissues identified robust transcriptomic changes from SCI and a smaller subset from atorvastatin treatment. Atorvastatin enhanced sensorimotor recovery within two weeks of treatment initiation, with effects persisting to the experimental endpoint. Pathway analysis showed atorvastatin enriched neural regeneration processes including Fatty Acid Transport, Axon Guidance, and the Endocannabinoid Developing Neuron Pathway; improved mitochondrial function via increased TCA Cycle II and reduced Mitochondrial Dysfunction; and decreased Inhibition of Matrix Metalloproteases. Key gene drivers included Fabp7, Unc5c, Rest, and Klf4. Together, these results indicate atorvastatin's potential in chronic SCI recovery, especially where already indicated for cardiovascular protection.

Amyloidogenic protein aggregation is a pathological hallmark of Alzheimer's Disease (AD). As such, this critical feature of the disease has been instrumental in guiding research on the mechanistic basis of disease, diagnostic biomarkers and preventative and therapeutic treatments. Here we review identified molecular triggers and modulators of aggregation for two of the proteins associated with AD: amyloid beta and tau. We aim to provide an overview of how specific molecular factors can impact aggregation kinetics and aggregate structure to promote disease. Looking toward the future, we highlight some research areas of focus that would accelerate efforts to effectively target protein aggregation in AD.